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Phototherapy can cause autophagy while killing tumour cells, leading to tumour recurrence and metastasis. Here, we constructed a laser and enzyme dual responsive nanodrug delivery system Tf-Te@CTSL-HCQ (TT@CH) to precisely regulate autophagy in synergy with phototherapy to inhibit the proliferation and metastasis of melanoma. Firstly, transferrin (Tf) was used as a nanoreactor to synthesise phototherapy agent Tf-Te by the biological template mineralisation method. Then, the thermosensitive liposome modified with FAP-α-responsive peptide (CAP) was used as a carrier to encapsulate autophagy inhibitor hydroxychloroquine (HCQ) and Tf-Te, to obtain an intelligent TT@CH delivery system. Once arriving at the tumour site, TT@CH can be cleaved by FAP-α overexpressed on cancer-associated fibroblasts (CAFs), and release Tf-Te and HCQ. Then Tf-Te can target melanoma cells and exert PTT/PDT anti-tumour effect. What's more, hyperpyrexia induced by PTT can further promote drugs release from TT@CH. Meanwhile, HCQ simultaneously inhibited autophagy of CAFs and melanoma cells, and down-regulated IL-6 and HMGB1 secretion, thus effectively inhibiting melanoma metastasis. Pharmacodynamic results exhibited the best anti-tumour effect of TT@CH with the highest tumour inhibition rate of 91.3%. Meanwhile, lung metastatic nodules of TT@CH treated mice reduced by 124.33 compared with that of mice in control group. Overall, TT@CH provided an effective therapy strategy for melanoma. [ABSTRACT FROM AUTHOR]

As the predominant stromal cells in the ccRCC surrounding environment, cancer-associated fibroblasts (CAFs) have been established as supportive of tumor growth. However, the detailed molecular mechanisms underlying the supporting role of CAFs in ccRCC have not been well characterized. Evidence from the clustering consensus analysis, single-cell analysis, and the experimental results illustrate that CAF-derived FGF7 plays a crucial role as a signaling mediator between CAFs and ccRCC tumor cells. Mechanistically, CAF-derived FGF7 triggers AKT activation to promote cell growth and cell invasion of ccRCC tumor cells. As a response, ccRCC tumor cells stimulate STAT3-mediated transcriptional regulation, directly increasing FGF7 expression at the chromatin level in CAFs. Moreover, there exists a positive clinical correlation between the abundance of CAFs, FGF7 expression, and the infiltration of M2 type macrophages. The RENCA in vivo mouse model also confirmed that FGF7 depletion could impede RCC development by reducing the recruitment of M2 type macrophages. Overall, this study delineates a key signaling axis governing the crosstalk between CAFs and ccRCC tumor cells, highlighting FGF7 as a promising therapeutic target of ccRCC. [ABSTRACT FROM AUTHOR]

Malignant tumors are a category of diseases that possess invasive and metastatic capabilities, with global incidence and mortality rates remaining high. In recent years, the pivotal role of fibrosis in tumor progression, drug resistance, and immune evasion has increasingly been acknowledged. Fibrosis enhances the proliferation, migration, and invasion of tumor cells by modifying the composition and structure of the extracellular matrix, thereby offering protection for immune evasion by tumor cells. The activation of cancer-associated fibroblasts (CAFs) plays a significant role in this process, as they further exacerbate the malignant traits of tumors by secreting a variety of cytokines and growth factors. Anti-fibrotic tumor treatment strategies, including the use of anti-fibrotic drugs and inhibition of fibrosis-related signaling pathways such as Transforming Growth Factor-β (TGF-β), have demonstrated potential in delaying tumor progression and improving the effectiveness of chemotherapy, targeted therapy, and immunotherapy. In the future, by developing novel drugs that target the fibrotic microenvironment, new therapeutic options may be available for patients with various refractory tumors. [ABSTRACT FROM AUTHOR]

The colony-stimulating factor 1 receptor (CSF-1R) plays a pivotal role in orchestrating cellular interactions within the tumor microenvironment (TME). Although the CSF-1R has been extensively studied in myeloid cells, the expression of this receptor and its emerging role in other cell types in the TME need to be further analyzed. This review explores the multifaceted functions of the CSF-1R across various TME cellular populations, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), cancer-associated fibroblasts (CAFs), endothelial cells (ECs), and cancer stem cells (CSCs). The activation of the CSF-1R by its ligands, colony-stimulating factor 1 (CSF-1) and Interleukin-34 (IL-34), regulates TAM polarization towards an immunosuppressive M2 phenotype, promoting tumor progression and immune evasion. Similarly, CSF-1R signaling influences MDSCs to exert immunosuppressive functions, hindering anti-tumor immunity. In DCs, the CSF-1R alters antigen-presenting capabilities, compromising immune surveillance against cancer cells. CSF-1R expression in CAFs and ECs regulates immune modulation, angiogenesis, and immune cell trafficking within the TME, fostering a pro-tumorigenic milieu. Notably, the CSF-1R in CSCs contributes to tumor aggressiveness and therapeutic resistance through interactions with TAMs and the modulation of stemness features. Understanding the diverse roles of the CSF-1R in the TME underscores its potential as a therapeutic target for cancer treatment, aiming at disrupting pro-tumorigenic cellular crosstalk and enhancing anti-tumor immune responses. [ABSTRACT FROM AUTHOR]

Wenxian Lin,1– 4 Lizhu Tang,1,2,5 Chenyi Zhuo,1 Xiuli Mao,1– 4 Jiajia Shen,6 Shaoang Huang,3 Shangyang Li,3,7 Yujuan Qin,3,4 Ju Liao,2,3 Yuhong Chen,8 Xiamin Zhang,3,4 Yuting Li,9 Jian Song,4 Lingzhang Meng,4 Xiaofeng Dong,10 Yueyong Li2 1Key Laboratory of Molecular Pathology for Hepatobiliary Diseases of Guangxi, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, The People’s Republic of China; 2Department of Interventional Oncology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, The People’s Republic of China; 3Graduate School, Youjiang Medical University for Nationalities, Baise, 533000, The People’s Republic of China; 4Institute of Cardiovascular Sciences, Guangxi Academy of Medical Sciences & The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530016, The People’s Republic of China; 5Department of Radiation Oncology, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, The People’s Republic of China; 6Department of Laboratory Medicine, Nanning Maternity and Child Health Hospital & Nanning Women and Children’s Hospital, Nanning, 530011, The People’s Republic of China; 7Department of Laboratory Medicine, Guangxi Academy of Medical Sciences & The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530016, The People’s Republic of China; 8Department of Nephrology, the Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, The People’s Republic of China; 9Graduate School, Guangxi University of Chinese Medicine, Nanning, 530200, The People’s Republic of China; 10Department of Hepatobiliary, Pancreas and Spleen Surgery, Guangxi Academy of Medical Sciences & The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530016, The People’s Republic of ChinaCorrespondence: Yueyong Li; Xiaofeng Dong, Email 305017674@qq.com; gandanyingcai@163.comBackground: Cancer-associated fibroblasts (CAFs) play a pivotal role in shaping the microenvironment of hepatocellular carcinoma (HCC). However, the mechanisms through which CAFs influence the progression of HCC remain incompletely understood.Methods: Single-cell RNA sequencing datasets (GSE158723 and GSE112271) were retrieved from the Gene Expression Omnibus (GEO) database at the National Center for Biotechnology Information (NCBI) and analyzed using R software. Our analysis suggested that CAFs may promote liver cancer cell development, possibly through the interaction of pleiotrophin (PTN) and syndecan-2 (SDC2). Clinical samples from HCC patients were collected and processed into frozen sections and single-cell suspensions for Masson staining, immunofluorescence staining, and flow cytometry. Additionally, Huh7 liver cancer cells and LO2 normal liver cells were cultured and subjected to immunofluorescence assays using cell slides.Results: The proportion of CAFs in cancerous tissues was higher than in adjacent non-cancerous tissues, and pleiotrophin (PTN) expression was elevated in cancer tissues compared to adjacent tissues. These findings aligned with the results of the single-cell RNA sequencing (scRNA-seq) analysis. Furthermore, SDC2 expression was significantly upregulated in Huh7 liver cancer cells compared to LO2 normal liver cells.Discussion: This study suggests that CAFs may contribute to HCC progression via the PTN/SDC2 signaling pathway. Our findings provide deeper insights into the interactions between CAFs and HCC cells within the tumor microenvironment (TME).Keywords: CAFs, HCC, PTN, scRNA-seq, TME

