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Glioblastoma (GBM), the most malignant primary brain tumor in adults, has poor prognosis irrespective of therapeutic advances due to its radio-resistance and infiltrative growth into brain tissue. The present study assessed functions and putative druggability of BRCA1-associated ATM activator 1 (BRAT1) as a crucial factor driving key aspects of GBM, including enhanced DNA damage response and tumor migration. By a stable depletion of BRAT1 in GBM and glioma stem-like (GSC) cell lines, we observed a delay in DNA double-strand break repair and increased sensitivity to radiation treatment, corroborated by in vitro and in vivo studies demonstrating impaired tumor growth and invasion. Proteomic and phosphoproteomic analyses further emphasize the role of BRAT1's cell migration and invasion capacity, with a notable proportion of downregulated proteins associated with these processes. In line with the genetic manipulation, we found that treatment with the BRAT1 inhibitor Curcusone D (CurD) significantly reduced GSC migration and invasion in an ex vivo slice culture model, particularly when combined with irradiation, resulting in a synergistic inhibition of tumor growth and infiltration. Our results reveal that BRAT1 contributes to GBM growth and invasion and suggest that therapeutic inhibition of BRAT1 with CurD or similar compounds might constitute a novel approach for anti-GBM directed treatments. [ABSTRACT FROM AUTHOR]

Objectives We studied the diagnostic accuracy and discordance of upper tract urothelial carcinoma (UTUC) by comparing biopsy and urinary cytology with matched nephroureterectomy specimens. Methods Sixty-nine patients with UTUC without neoadjuvant treatment were retrospectively identified who had matched biopsy and nephroureterectomy specimens. Twenty patients had concurrent upper tract cytology. H&E and cytology slides were re-reviewed. Statistical analysis was performed. Results Patients included 48 men and 21 women with a mean age of 69 years. A concordant grade between biopsy and surgical specimen was present in 49 (71%) patients. The mean size of biopsy specimens in the discordant group was significantly smaller than that in the concordant group. Invasion was evaluated in 48 biopsy cases that had adequate subepithelial tissue, and 33 of them were diagnosed with concordant invasion status. Mean tumor size in both tumor grade and invasion discordant groups was significantly larger than that in the concordant group. High-grade urothelial carcinoma was detected in 84% of cases using urinary cytology. Conclusions Our study demonstrates the diagnostic challenges of UTUC on small biopsy specimens. Biopsy specimen size and tumor size are significantly associated with the diagnostic discordance. Upper tract cytology showed high diagnostic accuracy and should be complementary to the biopsy. [ABSTRACT FROM AUTHOR]

Simple Summary: While tumor cell invasion beyond the surgically resectable "margin" of glioblastoma is thought to be associated with nearly 100% of recurrences and poor survival, no reliable methods exist for mapping the location of invading tumor cells within the human brain. Building on prior work demonstrating the ability of Q-space magnetic resonance imaging (QSI) to highlight structural alterations in tissue architecture, we hypothesized that using this imaging method to construct tumor-associated tractography might identify tumor-specific structures that underlie cellular invasion. Our results demonstrate that such tractography patterns can be observed in a tumor-specific manner, and provide preliminary evidence that those patterns may colocalize with invading tumor cells, and metrics derived from them may be associated with patient survival time. Background: The invasion of glioblastoma cells beyond the visible tumor margin depicted by conventional neuroimaging is believed to mediate recurrence and predict poor survival. Radiomic biomarkers that are associated with the direction and extent of tumor infiltration are, however, non-existent. Methods: Patients from a single center with newly diagnosed glioblastoma (n = 7) underwent preoperative Q-space magnetic resonance imaging (QSI; 3T, 64 gradient directions, b = 1000 s/mm2) between 2018 and 2019. Tumors were manually segmented, and patterns of inter-voxel coherence spatially intersecting each segmentation were generated to represent tumor-associated tractography. One patient additionally underwent regional biopsy of diffusion tract- versus non-tract-associated tissue during tumor resection for RNA sequencing. Imaging data from this cohort were compared with a historical cohort of n = 66 glioblastoma patients who underwent similar QSI scans. Associations of tractography-derived metrics with survival were assessed using t-tests, linear regression, and Kaplan–Meier statistics. Patient-derived glioblastoma xenograft (PDX) mice generated with the sub-hippocampal injection of human-derived glioblastoma stem cells (GSCs) were scanned under high-field conditions (QSI, 7T, 512 gradient directions), and tumor-associated tractography was compared with the 3D microscopic reconstruction of immunostained GSCs. Results: In the principal enrollment cohort of patients with glioblastoma, all cases displayed tractography patterns with tumor-intersecting tract bundles extending into brain parenchyma, a phenotype which was reproduced in PDX mice as well as in a larger comparison cohort of glioblastoma patients (n = 66), when applying similar methods. Reconstructed spatial patterns of GSCs in PDX mice closely mirrored tumor-associated tractography. On a Kaplan–Meier survival analysis of n = 66 patients, the calculated intra-tumoral mean diffusivity predicted the overall survival (p = 0.037), as did tractography-associated features including mean tract length (p = 0.039) and mean projecting tract length (p = 0.022). The RNA sequencing of human tissue samples (n = 13 tumor samples from a single patient) revealed the overexpression of transcripts which regulate cell motility in tract-associated samples. Conclusions: QSI discriminates tumor-specific patterns of inter-voxel coherence believed to represent white matter pathways which may be susceptible to glioblastoma invasion. These findings may lay the groundwork for future work on therapeutic targeting, patient stratification, and prognosis in glioblastoma. [ABSTRACT FROM AUTHOR]

Keratinocytes are major cellular components of the skin and are strongly involved in its homeostasis. Oncogenic events, starting mainly from excessive sun exposure, lead to the dysregulation of their proliferation and differentiation programs and promote the initiation and progression of non-melanoma skin cancers (NMSCs). Primary melanomas, which originate from melanocytes, initiate and develop in close interaction with keratinocytes, whose role in melanoma initiation, progression, and immune escape is currently being explored. Recent studies highlighted, in particular, unexpected modes of communication between melanocytic cells and keratinocytes, which may be of interest as sources of new biomarkers in melanomagenesis or potential therapeutic targets. This review aims at reporting the various contributions of keratinocytes in skin basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma, with a greater focus on the latter in order to highlight some recent breakthrough findings. The readers are referred to recent reviews when contextual information is needed. [ABSTRACT FROM AUTHOR]

Background: Vulvar squamous cell carcinoma (VSCC) is a rare disease with a poor prognosis. To date, there's no proper in vitro modeling system for VSCC to study its pathogenesis or for drug evaluation. Methods: We established healthy vulvar (HV)- and VSCC-like 3D full thickness models (FTMs) to observe the tumor-stroma interaction and their applicability for chemotherapeutic efficacy examination. VSCC-FTMs were developed by seeding VSCC tumor cell lines (A431 and HTB117) onto dermal matrices harboring two NF subtypes namely papillary fibroblasts (PFs) and reticular fibroblasts (RFs), or cancer-associated fibroblasts (CAFs) while HV-FTMs were constructed with primary keratinocytes and fibroblasts isolated from HV tissues. Results: HV-FTMs highly resembled HV tissues in terms of epidermal morphogenesis, basement membrane formation and collagen deposition. When the dermal compartment shifted from PFs to RFs or CAFs in VSCC-FTMs, tumor cells demonstrated more proliferation, EMT induction and stemness. In contrast to PFs, RFs started to lose their phenotype and express robust CAF-markers α-SMA and COL11A1 under tumor cell signaling induction, indicating a favored 'RF-to-CAF' transition in VSCC tumor microenvironment (TME). Additionally, chemotherapeutic treatment with carboplatin and paclitaxel resulted in a significant reduction in tumor-load and invasion in VSCC-FTMs. Conclusion: We successfully developed in vitro 3D vulvar models mimicking both healthy and tumorous conditions which serve as a promising tool for vulvar drug screening programs. Moreover, healthy fibroblasts demonstrate heterogeneity in terms of CAF-activation in VSCC TME which brings insights in the future development of novel CAF-based therapeutic strategies in VSCC. [ABSTRACT FROM AUTHOR]

