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Simple Summary: The interplay between the tumour and the immune system plays a vital role in disease progression. There are several mechanisms the tumour imposes to repress the immune response. Dysregulation of non-coding RNAs, the main role of which is to regulate transcription and translation, leads to expressional changes in various signaling molecules and can subsequently affect infiltration and/or activation of immune cells. Here, we focus on the miRNA/lncRNA/protein regulatory axes, which are known to influence the immune response in colorectal cancer. As the current staging and grading systems are not sufficient to stratify patients for therapy and predict the outcome of the disease, there is an urgent need to understand cancer in its complexity. The mutual relationship between tumour and immune or stromal cells leads to rapid evolution and subsequent genetic and epigenetic changes. Immunoscore has been introduced as a diagnostic tool for colorectal cancer (CRC) only recently, emphasising the role of the specific tumor microenvironment in patient's prognosis and overall outcome. Despite the fact that non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), cannot be translated into proteins, they significantly affect cell's transcriptome and translatome. miRNA binding to mRNA efficiently blocks its translation and leads to mRNA destruction. On the other hand, miRNAs can be bound by lncRNAs or circular RNAs (circRNAs), which prevents them from interfering with translation. In this way, ncRNAs create a multi-step network that regulates the cell's translatome. ncRNAs are also shed by the cell as exogenous RNAs and they are also found in exosomes, suggesting their role in intercellular communication. Hence, these mechanisms affect the tumor microenvironment as much as protein signal molecules. In this review, we provide an insight into the current knowledge of the microenvironment, lncRNAs', and miRNAs' interplay. Understanding mechanisms that underlie the evolution of a tissue as complex as a tumour is crucial for the future success in therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This study, which was conducted in healthy mice and mice bearing three mouse mammary gland cancers—4T1, 67NR, and E0771—showed that the divergent effects of vitamin D3 supplementation (5000 IU) or deficiency (100 IU of vitamin D3) observed in healthy mice led to the formation of various body microenvironments depending on the mouse strain. Developing tumors themselves modified the microenvironments by producing higher concentrations of osteopontin, SDF-1 (4T1), TGF-β (4T1 and E0771), CCL2, VEGF, FGF23 (E0771), and IL-6 (67NR), which influences the response to vitamin D3 supplementation/deficiency and calcitriol administration and leads to enhanced/decreased activation of lung fibroblasts and modulation of tumor tissue blood flow. Vitamin D3 and its analogs are known to modulate the activity of fibroblasts under various disease conditions. However, their impact on cancer-associated fibroblasts (CAFs) is yet to be fully investigated. The aim of this study was to characterize CAFs and normal fibroblasts (NFs) from the lung of mice bearing 4T1, 67NR, and E0771 cancers and healthy mice fed vitamin-D3-normal (1000 IU), -deficient (100 IU), and -supplemented (5000 IU) diets. The groups receiving control (1000 IU) and deficient diets (100 IU) were gavaged with calcitriol (+cal). In the 4T1-bearing mice from the 100 IU+cal group, increased NFs activation (increased α-smooth muscle actin, podoplanin, and tenascin C (TNC)) with a decreased blood flow in the tumor was observed, whereas the opposite effect was observed in the 5000 IU and 100 IU groups. CAFs from the 5000 IU group of E0771-bearing mice were activated with increased expression of podoplanin, platelet-derived growth factor receptor β, and TNC. In the 100 IU+cal group of E0771-bearing mice, a decreased blood flow was recorded with decreased expression of fibroblast growth factor 23 (FGF23) and C-C motif chemokine ligand 2 (CCL2) in tumors and increased expression of TNC