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Introduction: Tumor microenvironments (TMEs) encompass complex ecosystems of cancer cells, infiltrating immune cells, and diverse cell types. Intercellular and intracellular signals within the TME significantly influence cancer progression and therapeutic outcomes. Although computational tools are available to study TME interactions, explicitly modeling tumor progression across different cancer types remains a challenge. Methods: This study introduces a comprehensive framework utilizing single-cell RNA sequencing (scRNA-seq) data within a multilayer network model, designed to investigate molecular changes across glioma progression stages. The heterogeneous, multilayered network model replicates the hierarchical structure of biological systems, from genetic building blocks to cellular functions and phenotypic manifestations. Results: Applying this framework to glioma scRNA-seq data allowed complex network analysis of different cancer stages, revealing significant ligand‒receptor interactions and key ligand‒receptor-transcription factor (TF) axes, along with their associated biological pathways. Differential network analysis between grade III and grade IV glioma highlighted the most critical nodes and edges involved in interaction rewiring. Pathway enrichment analysis identified four essential genes— PDGFA (ligand), PDGFRA (receptor), CREB1 (TF), and PLAT (target gene)—involved in the Receptor Tyrosine Kinases (RTK) signaling pathway, which plays a pivotal role in glioma progression from grade III to grade IV. Discussion: These genes emerged as significant features for machine learning in predicting glioma progression stages, achieving 87% accuracy and 93% AUC in a 3-year survival prediction through Kaplan-Meier analysis. This framework provides deeper insights into the cellular machinery of glioma, revealing key molecular relationships that may inform prognosis and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC), characterized by a high incidence rate, poses significant clinical challenges owing to its poor prognosis despite advancements in diagnostic and therapeutic approaches. Therefore, a comprehensive understanding of the molecular mechanisms driving GC progression is crucial for identifying predictive markers and defining treatment targets. Deubiquitinating enzymes (DUBs), also called deubiquitinases, function as reverse transcriptases within the ubiquitin-proteasome system to counteract protein degradation. Recent findings suggest that DUB dysregulation could be a crucial factor in GC pathogenesis. In this review, we examined recent research findings on DUBs in the context of GC, elucidating their molecular characteristics, categorizations, and roles while also exploring the potential mechanisms underlying their dysregulation in GC. Furthermore, we assessed the therapeutic efficacy of DUB inhibitors in treating malignancies and evaluated the prevalence of aberrant DUB expression in GC. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is one of the deadliest malignant tumors. Despite significant advances in RCC treatment over the past decade, complete remission is rarely achieved. Consequently, there is an urgent need to explore and develop new therapies to improve the survival rates and quality of life for patients. In recent years, the development of tumor organoid technology has attracted widespread attention as it can more accurately simulate the spatial structure and physiological characteristics of tumors within the human body. In this review, we summarize the main methods currently used to construct kidney cancer organoids, as well as their various biological and clinical applications. Furthermore, combining organoids with other technologies, such as co-culture techniques and microfluidic technologies, can further develop organoids and address their limitations, creating more practical models. This approach summarizes the interactions between different tissues or organs during tumor progression. Finally, we also provide an outlook on the construction and application of kidney cancer organoids. These rapidly evolving kidney cancer organoids may soon become a focal point in the development of in vitro clinical models and therapeutic research for kidney cancer. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion This study aimed to assess the value of a HPV E6/E7 mRNA assay (Aptima® HPV [AHPV]) for primary cervical cancer screening combined with menopausal status.A total of 16 917 women underwent AHPV testing and had complete histopathological results at the Affiliated Hospital of Jining Medical University China between January 1, 2017 and March 31, 2022. We evaluated the performance of different screening strategies and combined strategies, as well as evaluations of different menopausal states.When identifying LSIL+ (includes low‐ and high‐grade squamous intraepithelial lesions and invasive cervical cancer [ICC]), the sensitivity (91.2%) and negative predictive value (NPV; 96.6%) were significantly higher for AHPV than for liquid‐based cytology assay (LBC; 33.2% and 84.7% for sensitivity and NPV, respectively). Furthermore, the co‐testing strategy (cytology combined with AHPV), when compared with AHPV, achieved a slightly higher sensitivity (93.6% vs. 91.2%, respectively, P < 0.001), a similar specificity (61.3% vs. 62.7%, respectively, P = 0.014), a similar positive predictive value (PPV; 37.5% vs. 37.8%, respectively, P = 0.709) and a similar NPV (97.5% vs. 96.6%, respectively, P = 0.001). Moreover, AHPV (when compared with menopausal women) achieved a higher sensitivity (93.5% vs. 77.7%, respectively, P < 0.001), a higher NPV (97.3% vs. 93.9%, respectively, P < 0.001), a similar PPV (37.8% vs. 37.0%, respectively, P = 0.618) and a slightly lower specificity (60.7% vs. 72.1%, respectively, P < 0.001) in premenopausal women. These results were similar when identifying HSIL+ (includes high‐grade squamous intraepithelial lesion and ICC).The present study suggests that initial screening with HPV E6/E7 mRNA testing rather than combined screening is a suitable candidate for cervical cancer screening in China (especially for premenopausal women) based on economic reasons. [ABSTRACT FROM AUTHOR]

Studying specific subpopulations of cancer-derived extracellular vesicles (EVs) could help reveal their role in cancer progression. In cancer, an increase in reactive oxygen species (ROS) happens which results in lipid peroxidation with a major product of 4-hydroxynonenal (HNE). Adduction by HNE causes alteration to the structure of proteins, leading to loss of function. Blebbing of EVs carrying these HNE-adducted proteins as a cargo or carrying HNE-adducted on EV membrane are methods for clearing these molecules by the cells. We have referred to these EVs as Redox EVs. Here, we utilize a surface tension-mediated extraction process, termed exclusion-based sample preparation (ESP), for the rapid and efficient isolation of intact Redox EVs, from a mixed population of EVs derived from human glioblastoma cell line LN18. After optimizing different parameters, two populations of EVs were analyzed, those isolated from the sample (Redox EVs) and those remaining in the original sample (Remaining EVs). Electron microscopic imaging was used to confirm the presence of HNE adducts on the outer leaflet of Redox EVs. Moreover, the population of HNE-adducted Redox EVs shows significantly different characteristics to those of Remaining EVs including smaller size EVs and a more negative zeta potential EVs. We further treated glioblastoma cells (LN18), radiation-resistant glioblastoma cells (RR-LN18), and normal human astrocytes (NHA) with both Remaining and Redox EV populations. Our results indicate that Redox EVs promote the growth of glioblastoma cells, likely through the production of H2O2, and cause injury to normal astrocytes. In contrast, Remaining EVs have minimal impact on the viability of both glioblastoma cells and NHA cells. Thus, isolating a subpopulation of EVs employing ESP-based immunoaffinity could pave the way for a deeper mechanistic understanding of how subtypes of EVs, such as those containing HNE-adducted proteins, induce biological changes in the cells that take up these EVs. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) recapitulate the developmental and homeostatic behaviors of tissue resident macrophages (TRMs) to promote tumor growth, invasion and metastasis. TRMs arise in the embryo and colonize developing tissues, initially to guide tissue morphogenesis and then to form complex networks in adult tissues to constantly search for threats to homeostasis. The macrophage growth factor, colony-stimulating factor-1 (CSF-1), which is essential for TRM survival and differentiation, is also responsible for the development of the unique motility machinery of mature macrophages that underpins their ramified morphologies, migratory capacity and ability to degrade matrix. Two CSF-1-activated kinases, hematopoietic cell kinase and the p110δ catalytic isoform of phosphatidylinositol 3-kinase, regulate this machinery and selective inhibitors of these proteins completely block macrophage invasion. Considering tumors co-opt the invasive capacity of TAMs to promote their own invasion, these proteins are attractive targets for drug development to inhibit tumor progression to invasion and metastasis. [ABSTRACT FROM AUTHOR]