Background: Tumor invasion and metastasis are responsible for the majority of cancer-related deaths. The identification of molecules involved in these processes is crucial to design effective treatments that can halt the progression of cancer. To spread and metastasize, tumor cells must restructure their cytoskeleton and emit protrusions. A key molecule in this process of creating these invading structures is Fascin1, the main protein involved in the formation of actin cytoskeleton bundles and a consistent marker of bad prognosis in several types of cancer. Recent studies have shown that imipramine, an FDA- and EMA-approved antidepressant, can block Fascin1and prevent the formation of actin bundles, making it a promising candidate for the treatment of Fascin1-expressing cancers. As a result, a clinical trial will be conducted to assess the efficacy of imipramine being the first experimental clinical study selecting patients based on Fascin1 expression. Methods: The HITCLIF trial is a multicenter, double-blind, placebo-controlled, randomized and non-commercial phase II clinical trial conducted in parallel groups to evaluate the effectiveness of the tricyclic antidepressant imipramine as anti-invasive agent in the treatment of localized colon, rectal and triple negative breast cancer patients with overexpression of Fascin1. Eligible patients will be randomly assigned, in a 1:1 ratio, to receive imipramine or placebo. Patients will be stratified into 2 groups according to whether administration of imipramine is concomitant with neoadjuvant chemotherapy regimen. Group A will receive imipramine alone without neoadjuvant chemotherapy, while Group B will receive imipramine treatment along with the standard neoadjuvant chemotherapy regimen. The primary endpoint of the trial is the grade of alteration in the prognostic histopathological features at invasive margins (tumor budding, cytoplasmic pseudo-fragments, tumor growth pattern, and peritumoral lymphocytic infiltration). Discussion: Fascin1 is an interesting therapeutical target as it plays a causative role in the invasion and metastasis of cancer cells. Moreover, its expression is virtually absent in normal epithelia but highly expressed in cancer with bad prognosis. In silico, in vitro and in vivo studies by our group have demonstrated that the antidepressant imipramine has Fascin1-dependant anti-invasive and antimetastatic effects in colorectal cancer cells. Now we are recruiting patients in a clinical trial based on Fascin1 over-expression in which administration of imipramine will be carried out during the period between the diagnosis biopsy and surgical resection to explore the drug effects on tumor invasive front. Clinical trial registration: https:///www.clinicaltrialsregister.eu/ctr-search/trial/2021-001328-17/ES, identifier 2021-001328-17. [ABSTRACT FROM AUTHOR]

Cancer is a predominant culprit behind worldwide death and accounts for up to 10 million deaths every year. Chemotherapy is the primary therapeutic method employed for cancer in clinical settings and is essential in controlling tumor progression. Despite the advances in this field, tumor invasion and metastasis during treatment remain a significant cause of treatment failure. Nevertheless, the underlying mechanisms involving such a disappointing phenomenon are still not fully elucidated. Vinorelbine (VNB) extends the lifespan of many cancer patients in the clinic as an emerging chemotherapy drug approved by Food and Drug Administration (FDA). However, VNB-induced tumor metastasis is still an intractable problem, which may be closely related to the abnormal oxidative stress generated during VNB-mediated treatment. Hence, the study aims to construct a reductive nanosystem loaded with VNB, called VNB-VNP, to improve cancer cure rates and reduce tumor metastasis. With the reductive component vitamin E, VNB-VNP can effectively reduce oxidative stress and significantly outperform free VNB in preventing tumor progression. The transcriptome analysis shows that VNB-VNP can alleviate the over-expression of ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), which may be the main reason why VNB-VNP can inhibit tumor invasion and metastasis. Overall, the research designs a new platform for VNB treatment, which demonstrates promising efficacy in inhibiting neoplastic progression and identifies a new mechanism associated with VNB-induced tumor metastasis, which may offer several valuable references for enhancing chemotherapy efficacy in clinical anti-tumor therapy. [ABSTRACT FROM AUTHOR]

Background: Tumor invasion and metastasis are responsible for the majority of cancer-related deaths. The identification of molecules involved in these processes is crucial to design effective treatments that can halt the progression of cancer. To spread and metastasize, tumor cells must restructure their cytoskeleton and emit protrusions. A key molecule in this process of creating these invading structures is Fascin1, the main protein involved in the formation of actin cytoskeleton bundles and a consistent marker of bad prognosis in several types of cancer. Recent studies have shown that imipramine, an FDA- and EMA-approved antidepressant, can block Fascin1and prevent the formation of actin bundles, making it a promising candidate for the treatment of Fascin1-expressing cancers. As a result, a clinical trial will be conducted to assess the efficacy of imipramine being the first experimental clinical study selecting patients based on Fascin1 expression. Methods: The HITCLIF trial is a multicenter, double-blind, placebo-controlled, randomized and non-commercial phase II clinical trial conducted in parallel groups to evaluate the effectiveness of the tricyclic antidepressant imipramine as anti-invasive agent in the treatment of localized colon, rectal and triple negative breast cancer patients with overexpression of Fascin1. Eligible patients will be randomly assigned, in a 1:1 ratio, to receive imipramine or placebo. Patients will be stratified into 2 groups according to whether administration of imipramine is concomitant with neoadjuvant chemotherapy regimen. Group A will receive imipramine alone without neoadjuvant chemotherapy, while Group B will receive imipramine treatment along with the standard neoadjuvant chemotherapy regimen. The primary endpoint of the trial is the grade of alteration in the prognostic histopathological features at invasive margins (tumor budding, cytoplasmic pseudo-fragments, tumor growth pattern, and peritumoral lymphocytic infiltration). Discussion: Fascin1 is an interesting therapeutical target as it plays a causative role in the invasion and metastasis of cancer cells. Moreover, its expression is virtually absent in normal epithelia but highly expressed in cancer with bad prognosis. In silico, in vitro and in vivo studies by our group have demonstrated that the antidepressant imipramine has Fascin1-dependant anti-invasive and anti-metastatic effects in colorectal cancer cells. Now we are recruiting patients in a clinical trial based on Fascin1 over-expression in which administration of imipramine will be carried out during the period between the diagnosis biopsy and surgical resection to explore the drug effects on tumor invasive front. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite remarkable progress in treating early-stage gastric cancer (GC), the clinical outcomes for patients with advanced disease remain very poor. Tissue invasion and metastasis constitute the major causes of cancer-related deaths, including GC. This highlights the urgent need to develop animal models that can recapitulate these processes to develop novel therapeutic strategies. We developed a highly reproducible and cost-effective procedure to establish orthotopic GC xenografts showing high engraftment and metastatic rates via the direct implantation of tumor cell suspensions. Compared with the routine method to establish orthotopic xenograft models by engrafting intact tumor fragments, our approach significantly shortens the experimental timeline and allows for the flexible adjustment of the number of tumor cells implanted to control the rate of tumor progression. Both dose- and time-dependent progressions of tumor invasion and metastasis were nicely recapitulated in our model. Our work provides valuable tools for studying GC progression and metastasis and developing effective therapies. Although the implantation of intact tumor fragments is a common practice to generate orthotopic xenografts to study tumor invasion and metastasis, the direct implantation of tumor cell suspensions is necessary when prior manipulations of tumor cells are required. However, the establishment of orthotopic xenografts using tumor cell suspensions is not mature, and a comparative study directly comparing their engraftment and metastatic capabilities is lacking. It is unclear whether tumor fragments are superior to cell suspensions for successful engraftment and metastasis. In this study, we employed three GC cell lines with varying metastatic capacities to stably express firefly luciferase for monitoring tumor progression in real time. We successfully minimized the risk of cell leakage during the orthotopic injection of tumor cell suspensions without Corning Matrigel by systematically optimizing the surgical procedure, injection volume, and needle size options. Comparable high engraftment and metastatic rates between these two methods were demonstrated using MKN-45 cells with a strong metastatic ability. Importantly, our approach can adjust the rate of tumor progression flexibly and cuts the experimental timeline from 10–12 weeks (for tumor fragments) to 4–5 weeks. Collectively, we provided a highly reproducible procedure with a shortened experimental timeline and low cost for establishing orthotopic GC xenografts via the direct implantation of tumor cell suspensions. [ABSTRACT FROM AUTHOR]