on CAFs. In the 67NR model, the impact of vitamin D3 on blood flow or CAFs and lung NFs was not observed despite changes in plasma and/or tumor tissue concentrations of osteopontin (OPN), CCL2, transforming growth factor-β, vascular endothelial growth factor, and FGF23. In healthy mice, divergent effects of vitamin D3 supplementation/deficiency were observed, which lead to the creation of various body microenvironments depending on the mouse strain. Tumors developing in such microenvironments themselves modified the microenvironments by producing, for example, higher concentrations of OPN and stromal-cell-derived factor 1 (4T1), which influences the response to vitamin D3 supplementation/deficiency and calcitriol administration. [ABSTRACT FROM AUTHOR]

The pre-metastatic niche constructed by cancer-associated fibroblasts (CAFs) plays a key role in the hypoxic tumor microenvironment (TME), promoting hepatocellular carcinoma (HCC) metastasis. Integrin, which is involved in cell-to-cell or cell-to-matrix interactions and TME regulation, affects tumor metastasis. However, the complex interactions between integrin-mediated HCC cells and CAFs remain unclear. Co-culture experiments were used to assess the behaviors of HCC cells and CAFs, demonstrating HCC metastatic traits and CAFs activation in vitro. Transcriptome sequencing analysis and molecular detection identified key genes, with overexpression and knockdown experiments further confirming their roles in HCC progression. Xenograft models validated these findings in vivo. We showed that HCC cells induced the conversion of normal hepatic stellate cells (HSCs) into CAFs and recruit additional CAFs, driven by lactate produced by HCC. Integrin beta 4 (ITGB4) was identified as a key gene in the process. Inhibiting ITGB4 reduced lactate secretion, reversed CAFs activation and recruitment, and decreased HCC metastasis, while overexpressing ITGB4 significantly enhanced these malignant phenotypes. ITGB4 influences glycolysis and HCC metastasis through the AKT/HK2 signaling pathway, and CAFs activation and recruitment through the TGF-β/Smads signaling pathway. Compared to tumors derived from control cells, ITGB4-knockdown tumors showed fewer and smaller intrahepatic metastatic nodules, reduced lactate production and CAFs formation, along with inhibition of AKT/HK2 and TGF-β/Smads signaling pathways. Our findings highlighted the impact of hypoxia on HCC progression, revealing the roles of ITGB4-mediated glycolysis and lactate-induced CAFs in the pre-metastatic niche on HCC metastasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Immune checkpoint inhibitors (ICIs) offer promise in breaking through the treatment and survival dilemma of triple-negative breast cancer (TNBC), yet only immunomodulatory subtype and ≈5% TNBC patients respond as monotherapy due to lack of effector immune cells (internal problem) and physical barrier (external limitation) formed by cancer-associated fibroblasts (CAFs). A hydrogel drug-delivery platform, ALG@TBP-2/Pt(0)/nintedanib (ALG@TPN), is designed to induce strong immune functions and the dual elimination of the internal and external tumor microenvironment (TME). Activated by white light, through type I and II photodynamic therapy (PDT), TBP-2 generates large amounts of reactive oxygen species (ROS) intracellularly, oxidizing mitochondrial DNA (mtDNA). The unique catalase activity of Pt(0) converts endogenous H 2 O 2 to O 2 , reducing the anoxia-limiting PDT and enhancing ROS generation efficacy. Abundant ROS can oxidize Pt(0) to cytotoxic Pt(II), damaging the nuclear DNA (nDNA). Dual damage to mtDNA and nDNA might bi-directionally activate the cGAS/STING pathway and enhance the immune cell response. Besides, nintedanib demonstrates a significant inhibitory effect on CAFs, weakening the immune barrier and deepening immune cell infiltration. Overall, the study provides a self-oxygenating hydrogel with the "PDT/chemotherapy/anti-CAFs" effect, triggering the cGAS/STING pathway to reshape the TME. Both internal and external interventions increase anti-TNBC immune responses., (© 2024 Wiley‐VCH GmbH.)