Abstract Background Cancer-associated fibroblasts (CAFs) have been reported that can affect cancer cell proliferation, metastasis, ferroptosis, and immune escape. METTL3-mediated N6-methyladenine (m6A) modification is involved in the tumorigenesis of colorectal cancer (CRC). Herein, we investigated whether METTL3-dependent m6A in CAFs-derived exosomes (exo) affected CRC progression. Methods qRT-PCR and western blotting analyses detected levels of mRNAs and proteins. Cell proliferation and metastasis were evaluated using MTT, colony formation, transwell, and wound healing assays, respectively. Cell ferroptosis was assessed by detecting cell viability and the levels of Fe+, reactive oxygen species, and glutathione after erastin treatment. Exosomes were isolated from CAFs by ultracentrifugation. The m6A modification profile was determined by methylated RNA immunoprecipitation assay and the interaction between METTL3 and ACSL3 (acyl-CoA synthetase 3) was verified using dual-luciferase reporter assay. Animal models were established for in vivo analysis. Results CAFs promoted CRC cell proliferation and metastasis, and suppressed cell ferroptosis. METTL3 was enriched in CAFs and was packaged into exosomes. The m6A modification and METTL3 expression were increased in CRC samples. Knockdown of METTL3 in CAFs-exo suppressed CRC cell proliferation and metastasis, and induced cell ferroptosis. Mechanistically, METTL3 induced ACSL3 m6A modification and stabilized its expression. The anticancer effects mediated by METTL3-silenced CAFs-exo could be rescued by ACSL3 overexpression. Moreover, in vivo assay also showed that CAFs-exo with decreased METTL3 could hinder CRC growth and metastasis in mice models. Conclusion CAFs promoted the proliferation and metastasis, and restrained the ferroptosis in CRC by exosomal METTL3-elicited ACSL3 m6A modification.

Abstract Background Tumor tissues comprise cancer cells and stromal cells, and their interactions form the cancer microenvironment. Therefore, treatments targeting cells other than cancer cells are also actively being developed, and among them, treatment targeting PD-1, an immune checkpoint molecule that is important in tumor immune evasion, has also been indicated for head and neck cancer. PD-L1, a ligand of PD-1, is expressed in both tumor cells and stromal cells, and the scoring system based on the combined positivity rates of both types of cells, the combined positive score (CPS), is used for predicting treatment effect. However, much is unknown regarding the expression of PD-L1. In this study, we histopathologically examined factors controlling the expression of PD-1/PD-L1. This study included 37 patients who underwent resection surgery for tongue squamous cell carcinoma in the Department of Oral and Maxillofacial Surgery at Tokyo Dental College Suidobashi Hospital. The expression levels of PD-L1, α-SMA, and p53 were assessed by immunohistochemical staining. Results Seven participants had CPS ≥ 20, twenty-four participants had 1 ≤ CPS

Abstract Objective To investigate the mechanism by which cancer-associated fibroblasts (CAFs) affect the growth and immune evasion of lung cancer cells. Methods Initially, datasets comparing CAFs with normal fibroblasts were downloaded from the GEO dataset GSE48397. Genes with the most significant differential expression were selected and validated using clinical data. Subsequently, CAFs were isolated, and the selected genes were knocked down in CAFs. Co-culture experiments were conducted with H1299 or A549 cells to analyze changes in lung cancer cell growth, migration, and immune evasion in vitro and in vivo. To further elucidate the upstream regulatory mechanism, relevant ChIP-seq data were downloaded from the GEO database, and the regulatory relationships were validated through ChIP-qPCR and luciferase reporter assays. Results OLR1 was significantly overexpressed in CAFs and strongly correlated with adverse prognosis in lung cancer patients. Knockdown of OLR1 markedly inhibited CAFs’ support for the growth and immune evasion of lung cancer cells in vitro and in vivo. ChIP-seq results demonstrated that PRRX1 can promote OLR1 expression by recruiting H3K27ac and H3K4me3, thereby activating CAFs. Knockdown of PRRX1 significantly inhibited CAFs’ function, while further overexpression of OLR1 restored CAFs’ support for lung cancer cell growth, migration, and immune evasion. Conclusion PRRX1 promotes OLR1 expression by recruiting H3K27ac and H3K4me3, activating CAFs, and thereby promoting the growth, migration, and immune evasion of lung cancer cells.

Introduction: Cancer-associated fibroblasts (CAFs) are abundant and influential elements of the tumor microenvironment (TME), giving support to tumor development in multiple ways. Among other mechanisms, CAFs are important regulators of immunological processes occurring in tumors. However, CAFmediated tumor immunomodulation in the context of radiotherapy remains poorly understood. In this study, we explore effects of radiation on CAFderived immunoregulatory signals to the TME. Methods: Primary CAF cultures were established from freshly collected human NSCLC lung tumors. CAFs were exposed to single-high or fractionated radiation regimens (1x18Gy or 3x6Gy), and the expression of different immunoregulatory cell-associated and secreted signaling molecules was analyzed 48h and 6 days after initiation of treatment. Analyses included quantitative measurements of released damage-associated molecular patterns (DAMPs), interferon (IFN) type I responses, expression of immune regulatory receptors, and secretion of soluble cytokines, chemokines, and growth factors. CAFs are able to survive ablative radiation regimens, however they enter into a stage of premature cell senescence. Results: Our data show that CAFs avoid apoptosis and do not contribute by release of DAMPs or IFN-I secretion to radiation-mediated tumor immunoregulation. Furthermore, the secretion of relevant immunoregulatory cytokines and growth factors including TGF-β, IL-6, IL-10, TNFα, IL-1β, VEGF, CXCL12, and CXCL10 remain comparable between non-irradiated and radiationinduced senescent CAFs. Importantly, radiation exposure modifies the cell surface expression of some key immunoregulatory receptors, including upregulation of CD73 and CD276. Discussion: Our data suggest that CAFs do not participate in the release of danger signals or IFN-I secretion following radiotherapy. The immune phenotype of CAFs and radiation-induced senescent CAFs is similar, however, the observed elevation of some cell surface immunological receptors on irradiated CAFs could contribute to the establishment of an enhanced immunosuppressive TME after radiotherapy. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate whether anlotinib could exert an inhibitory effect on the proliferation and invasion of cervical cancer cells by inhibiting cytokines secreted by activated cancer-associated fibroblasts (CAFs). Methods: CAFs were isolated from cervical cancer tissues and experimentally studied in vivo and in vitro. Molecular biology experimental methods were used to verify whether anlotinib could inhibit the pro-carcinogenic effects of CAFs derived from cervical cancer tissues. Results: CAFs promote the proliferation and invasion of cervical cancer cells. Anlotinib inhibited the activation of CAFs and suppressed the promotion of cervical cancer cells by CAFs. Anlotinib inhibited the expression of multiple cytokines within CAFs and suppressed the release of interleukin (IL)-6 (IL-6) and IL-8. In vivo studies have shown that anlotinib diminished the growth of xenografted cervical cancer cells, and treatment in combination with docetaxel had an even more significant tumor growth inhibitory effect. Conclusion: Anlotinib inhibits the pro-cancer effects of CAFs by suppressing the activation of CAFs and the secretion of pro-cancer cytokines. Our findings suggest that the combination of anlotinib and docetaxel may be a potential strategy for the treatment of refractory cervical cancer. [ABSTRACT FROM AUTHOR]

Background: Cancer-associated fibroblasts (CAFs) have been reported that can affect cancer cell proliferation, metastasis, ferroptosis, and immune escape. METTL3-mediated N6-methyladenine (m6A) modification is involved in the tumorigenesis of colorectal cancer (CRC). Herein, we investigated whether METTL3-dependent m6A in CAFs-derived exosomes (exo) affected CRC progression. Methods: qRT-PCR and western blotting analyses detected levels of mRNAs and proteins. Cell proliferation and metastasis were evaluated using MTT, colony formation, transwell, and wound healing assays, respectively. Cell ferroptosis was assessed by detecting cell viability and the levels of Fe+, reactive oxygen species, and glutathione after erastin treatment. Exosomes were isolated from CAFs by ultracentrifugation. The m6A modification profile was determined by methylated RNA immunoprecipitation assay and the interaction between METTL3 and ACSL3 (acyl-CoA synthetase 3) was verified using dual-luciferase reporter assay. Animal models were established for in vivo analysis. Results: CAFs promoted CRC cell proliferation and metastasis, and suppressed cell ferroptosis. METTL3 was enriched in CAFs and was packaged into exosomes. The m6A modification and METTL3 expression were increased in CRC samples. Knockdown of METTL3 in CAFs-exo suppressed CRC cell proliferation and metastasis, and induced cell ferroptosis. Mechanistically, METTL3 induced ACSL3 m6A modification and stabilized its expression. The anticancer effects mediated by METTL3-silenced CAFs-exo could be rescued by ACSL3 overexpression. Moreover, in vivo assay also showed that CAFs-exo with decreased METTL3 could hinder CRC growth and metastasis in mice models. Conclusion: CAFs promoted the proliferation and metastasis, and restrained the ferroptosis in CRC by exosomal METTL3-elicited ACSL3 m6A modification. [ABSTRACT FROM AUTHOR]