In this paper, we study the following chemotaxis system with signal-dependent motility arising from tumor invasion u t = Δ (φ (v) u) + ρ u - μ u l , x ∈ Ω , t > 0 , v t = Δ v + w z , x ∈ Ω , t > 0 , w t = - w z , x ∈ Ω , t > 0 , z t = Δ z - z + u , x ∈ Ω , t > 0 under homogeneous Neumann boundary conditions in a smooth bounded domain Ω ⊂ R n (n ≥ 1) , where the parameters ρ ≥ 0 , μ ≥ 0 and l > 1 are constants, the motility function φ (v) satisfies φ (v) ∈ C 3 ([ 0 , + ∞)) , φ 1 ≤ φ (v) ≤ φ 2 and | φ ′ (v) | ≤ φ 3 with φ 1 , φ 2 , φ 3 > 0. The purpose of this paper is to prove that the existence of global bounded solution for 1 ≤ n ≤ 3 . For n ≥ 4 , we prove that the nonnegative classical solution (u, v, w, z) is globally bounded if l > n 2 . In addition, we also show that all the global bounded solution will converge to the non-trivial constant steady state exponentially. [ABSTRACT FROM AUTHOR]

Background: The high invasiveness and infiltrative nature of Glioblastoma (GBM) pose significant challenges for surgical removal. This study aimed to investigate the role of KCNA1 in GBM progression. Methods: CCK8, colony formation assay, scratch assay, transwell assay, and 3D tumor spheroid invasion assays were to determine how KCNA1 affects the growth and invasion of GBM cells. Subsequently, to confirm the impact of KCNA1 in ferroptosis, western blot, transmission electron microscopy and flow cytometry were conducted. To ascertain the impact of KCNA1 in vivo, patient-derived orthotopic xenograft models were established. Results: In functional assays, KCNA1 promotes the growth and invasion of GBM cells. Besides, KCNA1 can increase the expression of SLC7A11 and protect cells from ferroptosis. The vivo experiments demonstrated that knocking down KCNA1 inhibited the growth and infiltration of primary tumors in mice and extended survival time. Conclusion: Therefore, our research suggests that KCNA1 may promote tumor growth and invasion by upregulating the expression of SLC7A11 and inhibiting ferroptosis, making it a promising therapeutic target for GBM. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Shanghai Jiaotong University (Medical Science) is the property of Journal of Shanghai Jiaotong University (Medical Science) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Heterogeneity is a critical basis for understanding how the tumor microenvironment (TME) contributes to tumor progression. However, an understanding of the specific characteristics and functions of TME subtypes (subTMEs) in the progression of cancer is required for further investigations into single-cell resolutions. Here, we analyzed single-cell RNA sequencing data of 250 clinical samples with more than 200,000 cells analyzed in each cancer datum. Based on the construction of an intercellular infiltration model and unsupervised clustering analysis, four, three, three, and four subTMEs were revealed in breast, colorectal, esophageal, and pancreatic cancer, respectively. Among the subTMEs, the immune-suppressive subTME (subTME-IS) and matrix remodeling with malignant cells subTME (subTME-MRM) were highly enriched in tumors, whereas the immune cell infiltration subTME (subTME-ICI) and precancerous state of epithelial cells subTME (subTME-PSE) were less in tumors, compared with paracancerous tissues. We detected and compared genes encoding cytokines, chemokines, cytotoxic mediators, PD1, and PD-L1. The results showed that these genes were specifically overexpressed in different cell types, and, compared with normal tissues, they were upregulated in tumor-derived cells. In addition, compared with other subTMEs, the expression levels of PDCD1 and TGFB1 were higher in subTME-IS. The Cox proportional risk regression model was further constructed to identify possible prognostic markers in each subTME across four cancer types. Cell-cell interaction analysis revealed the distinguishing features in molecular pairs among different subTMEs. Notably, ligand–receptor gene pairs, including COL1A1-SDC1, COL6A2-SDC1, COL6A3-SDC1, and COL4A1-ITGA2 between stromal and tumor cells, associated with tumor invasion phenotypes, poor patient prognoses, and tumor advanced progression, were revealed in subTME-MRM. C5AR1-RPS19, LGALS9-HAVCR2, and SPP1-PTGER4 between macrophages and CD8+ T cells, associated with CD8+ T-cell dysfunction, immunosuppressive status, and tumor advanced progression, were revealed in subTME-IS. The spatial co-location information of cellular and molecular interactions was further verified by spatial transcriptome data from colorectal cancer clinical samples. Overall, our study revealed the heterogeneity within the TME, highlighting the potential pro-invasion and pro-immunosuppressive functions and cellular infiltration characteristics of specific subTMEs, and also identified the key cellular and molecular interactions that might be associated with the survival, invasion, immune escape, and classification of cancer patients across four cancer types. [ABSTRACT FROM AUTHOR]

This work is devoted to introduce and study two quasispecies nonlinear ODE systems that model the behavior of tumor cell populations organized in different states. In the first model, replicative, senescent, extended lifespan, immortal and tumor cells are considered, while the second also includes immune cells. We fit the parameters regulating the transmission between states in order to approximate the outcomes of the models to a real progressive tumor invasion. After that, we study the identifiability of the fitted parameters, by using two sensitivity analysis methods. Then, we show that an adequate reduced fitting process (only accounting to the most identifiable parameters) gives similar results but saving computational cost. Three different therapies are introduced in the models to shrink (progressively in time) the tumor, while the replicative and senescent cells invade. Each therapy is identified to a dimensionless parameter. Then, we make a fitting process of the therapies’ parameters, in various scenarios depending on the initial tumor according to the time when the therapies started. We conclude that, although the optimal combination of therapies depends on the size of initial tumor, the most efficient therapy is the reinforcement of the immune system. Finally, an identifiability analysis allows us to detect a limitation in the therapy outcomes. In fact, perturbing the optimal combination of therapies under an appropriate therapeutic vector produces virtually the same results. [ABSTRACT FROM AUTHOR]