Engrailed 2 (EN2) is a homeodomain-containing protein whose aberrant expression is observed in various cancer types, yet its role in breast cancer remains unclear. This study investigates the roles and mechanisms of EN2 in breast cancer progression. Using online dataset analysis, we assessed the correlation between EN2 expression and breast cancer progression and chemotherapeutic sensitivity. Functional assays, including RT-qPCR, Western blot, cell viability, transwell migration and invasion, spheroid formation, and flow cytometry, were conducted to explore EN2's role. Mechanistic insights were obtained through luciferase reporter assays, ChIP, and Caspase 3 activity detection. Our results showed that EN2 is highly expressed in breast cancer patients, negatively correlating with survival rates and positively with disease progression and reduced chemotherapy sensitivity. Functional experiments confirmed EN2's oncogenic role, and it was found to promote the expression of the oncogenic Tenascin-C (TNC) gene. Notably, EN2 directly interacts with the super-enhancer region within the TNC locus. Elevated TNC expression mitigated the effects of EN2 knockdown on breast cancer cell progression. Our study unveils a novel mechanism by which EN2 regulates the TNC locus super-enhancer, thereby activating oncogenic pathways in breast cancer. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) plays a crucial role in cancer development and metastasis. This review summarizes the current research on how the TME promotes metastasis through molecular pathways, focusing on key components, such as cancer-associated fibroblasts, immune cells, endothelial cells, cytokines, and the extracellular matrix. Significant findings have highlighted that alterations in cellular communication within the TME enable tumor cells to evade immune surveillance, survive, and invade other tissues. This review highlights the roles of TGF-β and VEGF signaling in promoting angiogenesis and extracellular matrix remodeling, which facilitate metastasis. Additionally, we explored how metabolic reprogramming of tumor and stromal cells, influenced by nutrient availability in the TME, drives cancer progression. This study also evaluated the therapeutic strategies targeting these interactions to disrupt metastasis. By providing a multidisciplinary perspective, this study suggests that understanding the molecular basis of the TME can lead to more effective cancer therapies and identify potential avenues for future research. Future research on the TME should prioritize unraveling the molecular and cellular interactions within this complex environment, which could lead to novel therapeutic strategies and personalized cancer treatments. Moreover, advancements in technologies such as single-cell analysis, spatial transcriptomics, and epigenetic profiling offer promising avenues for identifying new therapeutic targets and improving the efficacy of immunotherapies, particularly in the context of metastasis. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence suggests that the CXC chemokine receptor 6 (CXCR6) is involved in tumor progression and the regulation of tumor immunity. However, its role in muscle-invasive bladder cancer (MIBC) remains largely unexplored. Methods: Data from 391 MIBC patients in the TCGA, 212 patients from GEO, 131 patients from our center, 195 patients in the IMvigor210 cohort, and single-cell RNA sequencing (scRNA-seq) data from 9 bladder cancer patients (GSE222315) were analyzed. Additionally, data from the GEPIA 2, TISCH2, TIMER2.0, and UALCAN platforms were utilized to investigate the prognostic and immunotherapeutic significance of CXCR6 in MIBC. Results: We observed that CXCR6 expression was significantly reduced in bladder cancer tumors and correlated with tumor stage and grade. Low CXCR6 expression was associated with poor recurrence-free survival (RFS) and overall survival (OS) in the TCGA cohort, a finding validated in both the meta-GEO dataset and our center's cohort. Multivariate analysis confirmed that low CXCR6 expression was an independent predictor of poor OS and RFS. A nomogram incorporating CXCR6 expression and other independent prognostic factors was developed to accurately predict 3- and 5-year OS. Gene set enrichment analysis indicated that immune activation-related pathways were significantly enriched in tumors with high CXCR6 expression. CIBERSORT analysis revealed that CXCR6 expression was positively correlated with CD8+ T cells, CD4+ T cells, activated NK cells, M1 macrophages, and activated dendritic cells in TCGA, findings further validated by TIMER2.0. scRNA-seq data showed that CXCR6 was predominantly expressed in T and NK cells and facilitated T/NK-myeloid interaction via the CXCR6-CXCL16 axis. Importantly, CXCL16+ macrophages and dendritic cells recruited CXCR6+ T and NK cells, which exhibited enhanced cytotoxicity, thereby amplifying anti-tumor immunity. Clinically, in the IMvigor210 immunotherapy cohort, higher CXCR6 expression was associated with improved anti-PD-L1 therapeutic outcomes. Conclusion: Our findings highlight CXCR6 as a critical biomarker for predicting prognosis and immunotherapeutic response in MIBC. [ABSTRACT FROM AUTHOR]

Background: Cisplatin resistance is the leading cause of mortality in muscle-invasive bladder cancer (MIBC) cases. Previous evidence suggests that abnormal epitranscriptome modifications are associated with reduced chemotherapy responses. However, the exact underlying mechanism remains largely unknown. Methods: Insulin-like growth factor-2 mRNA-binding protein 2 (IMP2) was identified by clustered regularly interspaced short palindromic repeats (CRISPR) data screening, single-cell RNA-sequencing and sample analysis. To evaluate the regulatory role of IMP2, functional studies were conducted both in vitro and in vivo. To elucidate the underlying mechanisms, various techniques including immunofluorescence, fluorescent in situ hybridization, RNA pull-down, coimmunoprecipitation, and RNA immunoprecipitation were used. Results: Our study revealed that IMP2 was overexpressed in chemoresistant MIBC and lung metastasis tissues. IMP2 inhibition markedly enhanced the sensitivity of BC cells to cisplatin both in vitro and in vivo. Mechanistically, IMP2 enhanced the mRNA stability of IPO4 and SLC7A11 in a m6A-dependent manner, augmenting the nuclear translocation of C/EBPδ to activate PRKDC-mediated DNA damage repair in response to cisplatin. Moreover, IMP2 upregulated SLC7A11 levels and suppressed cisplatin-induced ferroptosis. Combining ferroptosis and apoptosis inhibitors completely reversed cisplatin resistance caused by IMP2 overexpression. LINC00941, which was induced by HIF-1α-mediated transcriptional activation, specifically bound IMP2 and protects it from degradation. Conclusions: This work demonstrated a novel mechanism involving the IMP2-IPO4/SLC7A11 pathway as a promising treatment target for cisplatin-resistant bladder cancer. [ABSTRACT FROM AUTHOR]

Mitochondria are dynamic organelles integral to metabolic processes, coordination of essential biological pathways, and oncogenesis and tumor progression. Recent studies have revealed that mitochondria can be transferred between cells via multiple mechanisms, implicating their involvement in the pathogenesis and progression of ovarian cancer. This review provides a comprehensive analysis of intercellular mitochondrial transfer within the context of ovarian cancer and its tumor microenvironment. We also propose targeted pathways and therapeutic strategies that could be utilized to modulate diseases associated with mitochondrial transfer therapy. Finally, we examine recent advancements in this field and identify several unresolved questions. [ABSTRACT FROM AUTHOR]

Mitochondrial‐nuclear communication plays a vital role in maintaining cellular homeostasis. MOTS‐c, a short peptide derived from the 12S rRNA of mitochondrial DNA, has been suggested as a retrograde mitochondrial signal. Although recent clinical studies have suggested a possible link between MOTS‐c and human cancer, the role of MOTS‐c in tumorigenesis has yet to be investigated. Here, MOTS‐c levels are found to be reduced in both serum and tumor tissues from ovarian cancer (OC) patients, which are associated with poor patients' prognosis. Exogenous MOTS‐c inhibits the proliferation, migration and invasion of OC cells, and induces cell cycle arrest and apoptosis. Mechanistically, MOTS‐c interacts with LARS1 and promotes its ubiquitination and proteasomal degradation. In addition, USP7 was identified as a deubiquitinase of LARS1, and MOTS‐c can attenuates USP7‐mediated LARS1 deubiquitination by competing with USP7 for binding to LARS1. Besides, LARS1 was found to be increased and play an important oncogenic function in OC. More importantly, MOTS‐c displays a marked anti‐tumor effect on OC growth without systemic toxicity in vivo. In conclusion, this study reveals a crucial role of MOTS‐c in OC and provides a possibility for MOTS‐c as a therapeutic target for the treatment of this manlignacy. [ABSTRACT FROM AUTHOR]

LACTB is identified as a tumor suppressor in several tumors. However, preliminary study reveals that LACTB is overexpressed in osteosarcoma and indicates poor prognosis. Two missense mutations (rs34317102 and rs2729835) exist simultaneously in 92.31% of osteosarcoma patients and cause M5L and R469K double mutations in LACTB, suggesting the biologic function of LACTB protein may be altered in osteosarcoma. Moreover, LACTBM5L+R469K overexpression can promote malignant progression in different tumors, which suggests that the M5L and R469K mutations confer oncogene‐like functions to LACTB. Mechanistically, LACTBM5L+R469K not only reduces the wild type p53 via enhancing PSMB7 catalytic activity, but also protects p53R156P protein from lysosomal degradation, which suggesting LACTBM5L+R469K is a dual‐regulator for wt‐p53 and mutant p53, and derive oncogene‐like functions. More importantly, clavulanate potassium, a bacterial β‐lactamase inhibitor, can inhibit osteosarcoma proliferation and sensitize osteosarcoma to cisplatin by binding and blocking LACTBM5L+R469K. These findings revealed that the M5L and R469K double mutations can diminish the tumor suppressive ability of wild type LACTB and provide oncogene‐like functions to LACTB. Inhibiting LACTBM5L+R469K can suppress the progression of osteosarcoma harbouring wild‐type or mutant p53. Clavulanate potassium is a promising drug by targeting LACTBM5L+R469K‐p53 pathway for the treatment of osteosarcoma patients. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is recognized as the fifth most prevalent malignant tumor worldwide. It is characterized by diverse clinical symptoms, treatment responses, and prognoses. In GC prognosis, the promotion of epithelial–mesenchymal transition (EMT) fosters cancer cell invasion and metastasis, thereby triggering the dissemination of tumor cells. This study proposes a nucleic acid amplification circuit‐based hydrogel (NACH) assay for identifying exosomal miRNA derived from metastatic GC. The NACH assay employs the rolling circle amplification method and targets miRNA‐21, a tumor‐related oncogene, and miRNA‐99a, which promotes EMT. Specific amplification probes for each target are immobilized within the hydrogel, enabling a streamlined, one‐step amplification reaction. The NACH assay exhibits a detection limit of 1 fm for miRNA‐21 and miRNA‐99a, thereby enabling rapid and highly sensitive on‐site detection. Performance evaluation using exosomal miRNA extracted from cell culture media, mouse plasma, and human plasma revealed fluorescence intensity patterns similar to those obtained in qRT‐PCR. Furthermore, deploying a custom‐developed portable fluorometer for the NACH assay allows for diagnostic performance assessment and point‐of‐care testing using clinical samples from GC patients. These findings emphasize the potential of the NACH assay to be used as a robust tool for the genetic diagnosis of GC based on exosome detection. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) fosters cancer progression by supporting the differentiation and proliferation of myeloid‐derived suppressor cells (MDSCs), which play a critical role in suppressing immune responses and facilitating tumor growth. Recent findings by Dahal et al. reveal that platelet‐activating factor (PAF), a lipid mediator elevated in the TME, contributes to the differentiation of neutrophils into immunosuppressive neutrophils. They showed that inhibiting PAF signaling reduces MDSC‐mediated immunosuppression, thereby enhancing cytotoxic T‐cell activity. This approach may improve cancer immunotherapy outcomes, particularly when combined with checkpoint blockade therapies, suggesting a promising avenue for therapeutic development. [ABSTRACT FROM AUTHOR]