An important determinant for oral squamous cell carcinoma (OSCC) onset and outcome is the composition of the tumor microenvironment (TME). Thus, the study of the interactions occurring among cancer cells, immune cells, and cancer-associated fibroblasts within the TME could facilitate the understanding of the mechanisms underlying OSCC development and progression, as well as of its sensitivity or resistance to the therapy. In this context, it must be highlighted that the characterization of TME proteins is enabled by proteomic methodologies, particularly mass spectrometry (MS). Aiming to identify TME protein markers employable for diagnosing and prognosticating OSCC, we have retrieved a total of 119 articles spanning 2001 to 2023, of which 17 have passed the selection process, satisfying all its criteria. We have found a total of 570 proteins detected by MS-based proteomics in the TME of OSCC; among them, 542 are identified by a single study, while 28 are cited by two or more studies. These 28 proteins participate in extracellular matrix remodeling and/or energy metabolism. Here, we propose them as markers that could be used to characterize the TME of OSCC for diagnostic/prognostic purposes. Noteworthy, most of the 28 individuated proteins share one feature: being modulated by the hypoxia that is present in the proliferating OSCC mass. [ABSTRACT FROM AUTHOR]

Extracellular matrix (ECM) is a major component of the tumor environment, promoting the establishment of a pro-invasive behavior. Such environment is supported by both tumor- and stromal-derived metabolites, particularly lactate. In prostate cancer (PCa), cancer-associated fibroblasts (CAFs) are major contributors of secreted lactate, able to impact on metabolic and transcriptional regulation in cancer cells. Here, we describe a mechanism by which CAF-secreted lactate promotes in PCa cells the expression of genes coding for the collagen family. Lactate-exploiting PCa cells rely on increased α-ketoglutarate (α-KG) which activates the α-KG-dependent collagen prolyl-4-hydroxylase (P4HA1) to support collagen hydroxylation. De novo synthetized collagen plays a signaling role by activating discoidin domain receptor 1 (DDR1), supporting stem-like and invasive features of PCa cells. Inhibition of lactate-induced collagen hydroxylation and DDR1 activation reduces the metastatic colonization of PCa cells. Overall, these results provide a new understanding of the link between collagen remodeling/signaling and the nutrient environment exploited by PCa. Synopsis: Lactate, which is highly enriched in the prostate cancer environment, supports collagen remodeling and sensing in prostate cancer cells. Lactate-dependent metabolic rewiring sustains collagen hydroxylation via P4HA1 activation. De novo synthetized collagen activates discoidin domain receptor 1 (DDR1). P4HA1-DDR1-STAT3 axis is crucial for stemness and invasiveness of prostate cancer cells. Lactate, which is highly enriched in the prostate cancer environment, supports collagen remodeling and sensing in prostate cancer cells. [ABSTRACT FROM AUTHOR]

Background: Tumor tissues comprise cancer cells and stromal cells, and their interactions form the cancer microenvironment. Therefore, treatments targeting cells other than cancer cells are also actively being developed, and among them, treatment targeting PD-1, an immune checkpoint molecule that is important in tumor immune evasion, has also been indicated for head and neck cancer. PD-L1, a ligand of PD-1, is expressed in both tumor cells and stromal cells, and the scoring system based on the combined positivity rates of both types of cells, the combined positive score (CPS), is used for predicting treatment effect. However, much is unknown regarding the expression of PD-L1. In this study, we histopathologically examined factors controlling the expression of PD-1/PD-L1. This study included 37 patients who underwent resection surgery for tongue squamous cell carcinoma in the Department of Oral and Maxillofacial Surgery at Tokyo Dental College Suidobashi Hospital. The expression levels of PD-L1, α-SMA, and p53 were assessed by immunohistochemical staining. Results: Seven participants had CPS ≥ 20, twenty-four participants had 1 ≤ CPS < 20, and six participants had CPS < 1. The overall positivity rate of α-SMA, a marker for cancer-associated fibroblasts (CAFs), was 27% (10/37 participants), and the positivity rates of α-SMA for the three CPS groups were 85.7% (6/7 participants), 16.7% (4/24 participants), and 0% (0/6 participants), respectively. In addition, the overall positivity rate of p53 was 37.8% (14/37 participants), and the positivity rates of p53 for the three CPS groups were 71.4% (5/7 participants), 37.5% (9/24 participants), and 0% (0/6 participants), respectively. Conclusions: The expression of PD-L1 demonstrated an association with α-SMA and p53 positivity. In addition, compared with the expression of p53, the expression of α-SMA demonstrated a higher association with PD-L1 expression in patients with a high CPS. The abovementioned findings suggest that the interactions between CAFs, cancer cells, and immunocompetent cells may regulate the expression of PD-L1. [ABSTRACT FROM AUTHOR]

Neoplastic progression involves complex interactions between cancer cells and the surrounding stromal milieu, fostering microenvironments that crucially drive tumor progression and dissemination. Of these stromal constituents, cancer-associated fibroblasts (CAFs) emerge as predominant inhabitants within the tumor microenvironment (TME), actively shaping multiple facets of tumorigenesis, including cancer cell proliferation, invasiveness, and immune evasion. Notably, CAFs also orchestrate the production of pro-angiogenic factors, fueling neovascularization to sustain the metabolic demands of proliferating cancer cells. Moreover, CAFs may also directly or indirectly affect endothelial cell behavior and vascular architecture, which may impact in tumor progression and responses to anti-cancer interventions. Conversely, tumor endothelial cells (TECs) exhibit a corrupted state that has been shown to affect cancer cell growth and inflammation. Both CAFs and TECs are emerging as pivotal regulators of the TME, engaging in multifaceted biological processes that significantly impact cancer progression, dissemination, and therapeutic responses. Yet, the intricate interplay between these stromal components and the orchestrated functions of each cell type remains incompletely elucidated. In this review, we summarize the current understanding of the dynamic interrelationships between CAFs and TECs, discussing the challenges and prospects for leveraging their interactions towards therapeutic advancements in cancer. [ABSTRACT FROM AUTHOR]

Understanding the tumor microenvironment (TME) and extracellular matrix (ECM) is crucial in cancer research due to their impact on tumor progression. Collagens, major ECM components, regulate cell signaling and behavior. Of the 28 reported collagens, type XII collagen is known to be vital for ECM organization. Over-produced by cancer-associated fibroblasts (CAFs), its upregulation correlates with poor survival in various cancers. This study aimed to develop an ELISA for quantifying circulating type XII collagen as a cancer biomarker. A specific ELISA targeting the C-terminal of type XII collagen was developed and used to analyze serum samples from cancer patients (n = 203) and healthy controls (n = 33). Additionally, type XII collagen expression was assessed in CAFs and normal fibroblasts (NFs) from different tissues, both under TGF-β stimulated and non-stimulated conditions. The nordicPRO-C12 ELISA demonstrated robustness and specificity for type XII collagen. PRO-C12 levels were significantly elevated in patients with various cancers compared to healthy controls and effectively distinguished between cancer patients and controls. Findings were validated using gene expression data. Furthermore, Western blot analysis revealed increased type XII collagen expression in both CAFs and NFs upon TGF-β1 stimulation, suggesting a potential role of TGF-β1 in modulating the expression of type XII collagen in cancerous and normal tissue microenvironments. This study unveils a promising avenue for harnessing PRO-C12 as a non-invasive serum biomarker, enabling the quantification of type XII collagen fragments in cancer patients. Further investigations are warranted to explore the potential of PRO-C12 across different cancer types and disease stages, shedding light on its multifaceted role in cancer development. [ABSTRACT FROM AUTHOR]