Metabolic reprogramming occurs when tumor cells replenish themselves with nutrients required for growth to meet their metabolic needs. Cancer-associated fibroblasts (CAFs) are activated fibroblasts involved in building the c (TME) to promote tumor progression and metastasis. Metabolic reprogramming of CAFs can interact with cancer cells to generate metabolic crosstalk. Furthermore, CAF metabolic reprogramming has great potential as a new field of tumor treatment. This review summarizes the role of CAFs in TME and the mechanisms by which metabolic reprogramming of CAFs causes cancer progression and metastasis, demonstrating the great potential of CAF metabolic reprogramming in cancer chemotherapy and immunotherapy treatment. Furthermore, we provide an outlook for future CAF metabolic reprogramming for cancer treatment., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

While preclinical studies consistently implicate FGFR‑signalling in breast cancer (BC) progression, clinical evidence fails to support these findings. It may be that the clinical significance of FGFR ought to be analysed in the context of the stroma, activating or repressing its function. The present review aimed to provide such a context by summarizing the existing data on the prognostic and/or predictive value of selected cancer‑associated fibroblasts (CAFs)‑related factors, that either directly or indirectly may affect FGFR‑signalling. PubMed (https://pubmed.ncbi.nlm.nih.gov/) and Medline (https://www.nlm.nih.gov/medline/medline_home.html) databases were searched for the relevant literature related to the prognostic and/or predictive significance of: CAFs phenotypic markers (αSMA, S100A4/FSP‑1, PDGFR, PDPN and FAP), CAFs‑derived cognate FGFR ligands (FGF2, FGF5 and FGF17) or inducers of CAFs' paracrine activity (TGF‑β1, HDGF, PDGF, CXCL8, CCL5, CCL2, IL‑6, HH and EGF) both expressed in the tumour and circulating in the blood. A total of 68 articles were selected and thoroughly analysed. The findings consistently identified upregulation of αSMA, S100A4/FSP‑1, PDGFR, PDPN, HDGF, PDGF, CXCL8, CCL5, CCL2, IL‑6, HH and EGF as poor prognostic markers in BC, while evaluation of the prognostic value of the remaining markers varied between the studies. The data confirm an association of CAFs‑specific features with BC prognosis, suggesting that both quantitative and qualitative profiling of the stroma might be required for an assessment of the true FGFR's clinical value.

Abstract To identify novel cancer therapies, the tumor microenvironment (TME) has received a lot of attention in recent years in particular with the advent of clinical successes achieved by targeting immune checkpoint inhibitors (ICIs). The TME consists of multiple cell types that are embedded in the extracellular matrix (ECM), including immune cells, endothelial cells and cancer associated fibroblasts (CAFs), which communicate with cancer cells and each other during tumor progression. CAFs are a dominant and heterogeneous cell type within the TME with a pivotal role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis and chemotherapy resistance. CAFs mediate their effects in part by remodeling the ECM and by secreting soluble factors and extracellular vesicles. Exosomes are a subtype of extracellular vesicles (EVs), which contain various biomolecules such as nucleic acids, lipids, and proteins. The biomolecules in exosomes can be transmitted from one to another cell, and thereby affect the behavior of the receiving cell. As exosomes are also present in circulation, their contents can also be explored as biomarkers for the diagnosis and prognosis of cancer patients. In this review, we concentrate on the role of CAFs-derived exosomes in the communication between CAFs and cancer cells and other cells of the TME. First, we introduce the multiple roles of CAFs in tumorigenesis. Thereafter, we discuss the ways CAFs communicate with cancer cells and interplay with other cells of the TME, and focus in particular on the role of exosomes. Then, we elaborate on the mechanisms by which CAFs-derived exosomes contribute to cancer progression, as well as and the clinical impact of exosomes. We conclude by discussing aspects of exosomes that deserve further investigation, including emerging insights into making treatment with immune checkpoint inhibitor blockade more efficient.

Abstract Radiotherapy (RT) still represents a mainstay of treatment in clinical oncology. Traditionally, the effectiveness of radiotherapy has been attributed to the killing potential of ionizing radiation (IR) over malignant cells, however, it has become clear that therapeutic efficacy of RT also involves activation of innate and adaptive anti-tumor immune responses. Therapeutic irradiation of the tumor microenvironment (TME) provokes profound cellular and biological reconfigurations which ultimately may influence immune recognition. As one of the major constituents of the TME, cancer-associated fibroblasts (CAFs) play central roles in cancer development at all stages and are recognized contributors of tumor immune evasion. While some studies argue that RT affects CAFs negatively through growth arrest and impaired motility, others claim that exposure of fibroblasts to RT promotes their conversion into a more activated phenotype. Nevertheless, despite the well-described immunoregulatory functions assigned to CAFs, little is known about the interplay between CAFs and immune cells in the context of RT. In this review, we go over current literature on the effects of radiation on CAFs and the influence that CAFs have on radiotherapy outcomes, and we summarize present knowledge on the transformed cellular crosstalk between CAFs and immune cells after radiation.