Background: Molecular diversity of virus-associated cervical cancer remains a relatively underexplored issue, and interrelations of immunologic and angiogenic features during the establishment of a particular landscape of the cervical cancer microenvironment are not well-characterized, especially for its earliest clinical stages, although this may provide insight into the mechanisms behind the differences in tumor aggressiveness, treatment responsiveness and prognosis. In this research, we were aimed at identifying transcriptomic landscapes of earlystage cervical carcinoma that differ substantially in their immune-related characteristics, patterns of signaling pathways and composition of the microenvironment in comparison with immediate precursor (intraepithelial) lesions. Methods: We performed the Illumina platform-based RNA sequencing using a panel of fresh tissue samples that included human papillomavirus-positive cervical intraepithelial neoplastic lesions (CIN), invasive squamous carcinoma of the cervix of FIGO IA1-IIB stages, and morphologically normal epithelium. The derived transcriptomic profiles were bioinformatically analyzed and compared by patterns of signaling pathway activation, distribution of tumor-infiltrating cell populations, and genomic regions involved. Result: According to hierarchical cluster analysis of the whole-transcriptome profiles, tissue samples were distributed between three groups, or gene expression patterns (the one comprising most pre-cancer cases and the other two encompassing mostly early-stage invasive cancer cases). Differentially expressed genes were retrieved in each intergroup pairwise comparison followed by Gene Ontology analysis. Gene set enrichment analysis of the two groups of tumor samples in comparison with the CIN group identified substantial differences in immunological and angiogenic properties between tumorous groups suggesting the development of different molecular phenotypes. Cell composition analysis confirmed the diverse changes in the abundancies of immune and non-immune populations and, accordingly, different impacts of the immune and stromal compartments on the tumor microenvironment in these two groups of tumors compared to CIN. Positional gene expression analysis demonstrated that the identified transcriptomic differences were linked to different chromosomal regions and co-localized with particular gene families implicated in immune regulation, inflammation, cell differentiation, and tumor invasion. Conclusions: Overall, detection of different transcriptomic patterns of invasive cervical carcinoma at its earliest stages supports the diverse impacts of immune response- and angiogenesis-related mechanisms on the onset of tumor invasion and progression. This may provide new options for broadening the applicability and increasing the efficiency of target anti-angiogenic and immune-based therapy of virus-associated cervical carcinoma. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Pathophysiology is the property of Jinan University, School of Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: c-Met, a receptor tyrosine kinase, is involved in the growth, invasion and metastasis of a variety of cancers. In a set of cell lines from several solid tumors, a five-fold increase in c-Met expression after irradiation has been reported. This study aimed to assess if c-Met is likewise abundantly expressed in oral tongue squamous cell carcinoma (OTSCC) upon exposure to irradiation, followed by a Met-induced biological response. Materials and methods: Six OTSCC cell lines were exposed to gamma radiation doses of 2, 4, and 6 Gray. The changes in c-Met protein levels were assessed by western blot and flow cytometry. c-Met gene expression, cell migration, proliferation and cell cycle assays were performed as phenotypic readouts. Results: Irradiation resulted in upregulation of c.Met in all cell lines with different time kinetics. On average the cells displayed minimal c-Met expression on their surface ranging from 5 to 30% of total protein. Abrupt downregulation of c-Met surface expression occurred one hour after radiation but recovered 48 h post-radiation. Intracellularly, the highest level of expression was found on day 5 after radiation exposure. Irradiation induced aggressive invasive potential of the cells as determined in cell migration assays, particularly in cell lines with the highest c-Met expression. Conclusions: These results provide novel insights into both intracellular and extracellular dynamics of c-Met expression profiles upon irradiation of OTSCC cells in vitro. It might also suggest that radiation enhances cell migration, indicative of invasiveness, through c-Met up-regulation, at least for certain types of OTSCC cells. [ABSTRACT FROM AUTHOR]

A tumor invasion system, which is proposed in [2] as a modified tumor invasion system of Chaplain-Anderson type in [1], is considered in this paper. The system consists of three PDEs and one ODE. As a main characteristic, it is given that one of the PDEs has not only a quasi-variational structural degenerate diffusion but also a chemotaxis effect. Moreover, two kinds of quasi-variational structures are mixed in the diffusion. One is in the permeability of the tissue, which is regarded as a porous medium, and the other is in the constraint condition, which plays a role as double obstacles for the density of tumor cells. Actually, these quasi-variational structures depend on the density of extracellular matrix, which is also unknown in the system. The main purpose of this paper is to investigate the large-time behavior of a strong global-in-time solution to the tumor invasion system. In order to do this, it is a key point to find a suitable function space so that we can repeatedly apply the Ascoli-Arzelà compactness theorem for each component of the orbit associated with the strong global-in-time solution to the system under consideration. [ABSTRACT FROM AUTHOR]

Cancer is a disease with the highest mortality and morbidity rate worldwide. First-line drugs induce several side effects that drastically reduce the quality of life of people with this disease. Finding molecules to prevent it or generate less aggressiveness or no side effects is significant to counteract this problem. Therefore, this work searched for bioactive compounds of marine macroalgae as an alternative treatment. An 80% ethanol extract of dried Caulerpa sertularioides (CSE) was analyzed by HPLS-MS to identify the chemical components. CSE was utilized through a comparative 2D versus 3D culture model. Cisplatin (Cis) was used as a standard drug. The effects on cell viability, apoptosis, cell cycle, and tumor invasion were evaluated. The IC50 of CSE for the 2D model was 80.28 μg/mL versus 530 μg/mL for the 3D model after 24 h of treatment exposure. These results confirmed that the 3D model is more resistant to treatments and complex than the 2D model. CSE generated a loss of mitochondrial membrane potential, induced apoptosis by extrinsic and intrinsic pathways, upregulated caspases-3 and -7, and significantly decreased tumor invasion of a 3D SKLU-1 lung adenocarcinoma cell line. CSE generates biochemical and morphological changes in the plasma membrane and causes cell cycle arrest at the S and G2/M phases. These findings conclude that C. sertularioides is a potential candidate for alternative treatment against lung cancer. This work reinforced the use of complex models for drug screening and suggested using CSE's primary component, caulerpin, to determine its effect and mechanism of action on SKLU-1 in the future. A multi-approach with molecular and histological analysis and combination with first-line drugs must be included. [ABSTRACT FROM AUTHOR]

This commentary critiques the study "Route patterns of the collateral venous pathway in patients with tumors invading the superior sagittal sinus" by Pawit Jirawisan et al., highlighting its limitations in discussing parafalcine venous collaterals, reliance on invasive imaging modalities, and lack of structured assessments. It suggests improvements by incorporating alternative imaging techniques, acknowledging crucial venous structures, and providing grading systems for surgical decision-making. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the feasibility and accuracy of near-infrared fluorescence (NIRF) imaging for detecting the extent of tumor invasion in cervical cancer using indocyanine green (ICG). Methods: We enrolled 51 patients who were diagnosed with cervical cancer with FIGO stage IB1-IIA2 disease. Patients were administered indocyanine green (ICG) at a dose of 5 mg/kg 24 h prior to surgery. A customized near-infrared fluorescence (NIRF) imaging system was used to identify the extent of tumor invasion when radical hysterectomy specimens were harvested. The relationship between tumor fluorescence intensity and clinicopathological characteristics was analyzed. Results: Of the 51 enrolled patients, 3 patients did not have residual tumors after cervical conization, and tumor lesions were identified by NIRF imaging in all the remaining 48 patients. The results of NIRF imaging were in agreement with the postoperative pathological findings in 95.8% of the patients with stromal invasion, 100% of those with surgical margin invasion, 100% of those with parametrial tumor involvement, and 100% of patients with uterine corpus invasion. The mean signal-to-background ratio (SBR) of the cervical tumors was 2.91 ± 1.64, and the SBR was independent of clinicopathological characteristics. Fluorescence microscopy confirmed that ICG fluorescence was present in the tumor nests. Conclusions: NIRF imaging enables objective, accurate, and safe identification of tumor invasion during cervical cancer surgery. Clinical trial registration: ClinicalTrials.gov NCT04224467. [ABSTRACT FROM AUTHOR]

Background: Autophagy is a stress response mechanism that causes cellular components to degrade. Its defects were associated with multiple pathologies, including cancers. Thyroid cancer is known to be the most prevalent form of malignant neoplasm among endocrine tumors. The aim of the study was to seek and comprehensively explore the role of autophagy related genes and proteins play in thyroid cancers through bioinformatics analysis with their detection in the tissue samples. Methods: Bioinformatics analysis was performed to investigate autophagy related proteins and genes involvement in thyroid cancer progression. The experimental verification was done in cancer samples of one hundred and three patients with thyroid pathology included in the study. The miR-125blevel was detected by PCR in real time. Results and discussion: The bioinformatics analysis verified the miR-125b as a regulatory mechanism in autophagy. Its expression in patients with PTC was reduced by 6.75 times in cancer patients compared to the patients with benign tumors. The BRAFV600E mutations were associated with a decrease in hsa-miR-125b expression by 12.67 times compared to tumors with the wild-type gene. Conclusions: Our findings revealed involvement of the autophagy related proteins in cancer progression. The significant mechanisms of regulation are non-coding RNA sequences implicated in a variety of oncogenic processes. We found that miR-125b is a potential maker in thyroid cancer invasion, BRAV600E mutational status and risk of recurrence. [ABSTRACT FROM AUTHOR]