Objective: To investigate the mechanism by which cancer-associated fibroblasts (CAFs) affect the growth and immune evasion of lung cancer cells. Methods: Initially, datasets comparing CAFs with normal fibroblasts were downloaded from the GEO dataset GSE48397. Genes with the most significant differential expression were selected and validated using clinical data. Subsequently, CAFs were isolated, and the selected genes were knocked down in CAFs. Co-culture experiments were conducted with H1299 or A549 cells to analyze changes in lung cancer cell growth, migration, and immune evasion in vitro and in vivo. To further elucidate the upstream regulatory mechanism, relevant ChIP-seq data were downloaded from the GEO database, and the regulatory relationships were validated through ChIP-qPCR and luciferase reporter assays. Results: OLR1 was significantly overexpressed in CAFs and strongly correlated with adverse prognosis in lung cancer patients. Knockdown of OLR1 markedly inhibited CAFs' support for the growth and immune evasion of lung cancer cells in vitro and in vivo. ChIP-seq results demonstrated that PRRX1 can promote OLR1 expression by recruiting H3K27ac and H3K4me3, thereby activating CAFs. Knockdown of PRRX1 significantly inhibited CAFs' function, while further overexpression of OLR1 restored CAFs' support for lung cancer cell growth, migration, and immune evasion. Conclusion: PRRX1 promotes OLR1 expression by recruiting H3K27ac and H3K4me3, activating CAFs, and thereby promoting the growth, migration, and immune evasion of lung cancer cells. Highlights: OLR1 is significantly overexpressed in lung cancer-associated fibroblasts and is associated with adverse patient outcomes. OLR1+ CAFs promote the growth of lung cancer cells in vitro and in vivo, as well as immune evasion. PRRX1 serves as the master transcription factor regulating OLR1+ CAFs. PRRX1 can recruit super enhancer modifications in the cis-elements of the OLR1 gene. Overexpression of OLR1 weakens the inhibitory effect of shPRRX1 on CAFs' function. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is characterised by immune evasion that contribute to poor prognosis. Cancer‐associated fibroblasts (CAFs) play a pivotal role in orchestrating the PDAC tumour microenvironment. We investigated the role of CAF‐derived extracellular vesicle (EV)‐packaged long non‐coding RNAs (lncRNAs) in immune evasion and explored gene therapy using engineered EVs loading small interfering RNAs (siRNAs) as a potential therapeutic strategy. Our findings highlight the significance of EV‐packaged lncRNA RP11‐161H23.5 from CAF in promoting PDAC immune evasion by downregulating HLA‐A expression, a key component of antigen presentation. Mechanistically, RP11‐161H23.5 forms a complex with CNOT4, a subunit of the mRNA deadenylase CCR4‐NOT complex, enhancing the degradation of HLA‐A mRNA by shortening its poly(A) tail. This immune evasion mechanism compromises the anti‐tumour immune response. To combat this, we propose an innovative approach utilising engineered EVs as natural and biocompatible nanocarriers for siRNA‐based gene therapy and this strategy holds promise for enhancing the effectiveness of immunotherapy in PDAC. Overall, our study sheds light on the critical role of CAF‐derived EV‐packaged lncRNA RP11‐161H23.5/CNOT4/HLA‐A axis in PDAC immune evasion and presents a novel avenue for therapeutic intervention. [ABSTRACT FROM AUTHOR]

This study aims to identify key regulators of paraptosis in gastric cancer (GC) and explore their potential in guiding therapeutic strategies, especially in stomach adenocarcinoma (STAD). Genes associated with paraptosis were identified from the references and subjected to Cox regression analysis in the TCGA-STAD cohort. Using machine learning models, LPAR1 consistently ranked highest in feature importance. Multiple sequencing data showed that LPAR1 was significantly overexpressed in cancer-associated fibroblasts (CAFs). LPAR1 expression was significantly higher in normal tissues, and ROC analysis demonstrated its discriminative ability. Copy number alterations and microsatellite instability were significantly associated with LPAR1 expression. High LPAR1 expression correlated with advanced tumor grades and specific cancer immune subtypes, and multivariate analysis confirmed LPAR1 as an independent predictor of poor prognosis. LPAR1 expression was associated with different immune response metrics, including immune effector activation and upregulated chemokine secretion. High LPAR1 expression also correlated with increased sensitivity to compounds, such as BET bromodomain inhibitors I-BET151 and RITA, suggesting LPAR1 as a biomarker for predicting drug activity. FOXP2 showed a strong positive correlation with LPAR1 transcriptional regulation, while increased methylation of LPAR1 promoter regions was negatively correlated with gene expression. Knockdown of LPAR1 affected cell growth in most tumor cell lines, and in vitro experiments demonstrated that LPAR1 influenced extracellular matrix (ECM) contraction and cell viability in the paraptosis of CAFs. These findings suggest that LPAR1 is a critical regulator of paraptosis in GC and a potential biomarker for drug sensitivity and immunotherapy response. This underscores the role of CAFs in mediating tumorigenic effects and suggests that targeting LPAR1 could be a promising strategy for precision medicine in GC.

Malignant tumors are a category of diseases that possess invasive and metastatic capabilities, with global incidence and mortality rates remaining high. In recent years, the pivotal role of fibrosis in tumor progression, drug resistance, and immune evasion has increasingly been acknowledged. Fibrosis enhances the proliferation, migration, and invasion of tumor cells by modifying the composition and structure of the extracellular matrix, thereby offering protection for immune evasion by tumor cells. The activation of cancer-associated fibroblasts (CAFs) plays a significant role in this process, as they further exacerbate the malignant traits of tumors by secreting a variety of cytokines and growth factors. Anti-fibrotic tumor treatment strategies, including the use of anti-fibrotic drugs and inhibition of fibrosis-related signaling pathways such as Transforming Growth Factor-β (TGF-β), have demonstrated potential in delaying tumor progression and improving the effectiveness of chemotherapy, targeted therapy, and immunotherapy. In the future, by developing novel drugs that target the fibrotic microenvironment, new therapeutic options may be available for patients with various refractory tumors.

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive cancer with striking fibrosis, and its mortality rate is ranked second across human cancers. Cancer-associated fibroblasts (CAFs) play a critical role in PDAC progression, and we reviewed the molecular understanding of PDAC CAFs and novel therapeutic potential at present. CAFs-associated genes (CAFGs) were tentatively classified into three categories by stroma specificity representing stroma/epithelia expression ratios (SE ratios). The recent classification using single cell transcriptome technology clarified that CAFs were composed of myofibroblasts (myCAFs), inflammatory CAFs (iCAFs), and other minor ones (e.g., POSTN-CAFs and antigen presenting CAFs, apCAFs). LRRC15 is a myCAFs marker, and myCAFs depletion by diphtheria toxin induces the rapid accumulation of cytotoxic T lymphocytes (CTLs) and therefore augment PDL1 antibody treatments. This finding proposes that myCAFs may be a critical regulator of tumor immunity in terms of PDAC progression. myCAFs are located in CAFs adjacent to tumor cells, while iCAFs marked by PDPN and/or COL14A1 are distant from tumor cells, where hypoxic and acidic environments being located in iCAFs putatively due to poor blood supply is consistent with HIF1A and GPR68 expressions. iCAFs may be shared with SASP (secretion-associated phenotypes) in senescent CAFs. myCAFs are classically characterized by CAFGs induced by TGFB1, while chemoresistant CAFs with SASP may dependent on IL6 expression and accompanied by STAT3 activation. Recently, it was found that the unique metabolism of CAFs can be targeted to prevent PDAC progression, where PDAC cells utilize glucose, whereas CAFs in turn utilize lactate, which may be epigenetically regulated, mediated by its target genes including CXCR4. In summary, CAFs have unique molecular characteristics, which have been rigorously clarified as novel therapeutic targets of PDAC progression. [ABSTRACT FROM AUTHOR]

The cytosolic sulfotransferases (SULTs) are phase II conjugating enzymes, which are widely expressed in the liver and mainly mediate the sulfation of numerous xenobiotics and endogenous compounds. However, the role of various SULTs genes has not been reported in hepatocellular carcinoma (HCC). This study aims to analyze the expression and potential functional roles of SULTs genes in HCC and to identify the role of SULT2A1 in HCC stemness as well as the possible mechanism. We found that all of the 12 SULTs genes were differentially expressed in HCC. Moreover, clinicopathological features and survival rates were also investigated. Multivariate regression analysis showed that SULT2A1 and SULT1C2 could be used as independent prognostic factors in HCC. SULT1C4, SULT1E1, and SULT2A1 were significantly associated with immune infiltration. SULT2A1 deficiency in HCC promoted chemotherapy resistance and stemness maintenance. Mechanistically, silencing of SULT2A1 activated the AKT signaling pathway, on the one hand, promoted the expression of downstream stemness gene c-Myc, on the other hand, facilitated the NRF2 expression to reduce the accumulation of ROS, and jointly increased HCC stemness. Moreover, knockdown NR1I3 was involved in the transcriptional regulation of SULT2A1 in stemness maintenance. In addition, SULT2A1 knockdown HCC cells promoted the proliferation and activation of hepatic stellate cells (HSCs), thereby exerting a potential stroma remodeling effect. Our study revealed the expression and role of SULTs genes in HCC and identified the contribution of SULT2A1 to the initiation and progression of HCC. [ABSTRACT FROM AUTHOR]