Backgrounds: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the second leading cause of death among all cancers. The Ras-associated binding (Rab) proteins constitute the largest family of the Ras superfamily of small GTPases, which mainly mediate membrane trafficking processes. RAB6B is a member of Rab GTPases, and it has been found to be dysregulated in various tumors. However, the clinical significance, correlations with immune cells, and stroma infiltration of RAB6B in HCC remain unclear. Methods: RAB6B mRNA and protein expression in HCC were examined using the TIMER, HCCDB, UALCAN, and HPA databases. The genetic alterations of RAB6B were analyzed by cBioPortal and COSMIC databases. The correlations between RAB6B and tumor-infiltrating immune cells and cancer-associated fibroblasts were explored by using TIMER, TISIDB, and GEPIA databases. Coexpression networks of RAB6B were investigated based on LinkedOmics. Drug sensitivity was analyzed through the GDSC and CTRP databases. RAB6B was knocked down with siRNA in HCC cell lines. EdU assay was performed to detect the cell proliferation ability, flow cytometry was used to compare the differences in the ability of apoptosis, and MTT was used to evaluate the drug sensitivity in vitro. Results: RAB6B mRNA and protein expression were upregulated in the HCC tissues. Kaplan-Meier and Cox regression analyses suggested that highly expressed RAB6B was an independent prognostic factor for poor survival in HCC patients. Moreover, we found that RAB6B expression was positively correlated with the infiltration of immune cells in HCC, including some immunosuppressive cells, chemokines, and receptors, meanwhile RAB6B expression was associated with CD8+T cells exhaustion, resulting in an immunosuppressive microenvironment. Additionally, functional enrichment analysis indicated that RAB6B may be involved in ECM remodeling in the TME, and RAB6B expression was positively associated with CAFs infiltration. Furthermore, RAB6B presented a positive association with sensitivity to GDSC and CTRP drugs. RAB6B knockdown inhibited the cell proliferation and promoted apoptosis and sensitivity to cisplatin of HCC cells in vitro. Conclusion: Our study revealed that RAB6B is a potential biomarker for poor prognosis in HCC patients and correlates with the formation of the immunosuppressive microenvironment in HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: The extracellular matrix (ECM) controls fundamental properties of tumors, including growth, blood vessel investment, and invasion. The ECM defines rigidity of tumor tissue and individual ECM proteins have distinct biological effects on tumor cells. This article reviews the composition and biological functions of the ECM of clear cell renal cell carcinoma (ccRCC). The most frequent initiating genetic mutation in ccRCC inactivates the VHL gene, which plays a direct role in organizing the ECM. This is predicted to result in local ECM modification, which promotes the growth of tumor cells and the invasion of blood vessels. Later in tumor growth, connective tissue cells are recruited, which are predicted to produce large amounts of ECM, affecting the growth and invasive behaviors of tumor cells. Strategies to therapeutically control the ECM are under active investigation and a better understanding of the ccRCC ECM will determine the applicability of ECM-modifying drugs to this type of cancer. The extracellular matrix (ECM) of tumors is a complex mix of components characteristic of the tissue of origin. In the majority of clear cell renal cell carcinomas (ccRCCs), the tumor suppressor VHL is inactivated. VHL controls matrix organization and its loss promotes a loosely organized and angiogenic matrix, predicted to be an early step in tumor formation. During tumor evolution, cancer-associated fibroblasts (CAFs) accumulate, and they are predicted to produce abundant ECM. The ccRCC ECM composition qualitatively resembles that of the healthy kidney cortex in which the tumor arises, but there are important differences. One is the quantitative difference between a healthy cortex ECM and a tumor ECM; a tumor ECM contains a higher proportion of interstitial matrix components and a lower proportion of basement membrane components. Another is the breakdown of tissue compartments in the tumor with mixing of ECM components that are physically separated in healthy kidney cortex. Numerous studies reviewed in this work reveal effects of specific ECM components on the growth and invasive behaviors of ccRCCs, and extrapolation from other work suggests an important role for ECM in controlling ccRCC tumor rigidity, which is predicted to be a key determinant of invasive behavior. [ABSTRACT FROM AUTHOR]