The invasion of glioblastoma usually results in the recurrence and poor prognosis in patients with glioma. However, the underlying mechanisms involved in glioma invasion remains undefined. In this study, immunohistochemistry analyses of glioma specimens demonstrated that high expression of Par6 was positively correlated with malignancy and poor prognosis of patients with glioma. Par6-overexpressing glioma cells showed much more fibroblast-like morphology, suggesting that regulation of Par6 expression might be associated with tumor invasion in glioma cells. Further study indicated that Par6 overexpression subsequently increased CD44 and N-cadherin expression to enhance glioma invasion through activating MEK/ERK/STAT3 pathway, in vivo and in vitro. Moreover, we found that LIN28/let-7d axis was involved in this process via a positive feedback loop, suggesting that MEK/ERK/LIN28/let-7d/STAT3 cascade might be essential for Par6-mediated glioma invasion. Therefore, these data highlight the roles of Par6 in glioma invasion, and Par6 may serve as a potential therapeutic target for patients with glioma. [ABSTRACT FROM AUTHOR]

Introduction: Abnormal expression of integrin subunit beta 3 (ITGβ3), a geneencoding protein, is related to the occurrence and development of cancers; however, the biological role of ITGb3 in colon adenocarcinoma (COAD) remains unclear. Methods: We used the Cancer Genome Atlas database to obtain the clinical data of patients with COAD, analyzed the mRNA gene clusters related to ITGβ3, and analyzed the interaction signal pathway and interaction protein network of the differentially expressed gene clusters. The results showed that ITGβ3 expression in COAD tumor tissues was significantly downregulated compared with that in paracancerous tissues. Low ITGβ3 expression in tumor tissues is associated with poor overall survival of patients with COAD. In multivariate analysis, stage IV and ITGβ3 low expression were independent prognostic factors. Gene Ontology analysis showed that differentially expressed genes (DEGs) were significantly enriched in leukocyte migration, cell adhesion, and extracellular matrix (ECM) organization. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the DEGs were mainly enriched in ECM-receptor interactions, focal adhesion, and the PI3K-Akt signaling pathway. Protein-protein interaction network analysis revealed the hub and seed genes of the key modules related to ITGβ3. Finally, we analyzed the correlation between TGβ3 and immune-related genes and found that ITGβ3 expression was significantly correlated with tumor purity and infiltration level of dominant immune cells. Discussion: These findings indicate that ITGβ3 downregulation in COAD may profoundly affect genome stability and multiple steps of the cell cycle, alter the tumor immune microenvironment, and be related to the prognosis of patients with COAD. [ABSTRACT FROM AUTHOR]

Pipeline formation between tumor cells and the tumor microenvironment (TME) is a key event leading to tumor progression. These pipelines include blood vessels, lymphatics, and membranous vessels (the former two can be collectively referred to as vasculature). Pipeline regeneration is a feature of all solid tumors; it delivers nutrients to tumors and promotes tumor invasion and metastasis such that cancer cells grow rapidly, escape unfavorable TME, spread to secondary sites, generate tumor drug resistance, and promote postoperative tumor recurrence. Novel tumor therapy strategies must exploit the molecular mechanisms underpinning these pipelines to facilitate more targeted drug therapies. In this review, pipeline generation, influencing factors, pipeline functions during tumor progression, and pipeline potential as drug targets are systematically summarized. [ABSTRACT FROM AUTHOR]

Distant metastasis remains the primary cause of treatment failure and suggests a poor prognosis in nasopharyngeal carcinoma (NPC). Epithelial-mesenchymal transition (EMT) is a critical cellular process for initiating a tumor invasion and remote metastasis. Our previous study showed that the blockage of the stromal interaction molecule 1 (STIM1)-mediated Ca2+ signaling blunts the Epstein–Barr virus (EBV)-promoted cell migration and inhibits the dissemination and lymphatic metastasis of NPC cells. However, the upstream signaling pathway that regulates the STIM1 expression remains unknown. In this follow-up study, we demonstrated that the miRNA-185-5p/STIM1 axis is implicated in the regulation of the metastatic potential of 5–8F cells, a highly invasive NPC cell line. We demonstrate that the knockdown of STIM1 attenuates the migration ability of 5–8F cells by inhibiting the epidermal growth factor receptor (EGFR) phosphorylation-induced switch from E- to N-cadherin in vitro. In addition, the STIM1 knockdown inhibited the locoregional lymphatic invasion of the 5–8F cells in mice. Furthermore, we identified miRNA-185-5p as an upstream regulator that negatively regulates the expression of STIM1. Our findings suggest that the miRNA-185-5p/STIM1 axis regulates the invasiveness of NPC cell lines by affecting the EGFR activation-modulated cell adhesiveness. The miRNA-185-5p/STIM1 axis may serve as a potentially effective therapeutic target for the treatment of NPC. [ABSTRACT FROM AUTHOR]

The popular dietary supplements of Ginkgo biloba (Ginkgo) products have been reported to have anti-cancer activities in multiple cellular and animal studies, with the benefits yet to be proven with clinical trials. The mechanisms of action are not clear, forming a barrier to investigation in Gingko-specific benefits to cancer patients, especially when combined with other therapies. Here we reported on the discovery of a novel mechanism by which a Ginkgo golden leaf extract (GGLE) inhibited melanoma cell invasion and angiogenesis. GGLE did not inhibit melanoma cells via direct cytotoxicity. Instead, GGLE significantly inhibited total RNase activities in melanoma cells under both normoxia and hypoxia conditions. The RNase angiogenin was induced twofolds by hypoxia, and the induction was significantly suppressed by GGLE treatment in a dose dependent manner. As a result of angiogenin inhibition, GGLE inhibited melanoma cell migration and invasion in a dose dependent manner. Conditioned media from melanoma cell culture sufficiently induced in vitro angiogenesis in human endothelial cells, whereas the conditioned media of GGLE-treated melanoma cells significantly inhibited this angiogenetic activity. This was accompanied with markedly reduced angiogenin concentrations in the GGLE-treated melanoma cell conditioned media. We concluded that, instead of direct cytotoxicity, GGLE inhibited angiogenin synthesis and secretion by melanoma cells, resulting in inhibition of tumor cell invasion and tumor-induced angiogenesis. This new mechanism opens the door for investigation in GGLE influencing tumor microenvironment, and warrants further investigation and validation in vivo. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the oral and maxillofacial regions, with a high rate of metastasis. Cancerassociated fibroblasts (CAFs) play critical roles in tumor growth, metastasis and invasion, making them attractive therapeutic targets for cancer treatment. As an old anti-coccidiosis drug for poultry, Halofuginone (HF) has also been reported to possess anti-fibrosis and anti-cancer activities in the recent decades. However, whether it works by targeting CAFs in OSCC, and the mechanisms involved remain unclear. In the present study, we observed HF dose-dependently inhibits OSCC-derived CAF viability and proliferation. Meanwhile, HF decreased the expressions of α-SMA, FSP-1 and PDGFRβ, markers of the malignant phenotype of CAFs, both at mRNA and protein levels. Furthermore, functional studies demonstrated that HF dramatically attenuates the promotion effect of CAFs on OSCC cell migration and invasion. Mechanistically, the inhibition of MMP2 secretion and the upstream TGF-ß/Smad2/3 signaling pathway played an important role in these processes. In the orthotopic transplanted tongue carcinoma in mice model, we confirmed that HF administration inhibited tumor growth and lymph node metastasis (LNM) with reduced CAF population, MMP2 expression and collagen deposition in tumor. Altogether, these results indicate that HF can inhibit the migration and invasion of OSCC by targeting CAFs, which will provide new ideas for the treatment of OSCC. [ABSTRACT FROM AUTHOR]

High mobility group nucleosome binding (HMGN) protein is a non-histone protein that affects the chromatin function, leading to the regulation of gene expression. Several studies reported the aberrant expression of HMGN1-HMGN5 in variety of cancers. This study aimed to investigate a potential HMGN protein and its clinical impact in cholangiocarcinoma (CCA). Analysis of gene expression profiles of HMGNs in liver cancers from public database demonstrated the alteration of HMGN1-HMGN5 in CCA and hepatocellular carcinoma (HCC) tissues. HMGN3 was the only member that overexpressed in CCA, but not HCC, and hence was selected for further study. The immunohistochemistry of HMGN3 revealed that HMGN3 was weakly detected in normal bile ducts and hepatocytes but was gradually expressed in hyperproliferative bile ducts and CCA tissues, indicating the involvement of HMGN3 in development and progression of CCA. CCA exhibited significantly higher expression of HMGN3 than HCC, suggesting HMGN3 as a diagnostic marker distinguishing CCA from HCC. Univariate analysis revealed the association of high HMGN3 expression and tumor invasion of CCA patients. The expression of transforming growth factor β (TGF-β), a major inflammatory cytokine related to liver fluke-related CCA, was positively correlated with the expression of HMGN3 in CCA tissues. Treating CCA cell lines with recombinant TGF-β1 significantly induced the mRNA expression of HMGN3 but not the cholangiocytes. This finding signifies the positive correlation of TGF-β1 and HMGN3 observed in CCA tissues and the influence of TGF-β1 on HMGN3 expression. Further mechanistic studies are necessary to validate these findings. [ABSTRACT FROM AUTHOR]