Cancer, a condition managed through surgeries, chemotherapies, and radiation, often encounters challenges such as drug resistance and relapse during treatment. The need for higher drug dosages to prevent relapse contributes to drug resistance and increased toxicity. Combining herbal formulations with standard treatments, complementary and alternative medicine (CAM) offers an approach to mitigate resistance and toxicity associated with standard treatments, ultimately improving outcomes. The body's balance, which has been disturbed by chemotherapy and radiation, is restored by these natural/herbal compositions. In this study, we hypothesized that the herbal formulation (HF20), derived from Amaranthus spinosus parts, can reduce the levels of Interleukin-6 (IL-6), a pro-inflammatory cytokine. Additionally, the research also examined the role of Transforming Growth Factor-beta (TGF-β) and Vascular Endothelial Growth Factor (VEGF) in inducing the transformation of bone marrow mesenchymal stem cells (BM-MSCs) into cancer-associated fibroblasts (CAFs). A comprehensive understanding of HF20's anticancer and anti-inflammatory properties is essential. Also, HF20 brought down IL-6 levels in HeLa Cells. Investigating cytokine expression using different conditioned media (CM) with HeLa cells and BM-MSCs, the study found that BM-MSCs secreted higher concentrations of cytokines when co-cultured with HeLa cells. Additionally, HF20 reduced the levels of VEGF and TGF-β, indicating its potential in countering tumorigenesis and cancer metastasis. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common malignancy of the central nervous system in adults. GBM has high levels of therapy failure and its prognosis is usually dismal. The phenotypic heterogeneity of the tumor cells, dynamic complexity of non-tumor cell populations within the GBM tumor microenvironment (TME), and their bi-directional cross-talk contribute to the challenges of current therapeutic approaches. Herein, we discuss the etiology of GBM, and describe several major types of non-tumor cells within its TME, their impact on GBM pathogenesis, and molecular mechanisms of such an impact. We also discuss their value as potential therapeutic targets or prognostic biomarkers, with reference to the most recent works on this subject. We conclude that unless all "key player" populations of non-tumor cells within the TME are considered, no breakthrough in developing treatment for GBM can be achieved. [ABSTRACT FROM AUTHOR]

Our previous studies have shown that upregulation of SLC7A1 in epithelial ovarian cancer (EOC) tumor cells significantly increases cancer cell proliferation, migration, and cisplatin resistance; however, the molecular mechanism by which SLC7A1 functions in EOC remains unknown. In later studies, we found that SLC7A1 is also highly expressed in the interstitial portion of high‐grade serous ovarian cancer (HGSOC), but the significance of this high expression in the interstitial remains unclear. Here, we showed the Interstitial high expression of SLC7A1 in HGSOC by immunohistochemistry. SLC7A1 enriched in cancer‐associated fibroblasts (CAFs) was upregulated by TGF‐β1. Transwell assay, scratch assay, cck8 assay and cell adhesion assay showed that SLC7A1 highly expressed in CAFs promoted tumor cells invasion, migration and metastasis in vitro. The effect of SLC7A1 on MAPK and EMT pathway proteins in ovarian cancer (OC) was verified by RNA sequencing and western blotting. Overexpression of SLC7A1 in OC is involved in MAPK/ ERK pathway and EMT. In general, in HGSOC, CAFs overexpressing SLC7A1 supported the migration and invasion of tumor cells; SLC7A1 is highly expressed in ovarian cancer and is involved in ERK phosphorylation and EMT signaling in MAPK signaling pathway. This suggests that SLC7A1 may be a potential therapeutic target for OC metastasis. [ABSTRACT FROM AUTHOR]

Objectives: FERMT2 upregulation was associated with malignant tumor behaviors, including epithelial‐to‐mesenchymal (EMT). This study aimed to characterize the expression profile of FERMT2 in oral squamous cell carcinoma (OSCC) and to explore its involvement in the tumor microenvironment sculptured by oral cancer‐associated fibroblasts (OCAFs). Materials: Previous bulk‐seq (TCGA‐HNSC) and single‐cell RNA‐seq data sets were retrieved for bioinformatic analysis. Human OSCC lines SCC15 and CAL27, primary normal oral fibroblasts (NOFs), OCAFs, and THP‐1 cells were used for intro studies. Results: FERMT2 expression was significantly higher in CAFs compared with OSCC tumor cells and normal fibroblasts. Higher FERMT2 expression might independently predict unfavorable disease‐specific survival (DSS) in patients with OSCC. Knockdown of FERMT2 suppressed the expression and secretion of IGFBP7, SPARC, TIMP3, COL4A1, and IGFBP4 in OCAFs. OCAFs with FERMT2 knockdown had significantly weakened capability to induce the invasion of OSCC cells and the expression of mesenchymal markers. FERMT2 knockdown impaired the inducing effect of OCAFs on the migration of M0 macrophages and the expression of M2 macrophage markers. Conclusions: FERMT2 could modulate the production and secretion of IGFBP7, SPARC, COL4A1, and IGFBP4 in OCAFs, thereby inducing the EMT of OSCC and M2 macrophage polarization. [ABSTRACT FROM AUTHOR]

Background: Understanding how to modulate the microenvironment of tumors that are resistant to immune checkpoint inhibitors represents a major challenge in oncology.Here we investigate the ability of USP7 inhibitors to reprogram the tumor microenvironment (TME) by inhibiting secretion of vascular endothelial growth factor (VEGF) from fibroblasts. Methods: To understand the role played by USP7 in the TME, we systematically evaluated the effects of potent, selective USP7 inhibitors on co‐cultures comprising components of the TME, using human primary cells. We also evaluated the effects of USP7 inhibition on tumor growth inhibition in syngeneic models when dosed in combination with immune checkpoint inhibitors (ICIs). Results: Abrogation of VEGF secretion from fibroblasts in response to USP7 inhibition resulted in inhibition of tumor neoangiogenesis and increased tumor recruitment of CD8‐positive T‐lymphocytes, leading to significantly improved sensitivity to immune checkpoint inhibitors. In syngeneic models, treatment with USP7 inhibitors led to striking tumor responses resulting in significantly improved survival. Conclusions: USP7‐mediated reprograming of the TME is not linked to its previously characterized role in modulating MDM2 but does require p53 and UHRF1 in addition to the well‐characterized VEGF transcription factor, HIF‐1α. This represents a function of USP7 that is unique to fibroblasts, and which is not observed in cancer cells or other components of the TME. Given the potential for USP7 inhibitors to transform "immune desert" tumors into "immune responsive" tumors, this paves the way for a novel therapeutic strategy combining USP7 inhibitors with immune checkpoint inhibitors (ICIs). [ABSTRACT FROM AUTHOR]

IntroductionCancer-associated fibroblasts (CAFs) are abundant and influential elements of the tumor microenvironment (TME), giving support to tumor development in multiple ways. Among other mechanisms, CAFs are important regulators of immunological processes occurring in tumors. However, CAF-mediated tumor immunomodulation in the context of radiotherapy remains poorly understood. In this study, we explore effects of radiation on CAF-derived immunoregulatory signals to the TME.MethodsPrimary CAF cultures were established from freshly collected human NSCLC lung tumors. CAFs were exposed to single-high or fractionated radiation regimens (1x18Gy or 3x6Gy), and the expression of different immunoregulatory cell-associated and secreted signaling molecules was analyzed 48h and 6 days after initiation of treatment. Analyses included quantitative measurements of released damage-associated molecular patterns (DAMPs), interferon (IFN) type I responses, expression of immune regulatory receptors, and secretion of soluble cytokines, chemokines, and growth factors. CAFs are able to survive ablative radiation regimens, however they enter into a stage of premature cell senescence.ResultsOur data show that CAFs avoid apoptosis and do not contribute by release of DAMPs or IFN-I secretion to radiation-mediated tumor immunoregulation. Furthermore, the secretion of relevant immunoregulatory cytokines and growth factors including TGF-β, IL-6, IL-10, TNFα, IL-1β, VEGF, CXCL12, and CXCL10 remain comparable between non-irradiated and radiation-induced senescent CAFs. Importantly, radiation exposure modifies the cell surface expression of some key immunoregulatory receptors, including upregulation of CD73 and CD276.DiscussionOur data suggest that CAFs do not participate in the release of danger signals or IFN-I secretion following radiotherapy. The immune phenotype of CAFs and radiation-induced senescent CAFs is similar, however, the observed elevation of some cell surface immunological receptors on irradiated CAFs could contribute to the establishment of an enhanced immunosuppressive TME after radiotherapy.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterised by immune evasion that contribute to poor prognosis. Cancer‐associated fibroblasts (CAFs) play a pivotal role in orchestrating the PDAC tumour microenvironment. We investigated the role of CAF‐derived extracellular vesicle (EV)‐packaged long non‐coding RNAs (lncRNAs) in immune evasion and explored gene therapy using engineered EVs loading small interfering RNAs (siRNAs) as a potential therapeutic strategy. Our findings highlight the significance of EV‐packaged lncRNA RP11‐161H23.5 from CAF in promoting PDAC immune evasion by downregulating HLA‐A expression, a key component of antigen presentation. Mechanistically, RP11‐161H23.5 forms a complex with CNOT4, a subunit of the mRNA deadenylase CCR4‐NOT complex, enhancing the degradation of HLA‐A mRNA by shortening its poly(A) tail. This immune evasion mechanism compromises the anti‐tumour immune response. To combat this, we propose an innovative approach utilising engineered EVs as natural and biocompatible nanocarriers for siRNA‐based gene therapy and this strategy holds promise for enhancing the effectiveness of immunotherapy in PDAC. Overall, our study sheds light on the critical role of CAF‐derived EV‐packaged lncRNA RP11‐161H23.5/CNOT4/HLA‐A axis in PDAC immune evasion and presents a novel avenue for therapeutic intervention.