Background: Our study investigates the multifaceted role of the gene SLC30A6 across 33 distinct cancer types. Understanding the function and impact of SLC30A6 in cancer biology is crucial, as previous studies have hinted at its aberrant expression and potential involvement in tumor progression. This research aims to elucidate the expression patterns, methylation variations, mutational signatures, and survival implications of SLC30A6, along with its engagement with the immune system in various cancers and specially in pancreatic cancer. Methods: We conducted a comprehensive analysis of SLC30A6 using data from 33 different cancer types, and all data were analyzed in silico. The study involved examining expression levels, performing correlation analyses with clinical outcomes, assessing methylation variations, and identifying mutational signatures. Functional enrichment analyses were carried out to understand the gene's involvement in biological pathways. Additionally, we evaluated the relationship between SLC30A6 expression and immune cell infiltration levels to uncover its role in the tumor microenvironment. Results: SLC30A6 was found to be significantly up-regulated in the majority of the 33 cancer types analyzed. High expression levels of SLC30A6 were consistently correlated with poor survival outcomes, indicating its potential role in cancer prognosis. Functional enrichment analyses revealed that SLC30A6 is involved in key pathways related to tumor progression, including cell proliferation and apoptosis. Moreover, SLC30A6 showed significant associations with diverse immune pathways, suggesting its involvement in immune regulation. Notably, our analysis demonstrated a significant correlation between SLC30A6 expression and the infiltration levels of key immune cells, highlighting its dual immunosuppressive and immunostimulatory roles in a pan-cancer context. Moreover, SLC30A6 is significantly overexpression in pancreatic cancer and have shown different clinical associations as above. Conclusion: Our study provides comprehensive insights into the complex interplay between SLC30A6 and cancer development. These findings position SLC30A6 as a promising prognostic biomarker and therapeutic target across diverse cancer types, highlighting its importance in future cancer research and treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Basket clinical trials targeting the KRASG12C-mutation in solid tumors have shown initial promise, including in orphan KRASG12C head and neck cancer (HNC). However, development of resistance to KRASG12C-mutant-specific inhibitors (KRASG12Ci) remains a major obstacle. Here, we investigated the intrinsic (tumor-cell autonomus) and tumor-microenvironment (TME) mechanisms of resistance to the KRASG12Ci—MRTX849 and AMG510 in a unique syngenic murine KRASG12C-mutated HNC cell line. Methods: Western-blotting was used for protein abundance and activation, overexpression, and ligand activation studies to verify the intrinsic mechanism of resistance to KRASG12Ci in KRASG12C-mutated HNC cell line, 4NQO-L. In vitro KRASG12C-acquired-resistant cells were developed from 4NQO-L (4NQO-L-AcR). MRTX849/lapatinib combination efficacy, and CD8+ T-cells depletion, were assessed in C57BL/6 J mice and supplementation of anti-PD-1 (αPD-1) to MRTX849/lapatinib was also performed in 4NQO-L– KRASG12Ci-senisitve and 4NQO-L-AcR tumors. Immunohistochemistry (IHC) and Immunoflourescence (IF) analyses were performed to profile the TME and programmed death-ligand 1 (PD-L1) expression in tumors. Results: Activation and upregulation of EGFR and HER2/3 (pan-HERs) are the intrinsic mechanism of resistance to KRASG12Ci in 4NQO-L cells, and blocking pan-HERs signaling with lapatinib enhanced MRTX849 efficacy in vitro by inhibiting the MAPK and AKT/mTOR pathways. 4NQO-L-AcR upregulated the expression of pan-HERs, and lapatinib treatment re-sensitized 4NQO-L-AcR to MRTX849. In mice, MRTX849 showed a slight anti-tumor effect, but in combination with lapatinib a significant tumor growth delay was observed, but all tumors progressed over time. Histopathology analysis of the TME revealed infiltration of CD8+ T-cells after treatment combination, and these CD8+ T-cells play a key role in MRTX849/lapatinib efficacy. MRTX849/lapatinib treatment upregulated PD-L1 overexpression in both stromal and tumor cells, which presumably suppressed CD8+ T-cells and enabled immune escape and tumor progression. Supplementation of αPD-1 prolonged the progression-free survival of 4NQO-L-bearing mice treated with MRTX849/lapatinib. MRTX849/lapatinib treatment delayed tumor growth of 4NQO-L-AcR in mice; however, the percentages of CD8+ T-cells in 4NQO-L-AcR were low, and supplementation of MRTX849/lapatinib with αPD-1 did not improve the outcome. Conclusions: Our study highlights the critical need for blocking both intrinsic and extrinsic mechanisms of resistance for the prolonged response and shows that such treatment is ineffective in KRASG12Ci-AcR tumors. [ABSTRACT FROM AUTHOR]

Background: Although most pilocytic astrocytomas grow slowly, their progression in critical sites such as the brainstem or hypothalamus may prove fatal much more rapidly. Cystic progression may be more problematic than solid tumor. Patients with progressive cystic PAs located in eloquent deep areas of the brain are the best candidates for stereotactic radiosurgery. Objective: This retrospective case series aims to present the effective outcomes obtained from GKRS, targeting the mural nodules of symptomatic eloquently deep-seated cystic PAs in 9 consecutive patients treated at the IMC Gamma Knife Centre in Cairo, Egypt, between 2003 and 2021. Patient and methods: The median follow-up period was 84 months (range 24–240 months). The median treated mural nodule volume was 1.25 cm3 (range 0.32–1.97 cm3), treated with a median peripheral prescription dose of 12 Gy and a median maximum dose of 24 Gy. The median cyst volume in treated patients was 7.64cm3(range 1.66–40.6cm3). Results: At the last follow-up, 7 out of 9 patients (78%) achieved tumor control (marked reduction > 50% of the entire tumor volume in 6 patients and moderate tumor reduction < 50% in one patient) in addition to clinical improvement. The median time of confirmed tumor reduction was 18 months (range 12–32 months). Two patients reported progression of the treated tumor. The overall tumor control rates at 2, 5, and 7 years of follow-up were 88.9%, 78%, and 78%, respectively. Conclusion: The encouraging results of this series indicate that limiting the GKRS to the mural nodule of eloquently deep-seated cystic PAs may be a practical and effective pattern in the salvage of its treatment. Our data do not support radiation for extensive, large symptomatic cysts in deep-seated cystic PA or patients where microsurgical removal is feasible. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs have emerged as key players in the progression of head and neck squamous cell carcinoma (HNSC). Among them, ZEB1-AS1 was identified as an upregulated candidate in HNSC through comprehensive analysis of RNA-sequencing datasets. Here, elevated ZEB1-AS1 expression was correlated with poor prognosis in HNSC patients. Further investigations demonstrated that downregulation of ZEB1-AS1 induced epithelial-mesenchymal transition and increased sensitivity to cisplatin in Cal27 cells, while its upregulation reversed these effects, underscoring its pivotal role in tumor metastasis and cisplatin resistance in Cal27 cells. Mechanistically, ZEB1-AS1, located in cytoplasm and nucleus, directly regulated the expression of ZEB1, thereby influencing the expression of μ opioid receptor (MOR) and implicating in cancer progression. To advance clinical translation, we employed a nucleus-targeting nanoparticle platform for efficient delivery of a mixture of antisense oligonucleotides and siRNA (Silencer), effectively manipulating ZEB1-AS1 expression in vitro and in vivo. Besides, a predictive model for HNSC patients was developed by analyzing the expression levels of ZEB1-AS1, ZEB1, and MOR in the HNSC datasets. Our study underscored the critical role of ZEB1-AS1 in HNSC and its potential as a therapeutic target. By elucidating its functional mechanisms and utilizing a nucleus-targeting nanoparticle platform for efficient delivery, we proved the potential of ZEB1-AS1-targeted therapies in HNSC. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) play a pivotal role in sculpting the tumor microenvironment and influencing cancer progression, particularly through their interactions with various forms of regulated cell death (RCD), including apoptosis, pyroptosis, ferroptosis, and necroptosis. This review examines the interplay between TAMs and these RCD pathways, exploring the mechanisms through which they interact to promote tumor growth and advancement. We examine the underlying mechanisms of these intricate interactions, emphasizing their importance in cancer progression and treatment. Moreover, we present potential therapeutic strategies for targeting TAMs and manipulating RCD to enhance anti-tumor responses. These strategies encompass reprogramming TAMs, inhibiting their recruitment, and selectively eliminating them to enhance anti-tumor functions, alongside modulating RCD pathways to amplify immune responses. These insights offer a novel perspective on tumor biology and provide a foundation for the development of more efficacious cancer therapies. [ABSTRACT FROM AUTHOR]

Background: Data suggest that buccal mucosa squamous cell carcinoma (SCC) is the most common malignancy in India. In this study, we presented our 5-year clinical experience with oral SCC and examined factors associated with surgical outcomes. Methods: In this retrospective study, 45 patients diagnosed with SCC of buccal mucosa (January 2013–December 2018) underwent wide local excision (WLE) and neck dissection at our institution. Adjuvant radiotherapy (RT)/chemotherapy (CT) was given. Most were aged 60–69 (44.4%, n = 20), mean age of 58 ± 8.2 years, with a female-to-male ratio of 1.14. Tumor thickness, extracapsular spread (ECS), and survival were analyzed with ≥ 5-year follow-up for different stages. Results: The data was analyzed revealing that the T1 stage was most common (55.6%, n = 25), followed by T3 and T4 (15.6%, n = 7 each), then T2 (13.3%, n = 6). Smaller tumors had lower grades. Nodal involvement was seen in 44.4% (n = 20), with N2 stage being the most frequent. Larger tumors had a greater propensity for invasion. Survival probability was 71.1%. The T1 stage showed a higher survival rate than other stages. Nodal involvement reduced survival probability (29.5%). ECS with neural and vascular invasion significantly lowered survival (12%). All associations were highly significant (P < 0.001). Conclusion: Effective locoregional control is crucial for managing buccal mucosa SCC. Supraomohyoid neck dissection is recommended, even for the clinically negative neck with tumor thickness greater than 0.4 cm. Postoperative RT with or without CT, clear margins, and early detection enhance the survival outcomes of the patients. [ABSTRACT FROM AUTHOR]