Human dermis can be morphologically divided into the upper papillary and lower reticular dermis. Previously, we demonstrated that papillary (PFs) and reticular (RFs) fibroblasts show distinct morphology and gene expression profiles. Moreover, they differently affect tumor invasion and epithelial-to-mesenchymal transition (EMT) in in vitro 3D-organotypic cultures of cutaneous squamous cell carcinoma (cSCC). In this study, we examined if these distinct effects of PFs and RFs can be extrapolated in other epithelial/non-epithelial tumors such as melanoma and head and neck squamous cell carcinoma (HNSCC). To this end, 3D-Full-Thickness Models (FTMs) were established from melanoma (AN and M14) or HNSCC cell lines (UM-SCC19 and UM-SCC47) together with either PFs or RFs in the dermis. The interplay between tumor cells and different fibroblasts was investigated. We observed that all the tested tumor cell lines showed significantly stronger invasion in RF-FTMs compared to PF-FTMs. In addition, RF-FTMs demonstrated more tumor cell proliferation, EMT induction and basement membrane disruption. Interestingly, RFs started to express the cancer-associated fibroblast (CAF) biomarker α-SMA, indicating reciprocal interactions eventuating in the transition of RFs to CAFs. Collectively, in the melanoma and HNSCC FTMs, interaction of RFs with tumor cells promoted EMT and invasion, which was accompanied by differentiation of RFs to CAFs. [ABSTRACT FROM AUTHOR]

Breast adipose tissue (AT) participates in the physiological evolution and remodeling of the mammary gland due to its high plasticity. It is also a favorable microenvironment for breast cancer progression. However, information on the properties of human breast adipose progenitor cells (APCs) involved in breast physiology or pathology is scant. We performed differential enzymatic dissociation of human breast AT lobules. We isolated and characterized two populations of APCs. Here we report that these distinct breast APC populations selectively expressed markers suitable for characterization. The population preferentially expressing ALPL (MSCA1) showed higher adipogenic potential. The population expressing higher levels of INHBA and CD142 acquired myofibroblast characteristics upon TGF-β treatment and a myo-cancer-associated fibroblast profile in the presence of breast cancer cells. This population expressed the immune checkpoint CD274 (PD-L1) and facilitated the expansion of breast cancer mammospheres compared with the adipogenic population. Indeed, the breast, as with other fat depots, contains distinct types of APCs with differences in their ability to specialize. This indicates that they were differentially involved in breast remodeling. Their interactions with breast cancer cells revealed differences in the potential for tumor dissemination and estrogen receptor expression, and these differences might be relevant to improve therapies targeting the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Purpose: This case report describes the MRI appearance and significance of the myloglossus muscle, a variant extrinsic tongue muscle. Methods: The myloglossus muscle was incidentally discovered on imaging performed for head and neck cancer evaluation. Results: The myloglossus is best visualized on non-fat saturated T2 MRI and has signal characteristics that match those of muscle. It originates at the angle of the mandible and inserts into the tongue between the styloglossus and hyoglossus. Conclusion: Accurate identification and delineation of the extrinsic muscles of the tongue, including the myloglossus, is essential for proper staging and treatment of head and neck cancers. This case report attempts to fill a void in depicting the MRI appearance of myloglossus muscle. [ABSTRACT FROM AUTHOR]

The aim of this study was to perform a systematic review to assess the sensitivity, specificity, and accuracy of magnetic resonance imaging (MRI), computed tomography (CT), and intraoral ultrasound (US) to determine the depth of invasion (DOI) and/or tumor thickness (TT) in oral cavity cancers, with histopathological evaluation as the gold standard. Articles whose primary objective was to evaluate the accuracy (sensitivity and specificity) of MRI, CT, and US imaging to assess DOI and/or TT were searched in six major electronic databases, in addition to three grey literature databases. The methodological quality of the selected studies was evaluated by using the Quality Assessment Tool for Diagnostic Accuracy Studies-2. Twelve studies met the inclusion criteria and underwent qualitative analysis: six studies on MRI, three on US, and one on CT. The accuracy values for MRI ranged from 67 to 83%, with sensitivity values above 80% and specificity above 75%. For US, mean values of sensitivity ranged from 91 to 93%. For CT, accuracy was 75%. For the application of US, CT, MRI, good accuracy was reported in DOI and/or TT, as evaluated in the preoperative period. US offered advantages for detection of small lesions. [ABSTRACT FROM AUTHOR]

This paper deals with a nonlinear system (S) composed of three PDEs and one ODE below: (S) u t = ∇ ⋅ (d u (α (v) , w) ∇ β (w ; u)) − ∇ ⋅ (u ∇ λ (v)) , v t = d v Δ v + a w z , w t = − a w z , z t = d z Δ z − b z + c u. The system (S) was proposed as one of the mathematical models which describe tumor invasion phenomena with chemotaxis effects. The most important and interesting point is that the diffusion coefficient of tumor cells, denoted by d u , is influenced by both nonlocal effect of a chemical attractive substance, denoted by α (v) , and the local one of extracellular matrix, denoted by w. From this point, the first PDE in (S) contains a nonlinear cross diffusion. Actually, this mathematical setting gives an inner product of a suitable real Hilbert space, which governs the dynamics of the density of tumor cells u , a quasi-variational structure. Hence, the first purpose in this paper is to make it clear what this real Hilbert space is. After this, we show the existence of strong time local solutions to the initial-boundary problems associated with (S) when the space dimension is N = 1 , 2 , 3 by applying the general theory of evolution inclusions on real Hilbert spaces with quasi-variational structures. Moreover, for the case N = 1 we succeed in constructing a strong time global solution. [ABSTRACT FROM AUTHOR]

The success of anticancer therapies is often limited by heterogeneity within and between tumors. While much attention has been devoted to understanding the intrinsic molecular diversity of tumor cells, the surrounding tissue microenvironment is also highly complex and coevolves with tumor cells to drive clinical outcomes. Here, we propose that diverse types of solid tumors share common physical motifs that change in time and space, serving as universal regulators of malignancy. We use breast cancer and glioblastoma as instructive examples and highlight how invasion in both diseases is driven by the appropriation of structural guidance cues, contact-dependent heterotypic interactions with stromal cells, and elevated interstitial fluid pressure and flow. We discuss how engineering strategies show increasing value for measuring and modeling these physical propertiesfor mechanistic studies. Moreover, engineered systems offer great promise for developing and testing novel therapies that improve patient prognosis by normalizing the physical tumor microenvironment. [ABSTRACT FROM AUTHOR]

This paper is devoted to the study of a time-discrete scheme and its corresponding fully discretization approximating a d-dimensional chemotaxis model describing tumor invasion, d ≤ 3. This model describes the chemotactic attraction experienced by the tumor cells and induced by a so-called active extracellular matrix, which is a chemical signal produced by a biological reaction between the extracellular matrix and a matrix-degrading enzyme. In order to construct the numerical approximations and to control the chemo-attraction term in the tumor cells equation, we introduce an equivalent model with a new variable given by the gradient of the active extracellular matrix and use an inductive strategy. Then, we consider a first-order and non-linear time-discrete scheme which is mass-conservative and possesses the property of positivity for all the biological variables. After, we study the corresponding fully discrete finite element with “mass-lumping” approximation proving well-posedness, mass-conservation and the non-negativity of the extracellular matrix, the degrading enzyme, and the active extracellular matrix. In addition, we obtain uniform strong estimates required in the convergence analysis, and we prove optimal error estimates and convergence towards regular solutions. Finally, we provide some numerical results in agreement with our theoretical analysis with respect to the positivity and the error estimates. [ABSTRACT FROM AUTHOR]