Abstract Background Ovarian cancer (OC) is distinguished by its aggressive nature and the limited efficacy of current treatment strategies. Recent studies have emphasized the significant role of cancer-associated fibroblasts (CAFs) in OC development and progression. Methods Employing sophisticated machine learning techniques on bulk transcriptomic datasets, we identified fibroblast growth factor 7 (FGF7), derived from CAFs, as a potential oncogenic factor. We investigated the relationship between FGF7 expression and various clinical parameters. A series of in vitro experiments were undertaken to evaluate the effect of CAFs-derived FGF7 on OC cell activities, such as proliferation, migration, and invasion. Single-cell transcriptomic analysis was also conducted to elucidate the interaction between FGF7 and its receptor. Detailed mechanistic investigations sought to clarify the pathways through which FGF7 fosters OC progression. Results Our findings indicate that higher FGF7 levels correlate with advanced tumor stages, increased vascular invasion, and poorer prognosis. CAFs-derived FGF7 significantly enhanced OC cell proliferation, migration, and invasion. Single-cell analysis and in vitro studies revealed that CAFs-derived FGF7 inhibits the ubiquitination and degradation of hypoxia-inducible factor 1 alpha (HIF-1α) via FGFR2 interaction. Activation of the FGF7/HIF-1α pathway resulted in the upregulation of mesenchymal markers and downregulation of epithelial markers. Importantly, in vivo treatment with neutralizing antibodies targeting CAFs-derived FGF7 substantially reduced tumor growth. Conclusion Neutralizing FGF7 in the medium or inhibiting HIF-1α signaling reversed the effects of FGF7-mediated EMT, emphasizing the dependence of FGF7-mediated EMT on HIF-1α activation. These findings suggest that targeting the FGF7/HIF-1α/EMT axis may offer new therapeutic opportunities to intervene in OC progression.

Abstract Background Cancer-associated fibroblasts (CAFs) orchestrate a supportive niche that fuels cancer metastatic development in non-small cell lung cancer (NSCLC). Due to the heterogeneity and plasticity of CAFs, manipulating the activated phenotype of fibroblasts is a promising strategy for cancer therapy. However, the underlying mechanisms of fibroblast activation and phenotype switching that drive metastasis remain elusive. Methods The clinical implications of fibroblast activation protein (FAP)-positive CAFs (FAP+CAFs) were evaluated based on tumor specimens from NSCLC patients and bioinformatic analysis of online databases. CAF-specific circular RNAs (circRNAs) were screened by circRNA microarrays of primary human CAFs and matched normal fibroblasts (NFs). Survival analyses were performed to assess the prognostic value of circNOX4 in NSCLC clinical samples. The biological effects of circNOX4 were investigated by gain- and loss-of-function experiments in vitro and in vivo. Fluorescence in situ hybridization, luciferase reporter assays, RNA immunoprecipitation, and miRNA rescue experiments were conducted to elucidate the underlying mechanisms of fibroblast activation. Cytokine antibody array, transwell coculture system, and enzyme-linked immunosorbent assay (ELISA) were performed to investigate the downstream effectors that promote cancer metastasis. Results FAP+CAFs were significantly enriched in metastatic cancer samples, and their higher abundance was correlated with the worse overall survival in NSCLC patients. A novel CAF-specific circRNA, circNOX4 (hsa_circ_0023988), evoked the phenotypic transition from NFs into CAFs and promoted the migration and invasion of NSCLC in vitro and in vivo. Clinically, circNOX4 correlated with the poor prognosis of advanced NSCLC patients. Mechanistically, circNOX4 upregulated FAP by sponging miR-329-5p, which led to fibroblast activation. Furthermore, the circNOX4/miR-329-5p/FAP axis activated an inflammatory fibroblast niche by preferentially inducing interleukin-6 (IL-6) and eventually promoting NSCLC progression. Disruption of the intercellular circNOX4/IL-6 axis significantly suppressed tumor growth and metastatic colonization in vivo. Conclusions Our study reveals a role of the circRNA-induced fibroblast niche in tumor metastasis and highlights that targeting the circNOX4/FAP/IL-6 axis is a promising strategy for the intervention of NSCLC metastasis.

As the predominant stromal cells in the ccRCC surrounding environment, cancer-associated fibroblasts (CAFs) have been established as supportive of tumor growth. However, the detailed molecular mechanisms underlying the supporting role of CAFs in ccRCC have not been well characterized. Evidence from the clustering consensus analysis, single-cell analysis, and the experimental results illustrate that CAF-derived FGF7 plays a crucial role as a signaling mediator between CAFs and ccRCC tumor cells. Mechanistically, CAF-derived FGF7 triggers AKT activation to promote cell growth and cell invasion of ccRCC tumor cells. As a response, ccRCC tumor cells stimulate STAT3-mediated transcriptional regulation, directly increasing FGF7 expression at the chromatin level in CAFs. Moreover, there exists a positive clinical correlation between the abundance of CAFs, FGF7 expression, and the infiltration of M2 type macrophages. The RENCA in vivo mouse model also confirmed that FGF7 depletion could impede RCC development by reducing the recruitment of M2 type macrophages. Overall, this study delineates a key signaling axis governing the crosstalk between CAFs and ccRCC tumor cells, highlighting FGF7 as a promising therapeutic target of ccRCC.

The colony-stimulating factor 1 receptor (CSF-1R) plays a pivotal role in orchestrating cellular interactions within the tumor microenvironment (TME). Although the CSF-1R has been extensively studied in myeloid cells, the expression of this receptor and its emerging role in other cell types in the TME need to be further analyzed. This review explores the multifaceted functions of the CSF-1R across various TME cellular populations, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), cancer-associated fibroblasts (CAFs), endothelial cells (ECs), and cancer stem cells (CSCs). The activation of the CSF-1R by its ligands, colony-stimulating factor 1 (CSF-1) and Interleukin-34 (IL-34), regulates TAM polarization towards an immunosuppressive M2 phenotype, promoting tumor progression and immune evasion. Similarly, CSF-1R signaling influences MDSCs to exert immunosuppressive functions, hindering anti-tumor immunity. In DCs, the CSF-1R alters antigen-presenting capabilities, compromising immune surveillance against cancer cells. CSF-1R expression in CAFs and ECs regulates immune modulation, angiogenesis, and immune cell trafficking within the TME, fostering a pro-tumorigenic milieu. Notably, the CSF-1R in CSCs contributes to tumor aggressiveness and therapeutic resistance through interactions with TAMs and the modulation of stemness features. Understanding the diverse roles of the CSF-1R in the TME underscores its potential as a therapeutic target for cancer treatment, aiming at disrupting pro-tumorigenic cellular crosstalk and enhancing anti-tumor immune responses.

The association between cancer and inflammation is well established. Chronic inflammation represents a fundamental step in the development and progression of some types of cancer. Tumors are composed of a heterogeneous population of infiltrating cells including macrophages, fibroblasts, lymphocytes, granulocytes, and mast cells, which respond to signals from the microenvironment and, in turn, produce cytokines, chemokines, transcription factors, receptors, and miRNAs. Recent data demonstrate that, in addition to classical (M1) and alternative (M2) macrophage subtypes, there are many intermediate subtypes that potentially play different roles in response to environmental stimuli. Tumors are infiltrated by macrophages called TAMs that mainly display an M2-like phenotype and tumor growth-permissive activities. There is a bidirectional interaction between tumor cells and tumor-infiltrating cells that determines macrophage polarization and ultimately tumor progression or regression. These complex interactions are still unclear but understanding them is fundamental for the development of new therapeutic strategies. Re-educating tumor-permissive macrophages into anti-tumor macrophages is a new focus of research. This review aims to analyze the most recent articles investigating the interplay between tumors, tumor-infiltrating cells, and TAMs, and the strategies for re-educating tumor-permissive macrophages. [ABSTRACT FROM AUTHOR]