Objective: This study aims to explore the regulatory mechanisms of Wnt signaling in the invasion and recurrence of ameloblastoma (AM) to provide a new theoretical basis for its treatment. Methods: Bulk RNA sequencing was employed to analyze samples from AM patients, and identify differentially expressed genes. Subsequently, bioinformatics methods such as Weighted Gene Co-Expression Network Analysis (WGCNA), DESeq2, and KEGG enrichment analysis were utilized to construct gene co-expression networks and identify pathways associated with invasion and recurrence. Furthermore, in vitro experiments, including Cell Counting Kit-8 (CCK-8), Wound healing assays, Western blotting, and qPCR were conducted to validate the effects of Wnt signaling on AM biological functions and the expression of related genes and proteins. Results: Bioinformatics analysis revealed significant activation of the Wnt signaling pathway during AM invasion and recurrence, and differential gene analysis identified specific gene expression patterns associated with the Wnt signaling pathway. In vitro experiments further demonstrated that the standard Wnt/β-catenin pathway activator, Laduviglusib significantly activated Wnt signaling, leading to a marked increase in the mRNA and protein expression levels of TCF7, β-catenin, WNT2B, and LEF1, thereby enhancing the proliferation and migration capabilities of AM cells. Conclusion: This study reveals the critical role of aberrant Wnt signaling activation in AM proliferation and migration, identifying it as a key driver of AM invasion and recurrence. The findings provide new insights into the mechanisms underlying AM invasion and recurrence, laying the foundation for developing novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Muscle-invasive urothelial carcinoma (MIUC) is the most common type of bladder malignancy in dogs, but the treatments used in the clinic are relatively ineffective for most of them. Dogs represent a naturally- occurring model for human MIUC and the advances in veterinary oncology could benefit human oncology as well. The field of epigenetics presents unique opportunities for new cancer therapeutics or biomarkers, as epigenetic modification of key genes can regulate tumor initiation and progression. This review summarizes the existing literature on epigenetic changes in canine MIUC as compared to human MIUC and provides suggestions for future studies that could benefit both human and canine patients. [ABSTRACT FROM AUTHOR]

In recent years, the incidence of thyroid cancer has surged globally, posing significant challenges in its diagnosis, treatment, and prognosis. Exosomes, as a class of extracellular vesicles, are secreted by nearly all cell types and encapsulate a variety of nucleic acids and proteins reflective of their cell of origin, thereby facilitating critical intercellular communication. Recent advancements in understanding these exosomes have catalyzed their application in oncology, particularly through uncovering their roles in the pathogenesis, diagnosis, and therapy of cancers. Notably, the latest literature highlights the integral role of exosomes in refining diagnostic techniques, enhancing targeted therapies, optimizing radiotherapy outcomes, and advancing immunotherapeutic approaches in thyroid cancer management. This review provides a current synthesis of the implications of exosomes in thyroid cancer tumorigenesis and progression, as well as their emerging applications in diagnosis and treatment strategies. Furthermore, we discuss the profound clinical potential of exosome-based interventions in managing thyroid cancer, serving as a foundational reference for future therapeutic developments. [ABSTRACT FROM AUTHOR]

Background: In China, Tongguanteng injection (TGT) is widely used in the treatment or adjuvant treatment of various types of cancer. However, the effect and mechanism of TGT in osteosarcoma is not clear. Methods: The 143B and MG-63 cells were treated with different concentrations of TGT. Cell proliferation, migration, invasion and apoptosis were detected using CCK8 assay, transwell assay and flow cytometry. Differentially expressed genes (DEGs) were screened using RNA sequencing (RNA-seq). The identified mRNA and protein expression associated with the IRE1/CHOP pathway was validated by RT-PCR and western blot assay. To explore the underlying mechanisms, 4-phenylbutyric acid (4-PBA) was selected as a specific endoplasmic reticulum (ER) stress inhibitor. Small interfering RNA (siRNA) or pEX‐3-ERN1 plasmid was transfected into 143B cells to silence or overexpress IRE1, respectively. The potential downstream proteins, including CHOP, and apoptosis associated proteins, caspase-3 and PARP1 were determined. Furthermore, the effect of TGT was demonstrated in 143B cell tumor-bearing mice in vivo. H&E staining, TUNEL staining and immunohistochemistry were conducted in tumor tissues obtained from the xenograft mouse model. Results: TGT was shown to dramatically suppress the proliferation, migration and invasion, and induce apoptosis of osteosarcoma 143B and MG-63 cells in vitro. The identified DEGs included HSPA5 (encoding BiP) and ERN1 (encoding the IRE1 protein), as well as apoptosis-associated gene DDIT3 (encoding the CHOP protein). The term "IRE1-mediated unfolded protein response" was screened to be the most enriched biological process GO term. The expression of ER stress-associated proteins including ATF6, BiP, p-IRE1, XBP1s and CHOP, as well as apoptosis-associated cleaved caspase-3 and cleaved PARP1 proteins, was significantly upregulated by TGT treatment in osteosarcoma 143B cells, suggesting that TGT might promote the apoptosis of osteosarcoma 143B cells through the IRE1/CHOP pathway. Furthermore, knocking down IRE1 with si-IRE1 or inhibiting of ER stress with 4-PBA suppressed the expression of ATF6, BiP, XBP1s and CHOP induced by TGT, as well as the expression of cleaved caspase-3 and cleaved PARP1. On the contrary, overexpressing IRE1 promoted CHOP expression and induced osteosarcoma cell apoptosis. Consistent with in vitro results, TGT dramatically inhibited the tumor growth and promoted the expression of p-IRE1 and CHOP in tumor-bearing mice. Conclusion: The findings suggest that TGT exerts an anti-osteosarcoma effect in vitro and in vivo. The underlying mechanism might be associated with the activation of IRE1/CHOP pathway in ER stress. Our findings suggest that targeting IRE1/CHOP pathway might be a potential novel approach for osteosarcoma treatment. [ABSTRACT FROM AUTHOR]

Lipid metabolism reprogramming has emerged as a hallmark of malignant tumors. Lipids represent a complex group of biomolecules that not only compose the essential components of biological membranes and act as an energy source, but also function as messengers to integrate various signaling pathways. In tumor cells, de novo lipogenesis plays a crucial role in acquiring lipids to meet the demands of rapid growth. Increasing evidence has suggested that dysregulated lipid metabolism serves as a driver of cancer progression. Posttranslational modifications (PTMs), which occurs in most eukaryotic proteins throughout their lifetimes, affect the activity, abundance, function, localization, and interactions of target proteins. PTMs of crucial molecules are potential intervention sites and are emerging as promising strategies for the cancer treatment. However, there is limited information available regarding the PTMs that occur in cancer lipid metabolism and the potential treatment strategies associated with these PTMs. Herein, we summarize current knowledge of the roles and regulatory mechanisms of PTMs in lipid metabolism. Understanding the roles of PTMs in lipid metabolism in cancer could provide valuable insights into tumorigenesis and progression. Moreover, targeting PTMs in cancer lipid metabolism might represent a promising novel therapeutic strategy. [ABSTRACT FROM AUTHOR]

Aim: The present work set out to classify cell subpopulations related to liver metastasis from gastric cancer (GC) and the mechanisms of their interactions with other immune cell subpopulations. Background: GC is characterized by a high degree of heterogeneity and liver metastasis. Exploring the mechanism of liver metastasis of GC from the perspective of heterogeneity of the tumor microenvironment (TME) might help improve the efficacy of GC treatment. Objective: Based on the cellular subpopulation characteristics of GC with liver metastasis, the regulatory mechanisms contributing to GC progression were analyzed, with special focuses on the roles of signaling pathways, transcription factors (TFs) and ligand–receptor pairs. Methods: The GSE163558 dataset was downloaded from the Gene Expression Omnibus (GEO) database to collect single-cell transcriptomic data of GC patients and their metastasis groups for cell clustering and relevant analyses. Differentially expressed genes (DEGs) in the GC and GC liver metastasis groups were screened and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. SCENIC analysis was used to mine TFs that affected cellular subpopulations during liver metastasis from GC. The relative expression levels of TFs in GC were determined using qRT-PCR. Transwell and wound healing assays were utilized to verify the regulation of the TFs on the migration and invasion of GC cells. Interaction network between the cellular subpopulations was developed applying CellChat. Results: Single-cell clustering was performed to group six major cell subpopulations, namely, Myeloid cells, B cells, Mast cells, Epithelial cells, Fibroblasts, and TNK cells, among which the number of TNK cells was significantly increased in the GC liver metastasis group. Differentially enriched pathways of TNK cells between GC and GC liver metastasis groups mainly included IL-17 and Pi3k–Akt signaling pathways. TNK cell subsets could be further categorized into CD8 T cells, Exhausted T cells, NK cells, NKT cells, and Treg cells, with the GC liver metastasis group showing significantly more CD8 T cells and NKT cells. FOS and JUNB were the TFs of TNK cell marker genes that contributed to liver metastasis from GC and the invasion and migration of GC cell lines. Significant differences in immune cell communication ligand–receptor pairs existed between the GC and GC liver metastasis groups. Conclusion: This study revealed the critical role of TNK cell subsets in GC with liver metastasis applying single-cell transcriptomics analysis. The findings provided an important theoretical basis for developing novel therapies to inhibit liver metastasis from GC. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor receptor 2 (VEGFR-2) is a crucial mediator of angiogenesis, playing a pivotal role in both normal physiological processes and cancer progression. Tumors harness VEGFR-2 signaling to promote abnormal blood vessel growth, which is a key step in the metastasis process, making it a valuable target for anticancer drug development. While there are VEGFR-2 inhibitors approved for therapeutic use, they face challenges like drug resistance, off-target effects, and adverse side effects, limiting their effectiveness. The quest for new drug candidates with VEGFR-2 inhibitory activity often starts with the selection of key structural motifs present in molecules currently used in clinical practice, expanding the chemical space by generating novel derivatives bearing one or more of these moieties. This review provides an overview of recent advances in the development of novel VEGFR-2 inhibitors, focusing on the synthesis of new drug candidates with promising antiproliferative and VEGFR-2 inhibition activities, organizing them by relevant structural features. [ABSTRACT FROM AUTHOR]