Simple Summary: Laryngeal Squamous Cell Carcinoma (LSCC) is a squamous cancer with 2.4% new diagnoses each year, accounting for 25% of head and neck cancers, and has a high mortality rate. A deeper understanding of key mechanisms and knowledge of the putative target molecules of theranostic relevance are required. The receptor for neurotrophins p75NTR has been shown to be highly expressed in cancer stem cells (CSCs) of squamous epithelia, in LSCC as well as in other cancers. However, whether its cleavage product p75ICD expression, known to finely regulate the survival/death balance in neurons, is also a master regulator in cancer and LSCC in particular has not been directly addressed so far. To resolve this question, we performed a preliminary study using a limited number of LSCC specimens and studied p75ICD presence and expression pattern in LSCC specimens, showing that p75ICD may be a promising target in LSCC, requiring further investigation. We investigated the p75 Neurotrophin Receptor (p75NTR) expression and cleavage product p75NTR Intracellular Domain (p75ICD) as potential oncogenic and metastatic markers in human Laryngeal Squamous Cell Carcinoma (LSCC). p75NTR is highly expressed in Cancer Stem Cells (CSCs) of the laryngeal epithelia and it has been proposed as a marker for stemness, cell migration, and chemo-resistance in different squamous carcinomas. To investigate the clinical significance of p75NTR cleavage products in solid tumors, full-length and cleaved p75NTR expression was analyzed in laryngeal primary tumors from different-stage LSCC patients, diagnosed at the Policlinico Umberto I Hospital. Molecular and histological techniques were used to detect the expressions of p75NTR and p75ICD, and ATP Binding Cassette Subfamily G Member 2 (ABCG2), a CSC marker. We found regulated p75NTR cleavage during squamous epithelial tumor progression and tissue invasion. Our preliminary investigation suggests p75ICD expression and localization as possible features of tumorigenesis and metastaticity. Its co-localization with ABCG2 in squamous cells in the parenchyma invaded by the tumor formation allows us to hypothesize p75NTR and p75ICD roles in tumor invasion and CSC spreading in LSCC patients. These data might represent a starting point for a comprehensive analysis of p75NTR cleavage and of its clinical relevance as a potential molecular LSCC signature, possibly helping diagnosis, and improving prognosis and personalized therapy. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is one of the most aggressive cancers, with dismal prognosis despite continuous efforts to improve treatment. Poor prognosis is mostly due to the invasive nature of GBM. Thus, most research has focused on studying the molecular players involved in GBM cell migration and invasion of the surrounding parenchyma, trying to identify effective therapeutic targets against this lethal cancer. Our laboratory discovered the implication of TENM1, also known as ODZ1, in GBM cell migration in vitro and in tumor invasion using different in vivo models. Moreover, we investigated the microenvironmental stimuli that promote the expression of TENM1 in GBM cells and found that macrophage-secreted IL-6 and the extracellular matrix component fibronectin upregulated TENM1 through activation of Stat3. We also described that hypoxia, a common feature of GBM tumors, was able to induce TENM1 by both an epigenetic mechanism and a HIF2α-mediated transcriptional pathway. The fact that TENM1 is a convergence point for various cancer-related signaling pathways might give us a new therapeutic opportunity for GBM treatment. Here, we briefly review the findings described so far about the mechanisms that control the expression of the GBM invasion factor TENM1. [ABSTRACT FROM AUTHOR]

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Introduction: Glioblastoma (GBM) is the most aggressive central nervous system (CNS) tumor with astrocytic differentiation. The growth pattern of GBM mimics that of the precursor cell migration during the fetal development of the brain. Diaphanous homolog (Diaph3) has been established to play a role in both CNS maturation and cancer progression as it is required both for cell migration and division. Furthermore, Diaph3 has been shown to play a role in malignant disease progression through hyperactivation of the EGFR/MEK/ERK in loss of expression and its overexpression correlating to hyperactivity of the mTOR pathway, both of which are with a well-established role in GBM. Herein, we aimed at establishing the diagnostic role of Diaph3 immunohistochemistry expression patterns in GBM and their possible implications for molecular response to different therapies. Materials and methods: The study utilized a retrospective nonclinical approach. Results of Diaph3 immunohistochemical expression were compared to healthy controls and reactive gliosis and statistically analyzed for correlation with neuroradiological tumor parameters and patient survival. Results: Healthy controls showed individual weakly positive cells, while reactive gliosis controls showed a strong expression in astrocytic projections. GBM samples showed a heterogeneous positive reaction to Diaph3, mean number of positive cells 62.66%, median 61.5, range 12–96%. Areas of migrating cells showed a strong diffuse cytoplasmic reaction. Cells located in the tumor core and those in areas of submeningeal aggregation had no antibody expression. Statistical analysis revealed no correlation with tumor size or patient survival. Conclusion: The different expression pattern of Diaph3 in healthy controls, reactive gliosis and GBM shows promise as a clinical differentiating marker. Despite Diaph3 expression not correlating with survival and tumor size in GBM, there is an accumulating body of evidence that Diaph3 correlates with mTOR activity and can thus be used as a predictor for response to rapamycin and taxanes, clinical studies of which have shown promising, if mixed results in GBM. [ABSTRACT FROM AUTHOR]

Strong association of cancer incidence and its progression with mortality highlights the need to decipher the cellular and molecular mechanisms that drive tumor cells to rapidly progress to metastatic disease and therapy resistance. Epithelial-mesenchymal plasticity (EMP) emerged as a key regulator of metastatic outgrowth. It allows neoplastic epithelial cells to delaminate from their neighbors either individually or collectively, traverse the extracellular matrix (ECM) barrier, enter into the circulation, and establish distal metastases. Plasticity between epithelial and mesenchymal states and the existence of hybrid epithelial/mesenchymal (E/M) phenotypes are increasingly being reported in different tumor contexts. Small subset of cancer cells with stemness called cancer stem cells (CSCs) exhibit plasticity, possess high tumorigenic potential, and contribute to high degree of tumoral heterogeneity. EMP characterized by the presence of dynamic intermediate states is reported to be influenced by (epi)genomic reprograming, growth factor signaling, inflammation, and low oxygen generated by tumor stromal microenvironment. EMP alters the genotypic and phenotypic characteristics of tumor cells/CSCs, disrupts tissue homeostasis, induces the reprogramming of angiogenic and immune recognition functions, and renders tumor cells to survive hostile microenvironments and resist therapy. The present review summarizes the roles of EMP in tumor invasion and metastasis and provides an update on therapeutic strategies to target the metastatic and refractory cancers. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Modern Laboratory Medicine is the property of Journal of Modern Laboratory Medicine Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The BRAF inhibitor vemurafenib, approved for treating patients with BRAF V600E-mutant and unresectable or metastatic melanomas, rapidly induces cutaneous adverse events, including hyperkeratotic skin lesions and cutaneous squamous cell carcinomas (cSCC). To determine, how vemurafenib would provoke these adverse events, we utilized long-term in vitro skin equivalents (SEs) comprising epidermal keratinocytes and dermal fibroblasts in their physiological environment. We inserted keratinocytes with different genetic background [normal keratinocytes: NHEK, HaCaT (p53/mut), and HrasA5 (p53/mut+Hras/mut)] to analyze effects depending on the stage of carcinogenesis. We now show that vemurafenib activates MEK-ERK signaling in both, keratinocytes, and fibroblasts in vitro and in the in vivo -like SEs. As a consequence, vemurafenib does not provide a growth advantage but leads to a differentiation phenotype, causing accelerated differentiation and hyperkeratosis in the NHEK and normalized stratification and cornification in the transformed keratinocytes. Although all keratinocytes responded very similarly to vemurafenib in their expression profile, particularly with a significant induction of MMP1 and MMP3, only the HrasA5 cells revealed a vemurafenib-dependent pathophysiological shift to tumor progression, i.e., the initiation of invasive growth. This was shown by increased proteolytic activity allowing for penetration of the basement membrane and invasion into the disrupted underlying matrix. Blocking MMP activity, by the addition of ilomastat, prevented invasion with all corresponding degradative activities, thus substantiating that the RAS-RAF-MEK-ERK/MMP axis is the most important molecular basis for the rapid switch towards tumorigenic conversion of the HrasA5 keratinocytes upon vemurafenib treatment. Finally, cotreatment with vemurafenib and the MEK inhibitor cobimetinib prevented MEK-ERK hyperactivation and with that abolished both, the epidermal differentiation and the tumor invasion phenotype. This suggests that both cutaneous adverse events are under direct control of vemurafenib-dependent MEK-ERK hyperactivation and confirms the dependence on preexisting genetic alterations of the skin keratinocytes that determine the basis towards induction of tumorigenic progression. [ABSTRACT FROM AUTHOR]