Background: Cancer-associated fibroblasts (CAFs) orchestrate a supportive niche that fuels cancer metastatic development in non-small cell lung cancer (NSCLC). Due to the heterogeneity and plasticity of CAFs, manipulating the activated phenotype of fibroblasts is a promising strategy for cancer therapy. However, the underlying mechanisms of fibroblast activation and phenotype switching that drive metastasis remain elusive. Methods: The clinical implications of fibroblast activation protein (FAP)-positive CAFs (FAP+CAFs) were evaluated based on tumor specimens from NSCLC patients and bioinformatic analysis of online databases. CAF-specific circular RNAs (circRNAs) were screened by circRNA microarrays of primary human CAFs and matched normal fibroblasts (NFs). Survival analyses were performed to assess the prognostic value of circNOX4 in NSCLC clinical samples. The biological effects of circNOX4 were investigated by gain- and loss-of-function experiments in vitro and in vivo. Fluorescence in situ hybridization, luciferase reporter assays, RNA immunoprecipitation, and miRNA rescue experiments were conducted to elucidate the underlying mechanisms of fibroblast activation. Cytokine antibody array, transwell coculture system, and enzyme-linked immunosorbent assay (ELISA) were performed to investigate the downstream effectors that promote cancer metastasis. Results: FAP+CAFs were significantly enriched in metastatic cancer samples, and their higher abundance was correlated with the worse overall survival in NSCLC patients. A novel CAF-specific circRNA, circNOX4 (hsa_circ_0023988), evoked the phenotypic transition from NFs into CAFs and promoted the migration and invasion of NSCLC in vitro and in vivo. Clinically, circNOX4 correlated with the poor prognosis of advanced NSCLC patients. Mechanistically, circNOX4 upregulated FAP by sponging miR-329-5p, which led to fibroblast activation. Furthermore, the circNOX4/miR-329-5p/FAP axis activated an inflammatory fibroblast niche by preferentially inducing interleukin-6 (IL-6) and eventually promoting NSCLC progression. Disruption of the intercellular circNOX4/IL-6 axis significantly suppressed tumor growth and metastatic colonization in vivo. Conclusions: Our study reveals a role of the circRNA-induced fibroblast niche in tumor metastasis and highlights that targeting the circNOX4/FAP/IL-6 axis is a promising strategy for the intervention of NSCLC metastasis. [ABSTRACT FROM AUTHOR]

Background: Cyclo-oxygenase-2 (COX-2) and cancer associated fibroblasts (CAFs) play an important role in the development and progression of tumor malignancy in humans and animals, showing that both can influence the tumor microenvironment. However, the impact of these two markers in feline mammary carcinogenesis has not yet been addressed. Materials and Methods: In the present study, the clinicopathological significance of COX-2 immunoexpression and alpha-smooth muscle actin (a-SMA)-positive cancerassociated fibroblasts (CAFs) was determined and correlated with disease-free and overall survival of 50 felines with malignant mammary tumors. Results: COX-2 overexpression was positively associated with mitotic index (p=0.031), degree of malignancy (p=0.001), lymph node metastasis (p=0.001), vascular invasion (p=0.002), disease recurrence (p=0.019) and distant metastasis (p=0.036). a-SMA-positive CAFs were associated with mitotic index (p=0.004), lymph node metastasis (p=0.027), vascular invasion (p=0.05), disease recurrence (p=0.001) and distant metastasis (p=0.001). Additionally, both markers were correlated with disease-free and overall survival, emerging as predictors of poor prognosis. Conclusion: Our results indicate for the first time that the presence of two markers, COX-2 and a-SMA, is associated with carcinogenesis and worse prognosis in feline mammary cancer and that a-SMA-positive CAFs have a role in feline mammary tumorigenesis, cancer development, and clinical outcome. [ABSTRACT FROM AUTHOR]

Abstract Our previous studies have shown that upregulation of SLC7A1 in epithelial ovarian cancer (EOC) tumor cells significantly increases cancer cell proliferation, migration, and cisplatin resistance; however, the molecular mechanism by which SLC7A1 functions in EOC remains unknown. In later studies, we found that SLC7A1 is also highly expressed in the interstitial portion of high‐grade serous ovarian cancer (HGSOC), but the significance of this high expression in the interstitial remains unclear. Here, we showed the Interstitial high expression of SLC7A1 in HGSOC by immunohistochemistry. SLC7A1 enriched in cancer‐associated fibroblasts (CAFs) was upregulated by TGF‐β1. Transwell assay, scratch assay, cck8 assay and cell adhesion assay showed that SLC7A1 highly expressed in CAFs promoted tumor cells invasion, migration and metastasis in vitro. The effect of SLC7A1 on MAPK and EMT pathway proteins in ovarian cancer (OC) was verified by RNA sequencing and western blotting. Overexpression of SLC7A1 in OC is involved in MAPK/ ERK pathway and EMT. In general, in HGSOC, CAFs overexpressing SLC7A1 supported the migration and invasion of tumor cells; SLC7A1 is highly expressed in ovarian cancer and is involved in ERK phosphorylation and EMT signaling in MAPK signaling pathway. This suggests that SLC7A1 may be a potential therapeutic target for OC metastasis.

O presente texto é resultado do Trabalho de Conclusão de Curso - TCC no âmbito do Curso de Licenciatura em Pedagogia - CAFS-UFPI, que teve como objetivo analisar o perfil socioeconômico, profissional e formativo dos egressos do CL em Pedagogia do CAFS/UFPI, entre 2009 e 2019. Trata-se de uma pesquisa exploratória, com uma abordagem quantiqualitativa sob a técnica de análise de conteúdo. Referências básicas: CORRÊA (2022), MARIANO (2006), PDI/UFPI (2020/2024), BARDIN (2016), SELLTIZ (1967), entre outras. A coleta de dados foi realizada através de questionário com perguntas abertas e fechadas enviadas a 378 egressos que fizeram o curso de 2013.1 a 2019.4. Destes egressos, 60 devolveram os questionários respondidos. Os resultados/conclusões são: maioria é do sexo feminino, solteiras/os sem filhos e na faixa etária entre 18 e 35 anos; 54 egressos ganham na faixa de 1 até 5 salários mínimos e maioria tem origem social rural; maioria não trabalhava ao ingressar no curso, hoje 54 estão trabalhando; maioria continuou/continua estudando pós-graduação, latu e stricto sensu; maioria está satisfeita com o curso ao qual atribui conceitos de ótimo e bom; sugestões: fortalecer teoria-prática na atuação docente, formação continuada, ampliação de eventos de ensino, pesquisa, extensão, dentre outras.

Abstract Background Understanding how to modulate the microenvironment of tumors that are resistant to immune checkpoint inhibitors represents a major challenge in oncology.Here we investigate the ability of USP7 inhibitors to reprogram the tumor microenvironment (TME) by inhibiting secretion of vascular endothelial growth factor (VEGF) from fibroblasts. Methods To understand the role played by USP7 in the TME, we systematically evaluated the effects of potent, selective USP7 inhibitors on co‐cultures comprising components of the TME, using human primary cells. We also evaluated the effects of USP7 inhibition on tumor growth inhibition in syngeneic models when dosed in combination with immune checkpoint inhibitors (ICIs). Results Abrogation of VEGF secretion from fibroblasts in response to USP7 inhibition resulted in inhibition of tumor neoangiogenesis and increased tumor recruitment of CD8‐positive T‐lymphocytes, leading to significantly improved sensitivity to immune checkpoint inhibitors. In syngeneic models, treatment with USP7 inhibitors led to striking tumor responses resulting in significantly improved survival. Conclusions USP7‐mediated reprograming of the TME is not linked to its previously characterized role in modulating MDM2 but does require p53 and UHRF1 in addition to the well‐characterized VEGF transcription factor, HIF‐1α. This represents a function of USP7 that is unique to fibroblasts, and which is not observed in cancer cells or other components of the TME. Given the potential for USP7 inhibitors to transform “immune desert” tumors into “immune responsive” tumors, this paves the way for a novel therapeutic strategy combining USP7 inhibitors with immune checkpoint inhibitors (ICIs).

Renal cell carcinoma (RCC) is a common malignancy frequently diagnosed at the metastatic stage. We performed a comprehensive analysis of the tumor immune microenvironment (TIME) in RCC patients, including the peritumoral tissue microenvironment, to characterize the phenotypic patterns and functional characteristics of infiltrating immune cells. T cells from various compartments (peripheral blood, tumor, peritumoral area, and adjacent healthy renal tissue) were assessed using flow cytometry and Luminex analyses, both before and after T cell-specific stimulation, to evaluate activation status and migratory potential. Our findings demonstrated that tumor-infiltrating lymphocytes (TILs) exhibited heightened cytokine production compared to peritumoral T cells (pTILs), acting as the primary source of cytotoxic markers (IFN-γ, granzyme B, and FasL). CD8+ T cells primarily employed Fas Ligand for cytotoxicity, while CD4+ T cells relied on CD107a. In addition, a statistically significant negative correlation between patient mortality and the presence of CD4+CD107+ pTILs was demonstrated. The engagement with the PD-1/PD-L1 pathway was also more evident in CD4+ and CD8+ pTILs as opposed to TILs. PD-L1 expression in the non-leukocyte fraction of the tumor tissue was relatively lower than in their leukocytic counterparts and upon stimulation, peripheral blood T cells displayed much stronger responses to stimulation than TILs and pTILs. Our results suggest that tumor and peritumoral T cells exhibit limited responsiveness to additional activation signals, while peripheral T cells retain their capacity to respond to stimulatory signals