Simple Summary: Hsp90 is a protein that is often found in high levels inside cancer cells, helping them grow and spread. Yet, it is difficult to target with treatments because it's involved in many important normal cell functions. However, a subset of this population found outside the cells specifically cancer cells, called extracellular Heat-shock protein 90 (eHsp90), could be a better target for cancer therapy. eHsp90 plays a key role in helping cancer spread systemically by affecting the environment around the tumor, especially the extracellular matrix (ECM). eHsp90 changes the amount, nature and architecture of the ECM that surrounds the tumor and helps it spread locally within the tissue, which is a crucial step before ultimately metastasizing to other tissues as shown in mice models. Thus, targeting eHsp90 could help stop tumors from spreading by disrupting these processes. Identifying proteins that act in tumor invasiveness and metastasis remains a critical unmet need in our search for effective cancer therapy. Hsp90, an abundant intracellular chaperone protein, plays a key role in maintaining cell homeostasis, and its elevated activity is pivotal in cancer progression. Due to the reliance of cancer cells on Hsp90's chaperone function to sustain tumor growth and spread, Hsp90 inhibitors have been the subject of numerous clinical trials over the past two decades. However, these efforts have largely been unsuccessful, primarily due to the cellular toxicity caused by pan-Hsp90 inhibitors at doses required for anticancer efficacy. Therefore, novel approaches to target Hsp90 are necessary. An identified subpopulation of Hsp90 located outside cells (eHsp90) may offer a promising alternative as a therapeutic target against cancer. Studies including our own have shown that eHsp90 is released specifically by cancer cells, and eHsp90 has unique interactors and functions extracellularly to promote tumor invasiveness, the initial step in metastasis. Inhibition of eHsp90 has been shown to suppress metastasis in animal models, indicating its therapeutic potential, although the underlying mechanisms remain incompletely understood. Cancer cells modulate the tumor microenvironment (TME) during the invasion, especially the ECM proteins and the state of the ECM is a strong predictor of invasive and metastatic cancer. Given that most of the known eHsp90 clients are ECM proteins or are proteins involved in ECM modulation, ECM remodelling could be the key mechanism through which eHsp90 enhances invasiveness. This review will focus on ECM modulation by eHsp90 as a driver of cancer invasion and metastasis. We will also discuss the potency of inhibiting eHsp90 in inhibiting invasion and metastatic spread in preclinical models and the using circulating Hsp90 patient samples as a biomarker of cancer invasion and metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: In large bile ducts, the biliary lining epithelia and underlining capillaries (peribiliary capillary plexus [PCP]) form the biliary epithelia–PCP alignment, whereas the hepatocyte–sinusoid alignment composes hepatic lobules. High-grade biliary intraepithelial neoplasm (BilIN) and intraductal papillary neoplasm (IPNB), and intracholecystic papillary neoplasm (ICPN) have recently been proposed as the precursors of biliary tract carcinoma (BTC). All cases of high-grade BilIN and PGA, about half of IPNB, and one-third of ICPN with less-complicated structure were found to have hijacked the PCP as their supporting vessels (vessel co-option), while BTC were supplied by neo-angiogenetic vessels associated with fibrous stroma. The intraluminal components of the remaining cases of ICPN and IPNB with complicated structure presented sparse capillaries without fibrous stroma. Some BTC replaced hepatocytic cords and used pre-existing sinusoids as co-opted vessels. Visualization of pre-existing vessels could be a new pathological tool for the evaluation of vascular supply in BTC and its precursors. There are several types of microvasculature supplying neoplasms: "newly formed blood vessels" (neoangiogenesis), which are a component of the tumor microenvironment (TME) of invasive carcinoma with wound healing-like reaction; and "pre-existing blood vessels", which are used as tumor-supplying vessels by neoplasms (co-option vessels) and are likely to develop in hypervascularized organs. We herein review the microvasculature of neoplasms of biliary tract with reference to pre-existing vessels and vessel co-options. In the hepatobiliary system, intrahepatic large and extrahepatic bile ducts (large bile ducts) and the gallbladder as well as hepatic lobules are highly vascularized regions. In large bile ducts, the biliary lining epithelia and underlining capillaries (peribiliary capillary plexus [PCP]) form the biliary epithelia–PCP alignment, whereas the hepatocyte–sinusoid alignment composes hepatic lobules. Cholangiocarcinoma (CCA) and gallbladder carcinoma (GBC) are the main biliary tract carcinomas. CCA is subdivided into distal (d/CCA), perihilar (pCCA), and intrahepatic (iCCA), and iCCA is subdivided into small duct type (SD-iCCA) and large duct type (LD-iCCA). High-grade biliary intraepithelial neoplasm (BilIN), intraductal papillary neoplasm of the bile duct (IPNB), pyloric gland adenoma (PGA), and intracholecystic papillary neoplasm (ICPN) have recently been proposed as the precursors of LD-iCCA, p/dCCA, and GBC. In the large bile ducts and gallbladder, all cases of high-grade BilIN and PGA, about half of IPNB, and one-third of ICPN with less-complicated structure were found to have hijacked the PCP as their supporting vessels (vessel co-option), while p/dCCA, LD-iCCA, and GBC were supplied by neo-angiogenetic vessels associated with fibrous stroma. The intraluminal components of the remaining cases of ICPN and IPNB with complicated structure presented sparse capillaries without fibrous stroma, a unique microvasculature different from that of co-option or neoangiogenesis. Regarding iCCA showing invasion into the hepatic lobules, some SD-iCCAs replaced hepatocytic cords and used pre-existing sinusoids as co-opted vessels. Visualization of pre-existing vessels could be a new pathological tool for the evaluation of malignant progression and of vascular supply in CCAs and its precursors. [ABSTRACT FROM AUTHOR]

Simple Summary: The emerging era of digital pathology and Artificial Intelligence provides a better tool for the assessment of multiple morphological features extracted from scanned histological images. In this study, we aimed to develop an AI-based algorithm to measure and quantify features that represent intra-tumor heterogeneity in breast cancer and present them as an index. In our study, 162 features were extracted and quantified from whole slide images. These features showed a significant association with patient outcomes. When an overall heterogeneity score was used, it stratified luminal breast cancer patients into low- and high-risk groups, which can help in personalized therapy. Intra-tumor heterogeneity (ITH) is a fundamental characteristic of breast cancer (BC), influencing tumor progression, prognosis, and therapeutic responses. However, the complexity of ITH in BC makes its accurate characterization challenging. This study leverages deep learning (DL) techniques to comprehensively evaluate ITH in early-stage luminal BC and provide a nuanced understanding of its impact on tumor behavior and patient outcomes. A large cohort (n = 2561) of early-stage luminal BC was evaluated using whole slide images (WSIs) of hematoxylin and eosin-stained slides of excision specimens. Morphological features of both the tumor and stromal components were meticulously annotated by a panel of pathologists in a subset of cases. A DL model was applied to develop an algorithm to assess the degree of heterogeneity of various morphological features per individual case utilizing defined patches. The results of extracted features were used to generate an overall heterogeneity score that was correlated with the clinicopathological features and outcome. Overall, 162 features were quantified and a significant positive correlation between these features was identified. Specifically, there was a significant association between a high degree of intra-tumor heterogeneity and larger tumor size, poorly differentiated tumors, highly proliferative tumors, tumors of no special type (NST), and those with low estrogen receptor (ER) expression. When all features are considered in combination, a high overall heterogeneity score was significantly associated with parameters characteristic of aggressive tumor behavior, and it was an independent predictor of poor patient outcome. In conclusion, DL models can be used to accurately decipher the complexity of ITH and provide extra information for outcome prediction. [ABSTRACT FROM AUTHOR]