Background: Kidney-tonifying herbs (KTHs) are widely used to treat unexplained recurrent spontaneous abortion (URSA) based on the theory of traditional Chinese medicine (TCM). However, there is still a lack of systematic evaluation and mechanistic explanation for these treatments. Objective: The purpose of this study was to assess the clinical efficacy, and to investigate the potential mechanisms, of KTH based on TCM for the treatment of URSA. Methods: A systematic literature search was conducted within PubMed, Embase, China Biomedical Literature database, Web of Science (WOS), China National Knowledge Infrastructure (CNKI) database, and the Wanfang database to find articles reporting on the Chinese herbal formula based around KTH for treating URSA, which were published between January 2010 and June 2021. A full bibliometric analysis was carried out; in addition, randomized controlled trial (RCT) articles were selected for systematic evaluation and meta-analysis. The drugs with the highest frequency of KTHs were screened for meta-analysis. Finally, network analysis and molecular docking were used to study the key components and potential pathway of KTHs in the treatment of URSA. Results: The meta-analysis included nine RCTs involving 1,054 subjects. Compared with the control groups, the clinical efficacy of TCM-based KTHs in the treatment of URSA patients significantly improved outcomes. Additionally, a component target pathway network was identified, which included 32 potential blood activating components and 113 main targets. Japonine, sopranol, lysine, and matrine were considered the most important bioactive molecules for KTHs. The key potential therapeutic pathway for URSA was a tumor-related signaling pathway. The target genes for URSA regulated by KTHs were highly similar to tumor biological processes such as the regulation of apoptotic signaling pathways, inflammatory responses, angiogenesis, and epithelial metabolic transition. Conclusion: KTH has great potential for treating URSA. Because the maintenance of pregnancy has a high similarity with tumor invasion, the research relating to tumor mechanisms should also be followed up as it may lead to new ideas and breakthroughs for research into URSA. At the same time, embryonic and decidual cells share a high degree of cellular heterogeneity and spatial structural complexity with tumor cells, and a single cell combined with spatial omics may be the best future approach for validating KTH mechanisms. [ABSTRACT FROM AUTHOR]

Copyright of Practical Oncology Journal is the property of Journal of Practical Oncology Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Osteosarcoma (OS) is a common, highly malignant bone tumor. Tripartite motif-containing protein 59 (TRIM59) has been identified as a potential oncogenic protein involved in the initiation and progression of various human carcinomas. Nonetheless, the possible roles and molecular mechanisms of action of TRIM59 in OS remain unclear. In this study, we found that TRIM59 expression levels were frequently upregulated in OS tissues and cell lines. TRIM59 knockdown significantly suppressed the proliferation, migration, and invasion of OS cells and promoted OS cell apoptosis, whereas TRIM59 overexpression had the opposite effects. In vivo experiments demonstrated that TRIM59 knockdown suppressed OS tumor growth and metastasis in vivo. Furthermore, we found that TRIM59 directly interacted with phospho-STAT3 in OS cells. The downregulation of STAT3 levels attenuated TRIM59-induced cell proliferation and invasion. Taken together, our results indicate that TRIM59 promoted OS progression via STAT3 activation. Therefore, our study may provide a novel therapeutic target for OS. [ABSTRACT FROM AUTHOR]

Bladder cancer represents a highly heterogeneous disease characterized by distinct histological, molecular and clinical phenotypes, and a detailed analysis of tumor cell invasion and crosstalks within bladder tumor cells has not been determined. Here, we applied droplet‐based single‐cell RNA sequencing (scRNA‐seq) to acquire transcriptional profiles of 36 619 single cells isolated from seven patients. Single cell transcriptional profiles matched well with the pathological basal/luminal subtypes. Notably, in T1 tumors diagnosed as luminal subtype, basal cells displayed characteristics of epithelial‐mesenchymal transition (EMT) and mainly located at the tumor‐stromal interface as well as micrometastases in the lamina propria. In one T3 tumor, muscle‐invasive tumor showed significantly higher expression of cancer stem cell markers SOX9 and SOX2 than the primary tumor. We additionally analyzed communications between tumor cells and demonstrated its relevance to basal/luminal phenotypes. Overall, our single‐cell study provides a deeper insight into the tumor cell heterogeneity associated with bladder cancer progression. What's new? Extensive heterogeneity in bladder cancer has inspired novel approaches to the investigation of underlying mechanisms, including genomic and phenotypic single‐cell analyses. In this single‐cell characterization of tumor cell heterogeneity in bladder cancer, basal‐like tumor cells were found to possess epithelial‐to‐mesenchymal transition (EMT) features, including enrichment of EMT‐associated genes. Basal‐like cells further exhibited a potential to generate luminal daughter cells, making them possible precursors for local invasion. In addition, aggressive cells with upregulation of stemness‐related genes were observed in a muscle‐invasive T3‐stage tumor. The findings suggest that invasive cell subsets within bladder cancers may serve a significant role in disease progression. [ABSTRACT FROM AUTHOR]

Tumorigenesis involves metabolic reprogramming and abnormal lipid metabolism, which is manifested by increased endogenous fat mobilization, hypertriglyceridemia, and increased fatty acid synthesis. Fatty acid synthase (FASN) is a key enzyme for the de novo synthesis of fatty acids, and monoacylglycerol esterase (MGLL) is an important metabolic enzyme that converts triglycerides into free fatty acids. Both enzymes play an important role in lipid metabolism and are associated with tumor-related signaling pathways, the most common of which is the PI3K-AKT signaling pathway. They can also regulate the immune microenvironment, participate in epithelial-mesenchymal transition, and then regulate tumor invasion and metastasis. Current literature have shown that these two genes are abnormally expressed in many types of tumors and are highly correlated with tumor migration and invasion. This article introduces the structures and functions of FASN and MGLL, their relationship with abnormal lipid metabolism, and the mechanism of the regulation of tumor invasion and metastasis and reviews the research progress of the relationship of FASN and MGLL with tumor invasion and metastasis. [ABSTRACT FROM AUTHOR]

Tumor growth and progression are complex processes mediated by mutual interactions between cancer cells and their surrounding stroma that include diverse cell types and acellular components, which form the tumor microenvironment. In this environment, direct intercellular communications play important roles in the regulation of the biological behaviors of tumors. However, the underlying molecular mechanisms are insufficiently defined. We used an in vitro coculture system to identify genes that were specifically expressed at higher levels in cancer cells associated with stromal cells. Major examples included epithelial membrane protein 1 (EMP1) and stomatin, which positively and negatively regulate tumor progression, respectively. EMP1 promotes tumor cell migration and metastasis via activation of the small GTPase Rac1, while stomatin strongly suppresses cell proliferation and induces apoptosis of cancer cells via inhibition of Akt signaling. Here we highlight important aspects of EMP1, stomatin, and their family members in cancer biology. Furthermore, we consider the molecules that participate in intercellular communications and signaling transduction between cancer cells and stromal cells, which may affect the phenotypes of cancer cells in the tumor microenvironment. [ABSTRACT FROM AUTHOR]