Abstract Background Breast cancer (BC) patients tend to suffer from distant metastasis, especially bone metastasis. Methods All the analysis based on open-accessed data was performed in R software, dependent on multiple algorithms and packages. The RNA levels of specific genes were detected using quantitative Real-time PCR as a method of detecting the RNA levels. To assess the ability of BC cells to proliferate, we utilized the CCK8 test, colony formation, and the 5-Ethynyl-20-deoxyuridine assay. BC cells were evaluated for invasion and migration by using Transwell assays and wound healing assays. Results In our study, we identified the molecules involved in BC bone metastasis based on the data from multiple BC cohorts. Then, we comprehensively investigated the effect pattern and underlying biological role of these molecules. We found that in the identified molecules, the EMP1, ACKR3, ITGA10, MMP13, COL11A1, and THY1 were significantly correlated with patient prognosis and mainly expressed in CAFs. Therefore, we explored the CAFs in the BC microenvironment. Results showed that CAFs could activate multiple carcinogenic pathways and most of these pathways play an important role in cancer metastasis. Meanwhile, we noticed the interaction between CAFs and malignant, endothelial, and M2 macrophage cells. Moreover, we found that CAFs could induce the remodeling of the BC microenvironment and promote the malignant behavior of BC cells. Then, we identified MMP13 for further analysis. It was found that MMP13 can enhance the malignant phenotype of BC cells. Meanwhile, biological enrichment and immune infiltration analysis were conducted to present the effect pattern of MMP13 in BC. Conclusions Our result can improve the understanding of researchers on the underlying mechanisms of BC bone metastasis.

Abstract Background Cancer‐associated fibroblasts (CAFs) are a major stromal component of human breast cancers and often promote tumor proliferation, progression and malignancy. We previously established an experimental CAF (exp‐CAF) cell line equipped with a potent tumor‐promoting ability. It was generated through prolonged incubation of immortalized human mammary fibroblasts with human breast cancer cells in a tumor xenograft mouse model. Results Herein, we found that the exp‐CAFs highly express Runt‐related transcription factor 3 (RUNX3), while counterpart fibroblasts do not. In breast cancer patients, the proportion of RUNX3‐positive stromal fibroblast‐like cells tends to be higher in cancerous regions than in non‐cancerous regions. These findings suggest an association of RUNX3 with CAF characteristics in human breast cancers. To investigate the functional role of RUNX3 in CAFs, the exp‐CAFs with or without shRNA‐directed knockdown of RUNX3 were implanted with breast cancer cells subcutaneously in immunodeficient mice. Comparison of the resulting xenograft tumors revealed that tumor growth was significantly attenuated when RUNX3 expression was suppressed in the fibroblasts. Consistently, Ki‐67 and CD31 immunohistochemical staining of the tumor sections indicated reduction of cancer cell proliferation and microvessel formation in the tumors formed with the RUNX3‐suppressed exp‐CAFs. Conclusion These results suggest that increased RUNX3 expression could contribute to the tumor‐promoting ability of CAFs through mediating cancer cell growth and neoangiogenesis in human breast tumors.

Yue Zhang,1,&ast; Xue Han,1,&ast; Ke Wang,1 Da Liu,1 Xiaoyun Ding,2 Zhiqiang Hu,2 Jing Wang1,3 1School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, People’s Republic of China; 2Oncology Hospital, General Hospital of Ningxia Medical University, Yinchuan, 750004, People’s Republic of China; 3Key Laboratory of Ningxia Minority Medicine Modernization, Ministry of Education, Yinchuan, 750004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhiqiang Hu, Oncology Hospital, General Hospital of Ningxia Medical University, 804 Shengli Street, Yinchuan, 750004, People’s Republic of China, Tel/Fax +86 951 674 3771, Email hzqpty@163.com Jing Wang, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, People’s Republic of China, Tel/Fax +86 951 408 1046, Email jingwang_2023@nxmu.edu.cnPurpose: Immune checkpoint inhibitors (ICI) have received the most attention for triple negative breast cancer (TNBC), while the response rate to ICI remains limited due to insufficient T cell infiltration. It is therefore essential that alternative strategies are developed to improve the therapeutic outcomes of ICI in non-responsive TNBC cases. The efficacy of pH-responsive nanomicelles (P/A/B@NM) co-loaded with paclitaxel (PTX), CXCR4 antagonist AMD3100, and PD-1/PD-L1 inhibitor BMS-1 activating the T cell-mediated antitumor immune response were evaluated using a 4T1 antiPD-1-resistance breast tumor model.Methods: In vitro, pH-responsive antitumor effect of P/A/B@NM was investigated by assessing cell viability, migration and invasion. In vivo, the distribution of P/A/B@NM was visualized in 4T1 orthotopic TNBC model using an IVIS spectrum imaging instrument. The efficacy of the co-delivery nanocarriers was evaluated by monitoring mouse survival, tumor growth and metastasis, cancer-associated fibroblasts (CAFs)-mediated tumor stroma and immunosuppressive microenvironment components, and the recruitment and infiltration of CD8+ T cells.Results: The prepared P/A/B@NM in acid microenvironment demonstrates remarkable cytotoxicity against MDA-MB-231 cells, with an IC50 of 105 μg/mL. Additionally, it exhibits substantial inhibition of tumor cell migration and invasion. The P/A/B@NM based on co-delivery nanocarriers efficiently accumulate at the tumor site and release the drugs in a pH-responsive controlled manner. The nanomedicine-PTX, AMD3100, and BMS-1 formulation significantly inhibits tumor growth and lung/liver metastasis by inducing antitumor immune responses via CXCL12/CXCR4 axis blockade, and immunogenic cell death to reprogramme both tumor stroma and immunosuppressive microenvironment. As a result, CD8+ T cell infiltration is triggered into the tumor site, boosting the efficacy of ICI therapy synergistically.Conclusion: These results demonstrate that combination therapy using P/A/B@NM reshapes CAFs-mediated tumor stroma and immunosuppressive microenvironment, which can enhance the infiltration of CD8+ T cells, thereby reactivating anti-tumor immunity for non-responsive TNBC cases.Keywords: TNBC, immunotherapy, co-delivery nanomicelles, CAFs, immunosuppressive microenvironment

Abstract The receptor for advanced glycation end products (RAGE) is implicated in diabetes and obesity complications, as well as in breast cancer (BC). Herein, we evaluated whether RAGE contributes to the oncogenic actions of Insulin, which plays a key role in BC progression particularly in obese and diabetic patients. Analysis of the publicly available METABRIC study, which collects gene expression and clinical data from a large cohort (n = 1904) of BC patients, revealed that RAGE and the Insulin Receptor (IR) are co-expressed and associated with negative prognostic parameters. In MCF-7, ZR75 and 4T1 BC cells, as well as in patient-derived Cancer-Associated Fibroblasts, the pharmacological inhibition of RAGE as well as its genetic depletion interfered with Insulin-induced activation of the oncogenic pathway IR/IRS1/AKT/CD1. Mechanistically, IR and RAGE directly interacted upon Insulin stimulation, as shown by in situ proximity ligation assays and coimmunoprecipitation studies. Of note, RAGE inhibition halted the activation of both IR and insulin like growth factor 1 receptor (IGF-1R), as demonstrated in MCF-7 cells KO for the IR and the IGF-1R gene via CRISPR-cas9 technology. An unbiased label-free proteomic analysis uncovered proteins and predicted pathways affected by RAGE inhibition in Insulin-stimulated BC cells. Biologically, RAGE inhibition reduced cell proliferation, migration, and patient-derived mammosphere formation triggered by Insulin. In vivo, the pharmacological inhibition of RAGE halted Insulin-induced tumor growth, without affecting blood glucose homeostasis. Together, our findings suggest that targeting RAGE may represent an appealing opportunity to blunt Insulin-induced oncogenic signaling in BC.

Obstructive sleep apnea (OSA) is associated with severity of pneumonia; however, the mechanism by which OSA promotes lung cancer progression is unclear. Twenty-five lung cancer patients were recruited to investigate the relationship between OSA and cancer-associated fibroblast (CAFs) activation. Lung cancer cells (A549) and WI38 fibroblast cells were used to explore the hypoxia-induced TGFβ expression using qPCR, Western blot, and ELISA. Wound healing and transwell assays were performed to evaluate cancer cell migration and invasion. A549 or A549-Luc + WI38 xenograft mouse models were established to detect the intermittent hypoxia (IH) associated with lung tumor growth and epithelial–mesenchymal transition (EMT) in vivo. OSA promotes CAF activation and enrichment in lung cancer patients. Hypoxia (OSA-like treatment) activated TGFβ signaling in both lung cancer cells and fibroblasts, which promoted cancer cell migration and invasion, and enriched CAFs. IH promoted the progression and EMT process of lung cancer xenograft tumor. Co-inoculation of lung cancer cells and fibroblast cells could further promote lung cancer progression. IH promotes lung cancer progression by upregulating TGFβ signaling, promoting lung cancer cell migration, and increasing the CAF activation and proportion of lung tumors. [ABSTRACT FROM AUTHOR]