Simple Summary: Interactions between breast cancer (BCa) cells and carcinoma-associated fibroblasts (CAFs) in the tumor microenvironment (TME) are critical for cancer development and progression and can mitigate responses to therapies. Historically, it has been difficult to replicate in vivo long-term interactions between BCa cells and CAFs for in vitro studies and to define the precise roles of CAFs in BCa cell progression. Our novel microfluidic-capable culture devices called TAME (tissue architecture and microenvironment engineering) devices enable us to study cell-cell interactions of human breast cancer (BCa) cells and human CAFs through their secretome in 3D cultures for extended periods, up to and beyond 70 days. Using these systems, we observed that CAFs enhance BCa cell progression to an invasive phenotype. Moreover, secretome-mediated reciprocal interactions of BCa cells and CAFs promote their migration toward each other, suggesting that targeting signaling pathways to mediate interactions between BCa cells and CAFs could be a potential therapeutic approach for the prevention of BCa progression. Background/Objectives: Carcinoma-associated fibroblasts (CAFs), a prominent cell type in the tumor microenvironment (TME), significantly contributes to cancer progression through interactions with cancer cells and other TME components. Consequently, targeting signaling pathways driven by CAFs has potential to yield new therapeutic approaches to inhibit cancer progression. However, the mechanisms underlying their long-term interactions with cancer cells in vivo remains poorly understood. Methods: To address this, we developed a three-dimensional (3D) parallel coculture model of human triple-negative breast cancer (TNBC) cells and CAFs using our innovative TAME devices. This model allowed for the analysis of TNBC paracrine interactions via their secretome over extended culture periods (at least 70 days). Results: Using TNBC cell lines (MDA-MB-231, MCF10.DCIS, and HCC70), we found that TNBC spheroids in 3D parallel cocultures with CAFs exhibited more pronounced invasive finger-like outgrowths than those in cocultures of TNBC cells and normal fibroblasts (NFs) over a period of 50–70 days. We also established that the CAF-derived secretome affects TNBC migration towards the CAF secretome region. Additionally, we observed a preferential migration of CAFs, but not NFs, toward TNBC spheroids. Conclusions: Overall, our results suggest that paracrine interactions between TNBC cells and CAFs enhance TNBC invasive phenotypes and promote reciprocal migration. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study we examined whether a specific blood test score, the Scottish Inflammatory Prognostic Score (SIPS), could help predict outcomes in people with advanced lung cancer receiving immunotherapy. Immunotherapy, which uses the body's immune system to fight cancer, is effective for some patients but not all. SIPS is based on two common blood measures: albumin (a protein) and neutrophils (a type of immune cell). Our findings suggest that patients with low SIPS scores, indicating lower inflammation, generally lived longer and had slower cancer progression. SIPS could become a helpful tool for doctors to decide on treatments and guide patients about their prognosis. Using SIPS alongside other health information may improve care by helping select the most suitable therapies for people with advanced lung cancer. Further studies could confirm these findings and support SIPS as a standard measure in clinical care. Background: The Scottish Inflammatory Prognostic Score (SIPS), combining albumin (≥/<35 g/L) and neutrophil count (≤/>7.5 × 109/L), has been identified as a prognostic biomarker for patients with non-small cell lung cancer (NSCLC) undergoing treatment with pembrolizumab monotherapy. We sought to validate this biomarker of systemic inflammation in an external cohort. Methods: Patients treated with first-line pembrolizumab for advanced NSCLC with programmed death-ligand 1 (PD-L1) expression ≥ 50% at an English cancer centre were identified. Pre-treatment clinicopathological characteristics and the SIPS were recorded. The relationship between these and progression-free survival (PFS) and overall survival (OS) was examined. Results: Among 257 patients evaluated, 56% (n = 144) were classified as SIPS 0, 36% (n = 93) as SIPS 1, and 8% (n = 20) as SIPS 2. Factors such as age, performance status (PS) and brain metastases presence were significantly correlated with SIPS categories. Multivariate analysis revealed that both SIPS and PD-L1 status were independently associated with PFS and OS. The combination of SIPS with either PS or PD-L1 expression enhanced the ability to detect patients with the most favourable or poorest survival. Conclusions: Our study confirms the prognostic significance of the SIPS in patients with advanced NSCLC treated with pembrolizumab in the context of high PD-L1 expression. SIPS offers a straightforward, clinically applicable approach to patient stratification, potentially guiding therapeutic decisions and enhancing outcomes in advanced NSCLC. Future research should focus on validating these findings in prospective studies and exploring the integration of SIPS into clinical practice, alongside other prognostic markers, to optimize treatment strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Invasive Lobular Carcinoma (ILC) of the breast is the second most common type of breast cancer. However, it is characterized by diverse morphological and clinical features. Most importantly, some subtypes are more aggressive and their responses to treatment may vary. These features are due to distinct genetic mutations that influence the behavior of these tumors. Given the importance of this cancer subtype, this article aims to provide an overview of the genetic mutations responsible for metastasis, drug resistance and prognosis, while also highlighting gaps in the current literature. The latest advances in treatment are also a main point of discussion and one with the most prospects for new research. Invasive Lobular Carcinoma (ILC) presents a distinct subtype of breast cancer, representing 10–15% of cases, with unique clinical and molecular features. Characterized by a non-cohesive, single-file invasion pattern, ILC is typically estrogen receptor (ER)- and progesterone receptor (PR)-positive but human epidermal growth factor receptor 2 (HER2)-negative. Despite favorable prognostic features, its highly metastatic nature and predilection for atypical sites contribute to lower long-term survival compared to invasive breast carcinoma of no special type (NST). ILC's genetic landscape includes mutations in various genes (CDH1, BRCA2, ATM, etc.) and signaling pathways that impact treatment responses, especially in endocrine treatment. Furthermore, the diverse ILC subtypes complicate its management. Current challenges in chemotherapy, along with the targeted therapies, are also discussed. The present article aims to comprehensively review the recent literature, focusing on the pathological and molecular aspects of ILC, including associated genetic mutations influencing disease progression and drug resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: ASPM is a gene involved in cell division, and recent research shows that it plays an important role in breast cancer (BC). This study looked at large datasets of BC patients to see how ASPM is linked to tumor growth and patient outcomes. We found that patients with higher levels of ASPM had more aggressive forms of cancer and poorer chances of survival. This suggests that ASPM may be useful as a marker to predict how aggressive the BC is and how well it will respond to treatment. These findings could guide future research and potentially lead to new treatments targeting ASPM in cancer. Background: Assembly factor for spindle microtubules (ASPM) has gained significant attention in cancer research due to its association with tumor growth and progression. Through the analysis of large-scale genomic datasets, ASPM has been identified as the top upregulated gene in breast cancer (BC), characterized by high proliferation. This multicohort study aimed to investigate the clinicopathological and prognostic significance of ASPM mRNA and protein expression in BC. Methods: ASPM mRNA expression was assessed using the Cancer Genome Atlas (TCGA) BC cohort and has been further validated in the Molecular Taxonomy of BC International Consortium (METABRIC) (n = 1980), The Uppsala cohort (n = 249), in addition to the combined multicentric cohort (n = 7252). ASPM protein expression was evaluated in a large BC cohort (n = 1300) using immunohistochemistry. The correlations between ASPM expression, clinicopathological parameters, molecular subtypes and outcome were assessed. The response to taxane treatment was compared to the clinical prognosis of ASPM using the ROC plotter. Results: High ASPM mRNA and protein expression were significantly associated with aggressive BC features and poor survival across all cohorts. The association with poor outcomes was maintained in the adjuvant chemotherapy and radio-therapy-treated patients. Responders to taxane treatment showed significantly elevated ASPM levels compared to non-responders. Conclusions: High ASPM expression predicts poor prognosis in BC. It may play a role in treatment resistance within a specific subgroup of patients. Further clinical trials are warranted to explore the potential of ASPM as a target for therapeutic interventions in cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Based on the predicament of the scarcity of clinical drugs for breast cancer and the potential of targeting AGK in the treatment of breast cancer, this study employed a structure-based drug screening strategy that integrates in vitro cell lines and subcutaneous tumor models in nude mice to identify potential marketed drugs targeting AGK, with the aim of providing survival benefits for breast cancer patients. Background: Currently, there is a significant lack of effective pharmacological agents for the treatment of breast cancer. Acylglycerol Kinase (AGK), a lipid kinase, has been found to be aberrantly expressed in breast cancer and is closely associated with tumor proliferation, migration, and invasion. However, no clinical anti-tumor drugs specifically targeting this kinase have been developed. Methods: siRNA was utilized to knock down the AGK gene; CCK8 and colony formation assays were employed to evaluate the in vitro proliferative capacity of tumor cells. Molecular dynamics simulations and BIL assays were conducted to analyze drug binding affinity. Annexin V/PI staining was used to assess apoptotic phenomena; subcutaneous xenograft tumor experiments in nude mice were performed to confirm the in vivo anti-tumor efficacy of the drug. Results: Netupitant exhibited stable binding affinity for AGK and interacted with amino acids within the ATP-binding region of the enzyme. The IC50 values for the SK-BR-3 and MDA-MB-231 cell lines were determined as 16.15 ± 4.25 µmol/L and 24.02 ± 4.19 µmol/L, respectively; at a concentration of 2.5 µmol/L, Netupitant effectively inhibited clonogenic capacity in breast cancer cells; furthermore, treatment with 10 µmol/L significantly induced apoptosis in these cells. Doses of 50 mg/kg and 100 mg/kg Netupitant markedly suppressed growth rates of subcutaneous xenograft tumors in nude mice while also promoting apoptotic processes. Both in vivo and in vitro studies indicated that Netupitant could inhibit the activation of the PI3K/AKT/mTOR signaling pathway. Conclusions: By targeting AGK, Netupitant inhibits its kinase activity, which leads to reduced phosphorylation levels of PTEN, thereby suppressing the activation of the PI3K/AKT/mTOR signaling pathway and ultimately resulting in apoptosis in breast cancer cells. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aimed to understand how specific characteristics of liver cancer, specifically the spread of cancer to blood vessels or other parts of the body, affect treatment outcomes. By analyzing data from 362 patients who received first-line treatment for liver cancer that could not be surgically resected, the researchers identified patterns that could assist in predicting how well patients will respond to treatment. Patients whose cancer had spread only to other parts of the body lived longer than those whose cancer had spread to the blood vessels or both areas. These findings suggest that patients whose cancer had spread only outside the liver may represent a distinct group that could benefit from specific treatment strategies. This new insight may help doctors tailor treatments for liver cancer and improve patient outcomes. Objectives: This study focused on the presence or absence of vascular invasion and extrahepatic metastasis in hepatocellular carcinoma (HCC) and examined their impact on systemic treatment outcomes. Methods: We retrospectively analyzed 362 patients with unresectable HCC who received first-line systemic therapy. The prognostic evaluation was based on the presence of vascular invasion and extrahepatic metastasis at the time of treatment initiation. Results: Patients with vascular invasion or extrahepatic metastasis (advanced group) had significantly worse outcomes than those without these features (intermediate group), with median survival times of 434 and 658 days, respectively. Further subdivision of the advanced group into three categories—patients with only extrahepatic metastasis (m group, n = 77), patients with only vascular invasion (v group, n = 78), and patients with both vascular invasion and extrahepatic metastasis (vm group, n = 52)—revealed that the m group had significantly better outcomes than those in the other two groups, with median survival times of 649, 323, and 187 days, respectively. A comparison of the clinical backgrounds among the three groups demonstrated that the m group had significantly better liver function at the time of treatment initiation than that in the other two groups. Multivariable analysis, including performance status, Child–Pugh score, and the use of immune checkpoint inhibitors as first-line therapy, identified the m group as an independent and significant prognostic factor (hazard ratio, 0.50). Conclusions: Unresectable HCC with extrahepatic metastasis and no vascular invasion represents a novel staging category for systemic treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Upper tract urothelial carcinoma (UTUC) is a rare but aggressive cancer that is difficult to predict and treat effectively. Current methods for assessing a patient's outlook often fall short. Our research introduces a new approach that could change this. We look at the fat surrounding the kidney using detailed CT scan analysis, combined with standard clinical information. This method provides a more accurate prediction of how patients with UTUC might fare. By examining the texture and patterns in this fat tissue, we can potentially detect early signs of cancer spread that are not visible to the naked eye. Our findings could help doctors make better treatment decisions, such as whether to use chemotherapy before surgery or how extensive the surgery should be. This personalized approach aims to improve outcomes for patients with this challenging cancer. Background: Upper tract urothelial carcinoma (UTUC) presents significant challenges in prognostication due to its rarity and complex anatomy. This study introduces a novel approach integrating perirenal fat (PRF) radiomics with clinical factors to enhance prognostic accuracy in UTUC. Methods: The study retrospectively analyzed 103 UTUC patients who underwent radical nephroureterectomy. PRF radiomics features were extracted from preoperative CT scans using a semi-automated segmentation method. Three prognostic models were developed: clinical, radiomics, and combined. Model performance was assessed using concordance index (C-index), time-dependent Area Under the Curve (AUC), and integrated Brier score. Results: The combined model demonstrated superior performance (C-index: 0.784, 95% CI: 0.707–0.861) compared to the radiomics (0.759, 95% CI: 0.678–0.840) and clinical (0.653, 95% CI: 0.547–0.759) models. Time-dependent AUC analysis revealed the radiomics model's particular strength in short-term prognosis (12-month AUC: 0.9281), while the combined model excelled in long-term predictions (60-month AUC: 0.8403). Key PRF radiomics features showed stronger prognostic value than traditional clinical factors. Conclusions: Integration of PRF radiomics with clinical data significantly improves prognostic accuracy in UTUC. This approach offers a more nuanced analysis of the tumor microenvironment, potentially capturing early signs of tumor invasion not visible through conventional imaging. The semi-automated PRF segmentation method presents advantages in reproducibility and ease of use, facilitating potential clinical implementation. [ABSTRACT FROM AUTHOR]

Simple Summary: This research examines how the loss of the Y chromosome (LoY) in men may contribute to the development and progression of certain cancers, particularly in the urinary system. Traditionally, the Y chromosome was primarily associated with male sex determination and sperm production, but recent studies suggest it plays a wider role in health and disease. LoY appears to disrupt immune function and increase genetic instability, factors that may heighten cancer risk and impact treatment outcomes. Our review highlights that LoY could serve as an early indicator of certain cancers and might help predict cancer behavior. Understanding LoY's role could lead to new diagnostic tools and treatments, especially for cancers where Y chromosome alterations are linked to poorer outcomes. Background: The Y chromosome (ChrY) is essential for male sex determination and spermatogenesis. However, recent studies have revealed its broader role in various physiological processes and disease susceptibility, including cancer. Methods: A comprehensive literature review was conducted using databases like MEDLINE, Scopus, Web of Science, and Google Scholar. The review included clinical and preclinical studies in animals and humans focusing on the role of LoY in urological tumors. Data on the frequency of LoY, its clinical implications, and underlying mechanisms were extracted and analyzed. Results: The evidence suggests that LoY is associated with an increased risk of urologic neoplasms, potentially serving as an early marker of genomic instability. Studies reveal that LoY in urologic cancers correlates with worse survival outcomes and may contribute to tumor progression. LoY may interfere with chromatin structure and epigenetic regulation, suggesting its role as a contributor to early tumorigenesis. Conclusions: LoY appears to be a structural aberration with unique biological and clinical relevance in urologic cancers, possibly serving as a biomarker for genomic instability. Further research is necessary to identify specific Y-linked genes affected by LoY, potentially informing targeted therapies and early diagnostic strategies for these cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Annexin A2 is a protein that plays a role in many important cell functions, but when its levels are not properly regulated, it can contribute to the development of cancer, particularly in the digestive system. This review looks at the current understanding of how Annexin A2 is involved in cancers of the digestive system, including its potential to help diagnose cancer, predict how a patient will respond to treatment, and even serve as a target for new therapies. Some early studies suggest that blocking this protein or stopping it from interacting with other molecules could slow down cancer growth, prevent the spread of cancer, and make cancer cells more responsive to treatment. By exploring this protein further, scientists hope to develop better tools to diagnose and fight cancer, ultimately benefiting society by improving survival rates and quality of life for patients. Annexin A2 (ANXA2) is a protein that is involved in many physiological and pathological cellular processes. There is compelling evidence that its dysregulated expression, be it up- or downregulation, contributes to the oncogenesis of various neoplasms, including those of the digestive system. The present review summarizes the current knowledge on the role of ANXA2 in the main tumors of the digestive system. The clinical significance of ANXA2 is primordial, due to its potential use as a diagnostic and prognostic biomarker, and as a part of therapeutic protocols. Certain preclinical studies have shown that inhibiting ANXA2 or disrupting its interactions with key molecules can suppress tumor growth, invasion, and metastasis, as well as increase the cancer cells' sensitivity to treatment in various cancers. Further research is needed to fully elucidate the complex role of ANXA2 in the carcinogenesis of tumors of the digestive system, and to translate these findings into clinical applications for improved diagnosis, prognosis, and treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Green healthcare relates to using naturally derived sources as medicines to treat and personalize treatments for various diseases. Cancer is one primary global health concern due to its rapid evolution and high prevalence, especially lung cancer. Cinobufagin (CB), a bufadienolide derived primarily from the parotid glands of frogs, has shown promise in combating lung cancer. Our objective with this systematic review is to synthesize the current evidence on CB's effects against lung cancer, focusing on its mechanisms of action, efficacy, and potential clinical implications. Our results indicated that CB reduces lung cancer tumor growth via increased apoptosis by reducing cancer cells' viability. In addition, CB also has impacted migration and invasion across multiple lung cancer cell lines and xenograft models. The molecular pathways involved Bcl-2, Bax, cleaved caspases, caveolin-1, FLOT2, Akt, STAT3, and FOXO1. CB achieved these effects with minimal toxicity. Cinobufagin (CB), a bufadienolide, has shown promising potential as an anticancer agent, particularly in combating lung cancer. This systematic review synthesizes preclinical evidence on CB's effects against lung cancer, focusing on its mechanisms of action, efficacy, and potential clinical implications. We analyzed data from various preclinical studies involving both in vitro cell line models and in vivo animal models. The reviewed studies indicate that CB effectively reduces cell viability, induces apoptosis, and inhibits cell proliferation, migration, and invasion across multiple lung cancer cell lines and xenograft models. Specifically, CB was found to decrease cell viability and increase apoptosis in lung cancer cells by modulating key molecular pathways, including Bcl-2, Bax, cleaved caspases, caveolin-1, FLOT2, Akt, STAT3, and FOXO1. In vivo studies further demonstrated significant inhibition of tumor growth with minimal toxicity. However, limitations include reliance on in vitro models, which may not fully represent in vivo tumor dynamics, and a lack of long-term safety data. The studies also vary in their methodologies and cell line models, which may not accurately encompass all lung cancer subtypes or predict human responses. Despite these limitations, CB's ability to target specific molecular pathways and its promising results in preclinical models suggest it could be a valuable addition to lung cancer treatment strategies. Our review suggests further clinical trials to validate its efficacy and safety in humans. Future research should explore combination therapies and optimize delivery methods to enhance clinical outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Malignant peripheral nerve sheath tumors (MPNSTs) are a diagnostic and therapeutic challenge requiring interdisciplinary teamwork. With this study, we aimed to investigate the perioperative outcomes in patients with these tumors. We demonstrated that an increase in the levels of SUVs on preoperative [18F]FDG PET and large tumor volumes may be a predictive marker for highly proliferative tumors with a poor prognosis, particularly in patients with underlying Neurofibromatosis type 1. Surgery for MPNSTs can improve symptoms, particularly medication-resistant pain, and should also be considered in advanced disease for symptom control/improvement. Background/Objectives: This retrospective observational study aimed to investigate the perioperative outcome in Malignant Peripheral Nerve Sheath Tumors (MPNSTs) with and without relation to Neurofibromatosis Type 1 (NF1) and to detect possible influencing factors. Methods: Clinical reports, histopathological evaluations, imaging, and treatment characteristics were reviewed in 35 operated MPNSTs in 33 patients. Possible predictive valuables included disease type, preoperative tumor volume, SUV and MIB-1 proliferation index, resection margins, the presence of metastasis, and whether radio-/chemotherapy was received. Results: Patients with NF1 were younger (mean age: 29 ± 13, 8–54 years) than sporadic cases (mean age: 45 ± 13, 24–67 years) and exhibited significantly larger preoperative tumor volumes (mean 299 vs. 18 cm3, p = 0.048). Most tumors were located in the facial/cervical/neck area (34%, n = 12), followed by the trunk (31%, n = 11), lower extremity (17%, n = 6), upper extremity (14%, n = 5), and intraspinal area (3%, n = 1). NF1-associated MPNSTs appeared predominantly on the trunk (39%) and sporadically in the facial/cervical/neck area (50%). Complete resection was possible in 66% and an improvement in or stability of function was achieved in most cases (motor 69%, sensory 74%), as well as a decrease in pain intensity (63%). NF1-associated MPNSTs exhibited more severe pain scores (median VRS scale 2, p = 0.002) compared to sporadic tumors (median VRS scale 0.5). Sporadic MPNSTs located at the head/facial/brachial plexus and upper extremities exhibited better preoperative functions compared to those on the lower extremities. In 12 cases with available [18F]FDG PET, the mean preoperative SUV (9.8 ± 7.2) positively correlated with the mean maximum MIB-1 index (34 ± 26%, p = 0.005) and the mean preoperative tumor volume (474.7 ± 68.6 cm3, p = 0.047). The overall survival (OS) was significantly longer in tumors with higher resection extents (R0, p = 0.01) and without accompanying metastasis (p = 0.046), and tended to be longer, but not significantly so, in sporadic MPNSTs. In six and seven tumors, with R1/R2 resection margins and present metastasis, respectively, solid or combined neo-/adjuvant radio-/chemotherapy led to a significantly shorter OS (p = 0.014). Conclusions: NF1-associated MPNSTs have larger tumor volumes, higher SUVs and MIB-1 proliferation indices, and a shorter overall survival period. Nevertheless, surgery can improve symptoms, particularly medication-resistant pain, and should also be considered in advanced disease for symptom control/improvement. [ABSTRACT FROM AUTHOR]

The migratory and invasive capabilities of melanoma cells contribute to metastasis. Therefore, targeting the genes driving these processes can support melanoma therapy. Rab27A and Rab27B contribute to tumor formation progression in many types of cancer through various mechanisms, including the secretion of small extracellular vesicles (sEVs). We explored the role of these GTPases in melanoma cell functioning in three RAB27A knockout (KO) cell lines (A375, DMBC12, and SkMel28) and a double RAB27A/B KO A375 cell line. The loss of RAB27A impaired the migration and invasion of DMBC12 and SkMel28 cells; however, the behavior of highly aggressive A375 cells was unaffected. The RAB27A/B double knockout moderately decreased the migratory capacity of A375 cells without disturbing their invasiveness. Additionally, the silencing of RAB27A did not affect the number and mean size of the sEVs, despite some alterations in the protein content of the vesicles. Both Rab27 isoforms can, at least partially, act independently. The potential role of Rab27A in the functioning of melanoma cells depends on the individual character of the cell line, but not on its basal expression, and seems to be unrelated to the secretion of sEVs. [ABSTRACT FROM AUTHOR]

Secreted phospholipase 2 (sPLA2) is the largest family of phospholipase A2 (PLA2) enzymes with 11 mammalian isoforms. Each sPLA2 exhibits different localizations and specific properties, being involved in a very wide spectrum of biological processes. The enzymatic activity of sPLA2 has been well described; however, recent findings have shown that they could regulate different signaling pathways by acting directly as ligands. Arachidonic acid (AA) and its derivatives are produced by sPLA2 in collaboration with other molecules in the extracellular space, making important impacts on the cellular environment, being especially relevant in the contexts of immunity and cancer. For these reasons, this review focuses on sPLA2 functions in processes such as the promotion of EMT, angiogenesis, and immunomodulation in the context of tumor initiation and progression. Finally, we will also describe how this knowledge has been applied in the search for new sPLA2 inhibitory compounds that can be used for cancer treatment. [ABSTRACT FROM AUTHOR]

Erythropoietin-producing hepatocellular A2 (EphA2) is a member of the Eph tyrosine kinase receptor family that has been linked to various biological processes. In tumors, EphA2 overexpression is associated with noncanonical pathway activation, tumor progression, and a poor prognosis, which has emphasized its importance as a marker of malignancy. Studies on numerous cancer models have highlighted EphA2's dual and often contradictory action, which can be attributed to EphA2′s interactions involving multiple pathways and different ligands, as well as the heterogeneity of the tumor microenvironment. In this review, we summarize the main mechanisms underlying EphA2 dysregulation in cancer, highlighting its molecular complexity. Then, we analyze therapies that have been developed over time to counteract its action. We discuss the limitations of the described approaches, emphasizing the fact that the goal of new options is high specificity without losing therapeutic efficacy. For this reason, immunotherapy or the emerging field of targeted protein degradation with proteolysis-targeting chimeras (PROTACs) may represent a promising solution that can be developed based on a deeper understanding of the molecular mechanisms sustaining EphA2 oncogenic activity. [ABSTRACT FROM AUTHOR]

Obesity is a common risk factor in multiple tumor types, including prostate cancer. Obesity has been associated with driving metastasis, therapeutic resistance, and increased mortality. The effect of adipose tissue on the tumor microenvironment is still poorly understood. This review aims to highlight the work conducted in the field of obesity and prostate cancer and bring attention to areas where more research is needed. In this review, we have described key differences between healthy adipose tissues and obese adipose tissues, as they relate to the tumor microenvironment, focusing on mechanisms related to metabolic changes, abnormal adipokine secretion, altered immune cell presence, and heightened oxidative stress as drivers of prostate cancer formation and progression. Interestingly, common treatment options for prostate cancer ignore the adipose tissue located near the site of the tumor. Because of this, we have outlined how excess adipose tissue potentially affects therapeutics' efficacy, such as androgen deprivation, chemotherapy, and radiation treatment, and identified possible drug targets to increase prostate cancer responsiveness to clinical treatments. Understanding how obesity affects the tumor microenvironment will pave the way for understanding why some prostate cancers become metastatic or treatment-resistant, and why patients experience recurrence. [ABSTRACT FROM AUTHOR]

Galectin-1 is implicated in several pro-tumourigenic mechanisms and is considered immune-suppressive. The pharmacological inhibition of galectin-1 may be beneficial in cancers in which galectin-1 is overexpressed and driving cancer progression. This study aimed to further characterise the immunosuppressive cytokines influenced by galectin-1 in in vitro immune cell cultures and an in vivo inflammatory model using a recently discovered selective inhibitor of galectin-1, GB1908. To enable a translational approach and link mouse and human pharmacology, anti-CD3/anti-CD28 stimulated T cells cultured from human whole blood and mouse spleens were compared. For in vivo studies of T cell-mediated inflammation, the concanavalin-A (Con-A) mouse model was used to induce a T lymphocyte-driven acute liver injury phenotype. The inhibition of galectin-1 with GB1908 reduced IL-17A, IFNγ and TNFα in a concentration-dependent manner in both mouse and human T cells in vitro. The immunosuppressive cytokines measured in Con-A-treated mice were all upregulated compared to naïve mice. Subsequently, mice treated with GB1908 demonstrated a significant reduction in IL-17A, IFNγ, IL-6 and TNFα compared to vehicle-treated mice. In conclusion, galectin-1 induced the production of several important immune-suppressive cytokines from T cells in vitro and in vivo. This result suggests that, in the context of cancer therapy, a selective galectin-1 could be a viable approach as a monotherapy, or in combination with chemotherapeutic agents and/or checkpoint inhibitors, to enhance the numbers and activity of cytotoxic T cells in the tumour microenvironment of high galectin-1 expressing cancers. [ABSTRACT FROM AUTHOR]

Melanoma is a malignant, highly metastatic neoplasm showing increasing morbidity and mortality. Tumor invasion and angiogenesis are based on remodeling of the extracellular matrix (ECM). Selective inhibition of functional components of cell–ECM interaction, such as hyaluronic acid (HA), matrix metalloproteinases (MMPs), and integrins, may inhibit tumor progression and enhance the efficacy of combination treatment with immune checkpoint inhibitors (ICIs), chemotherapy, or immunotherapy. In this review, we combine the results of different approaches targeting extracellular matrix elements in melanoma in preclinical and clinical studies. The identified limitations of many approaches, including side effects, low selectivity, and toxicity, indicate the need for further studies to optimize therapy. Nevertheless, significant progress in expanding our understanding of tumor biology and the development of targeted therapies holds great promise for the early approaches developed several decades ago to inhibit metastasis through ECM targeting. [ABSTRACT FROM AUTHOR]

Lymphoma growth, progression, and dissemination require tumor cell interaction with supporting vessels and are facilitated through tumor-promoted angiogenesis, lymphangiogenesis, and/or lymphoma vessel co-option. Vessel co-option has been shown to be responsible for tumor initiation, metastasis, and resistance to anti-angiogenic treatment but is largely uncharacterized in the setting of lymphoma. We developed an in vitro model to study lymphoma–vessel interactions and found that mantle cell lymphoma (MCL) cells co-cultured on Matrigel with human umbilical vein (HUVEC) or human lymphatic (HLEC) endothelial cells migrate to and anneal with newly formed capillary-like (CLS) or lymphatic-like (LLS) structures, consistent with lymphoma–vessel co-option. To inhibit this interaction, we constructed an antibody fusion protein, αCD20-EndoP125A, linking mutant anti-angiogenic endostatin (EndoP125A) to an αCD20-IgG1-targeting antibody. αCD20-EndoP125A inhibited both CLS and LLS formation, as well as MCL migration and vessel co-option. Lymphoma vessel co-option requires cell migration, which is regulated by chemokine–chemokine receptor interactions. CXCL12 and its receptor, CXCR4, are highly expressed by both endothelial cells forming CLS and by MCL cells during vessel co-option. αCD20-EndoP125A suppressed expression of both CXCL12 and CXCR4, which were required to facilitate CLS assembly and vessel co-option. We also tested αCD20-EndoP125A effects in vivo using an aggressive murine B cell lymphoma model, 38c13-hCD20, which demonstrated rapid growth and dissemination to tumor-draining lymph nodes (TDLNs) and the spleen, lung, and brain. The pattern of lymphoma distribution and growth within the lung was consistent with vessel co-option. As predicted by our in vitro model, αCD20-EndoP125A treatment inhibited primary tumor growth, angiogenesis, and lymphangiogenesis, and markedly reduced the number of circulating tumor cells and lymphoma dissemination to TDLNs and the lungs, spleen, and brain. αCD20-EndoP125A inhibited lymphoma vessel co-option within the lung. Marked inhibition of MCL primary tumor growth and dissemination were also seen using an MCL xenograft model. The ability of αCD20-EndoP125A to inhibit angiogenesis, lymphangiogenesis, and lymphoma vessel co-option provides a novel therapeutic approach for inhibition of lymphoma progression and dissemination. [ABSTRACT FROM AUTHOR]

Podoplanin (PDPN) overexpression is associated with poor clinical outcomes in various tumors. PDPN is involved in malignant tumor progression by promoting invasiveness and metastasis. Therefore, PDPN is considered a promising target of monoclonal antibody (mAb)-based therapy. Because PDPN also plays an essential role in normal cells such as kidney podocytes, cancer specificity is required to reduce adverse effects on normal cells. We developed a cancer-specific mAb (CasMab) against PDPN, PMab-117 (rat IgM, kappa), by immunizing rats with PDPN-overexpressed glioblastoma cells. The recombinant mouse IgG2a-type PMab-117 (PMab-117-mG2a) reacted with the PDPN-positive tumor PC-10 and LN319 cells but not with PDPN-knockout LN319 cells in flow cytometry. PMab-117-mG2a did not react with normal kidney podocytes and normal epithelial cells from the lung bronchus, mammary gland, and corneal. In contrast, one of the non-CasMabs against PDPN, NZ-1, showed high reactivity to PDPN in both tumor and normal cells. Moreover, PMab-117-mG2a exerted antibody-dependent cellular cytotoxicity in the presence of effector splenocytes. In the human tumor xenograft models, PMab-117-mG2a exhibited potent antitumor effects. These results indicated that PMab-117-mG2a could be applied to antibody-based therapy against PDPN-expressing human tumors while reducing the adverse effects. [ABSTRACT FROM AUTHOR]