The main reason for treatment failure in ovarian cancer is chemoresistance and the presence of metastasis. Ascites, which allows the physical movement of cancer cells, the lymphovascular pathway, and several molecular factors and signalling axes, are involved in metastasis. Ascites, with the involvement of cytokines and chemokines, MAPK/STAT1 and NOTCH as well as CXCL12/CXCR4 signaling pathways and circulating anoikis induces cancer dissemination, in particular to the peritoneum and omentum. The spread of lymphatic and bloodstream cancer cells is a multi-stage process. Tumour infiltration of the stroma and lymphovascular space (LVSI) produces biologically active cancer-associated fibroblasts and macrophages (CAFs, TAMs) that secrete numerous cytokines, chemokines and growth factors, inhibit NK function, induce epithelial-mesenchymal transition (EMT), resulting in an increase of the metastatic potential of cancer cells and the formation of cancer stem cells (CSCs). Overexpression of some genes, and microRNAs, in LVSI-(LMGS) associated with metastasis has been identified. The role of extracellular vesicles (EVs) transporting metastasis-associated factors has been described as has the role of cancer stem cells (CSCs) in chemotherapy resistance and metastasis. Sirtuins, enzymes involved in metastasis formation, have also been detected. Certain types of microRNAs (miR-509-3p, microRNA-506-3p) and melatonin have been shown to inhibit metastasis. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OvCa) is one of the most widespread malignant tumors, which has the highest morbidity and unsatisfactory clinical outcomes among all gynecological malignancies in the world. Previous studies found that cancer-associated fibroblasts (CAFs) play significant roles in tumor growth, progression, and chemoresistance. In the current research, weighted gene co-expression network analysis (WGCNA), univariable COX regression, and the least absolute shrinkage and selection operator (LASSO) analysis were applied to recognize CAF-specific genes. After multiple bioinformatic analyses, four genes (AXL, GPR176, ITGBL1, and TIMP3) were identified as OvCa-specific CAF markers and used to construct the prognostic signature (CAFRS). Furthermore, the specificity of the four genes' expression was further validated at the single-cell level, which was high- selectively expressed in CAFs. In addition, our results showed that CAFRS is an independent significant risk factor affecting the clinical outcomes of OvCa patients. Meanwhile, patients with higher CAFRS were more likely to establish chemoresistance to platinum. Besides, the CAFRS were notably correlated with well-known signal pathways that were related to tumor progression. In summary, our study identifies four CAF-specific genes and constructs a novel prognostic signature, which may provide more insights into precise prognostic assessment in OvCa. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is a malignancy that belongs to one of the most common leading causes of cancer death. Cancer-associated fibroblasts (CAFs) promote the GC cells' malignant behavior. It is still unknown how GC converts normal fibroblasts (NFs) to CAFs. Methods: GC cells were co-cultured with NFs. Bioinformatics was used to analyze the genes and signaling pathways that were changed in fibroblast. RT-PCR, western blot, and Elisa assays were used to detect the expression of cytokines in fibroblast and condition medium. Western blot and immunofluorescence demonstrated activation of relevant pathways in CAFs-like cells. Transwell, scrape, colony formation, and CCK-8 assays were performed to reveal the feedback effect of CAFs-like cells on GC cells. Results: GC promoted the conversion of NFs to CAFs by secreting Interleukin 17A (IL-17). It included both morphological and molecular marker changes. This process was achieved by activating the nuclear factor-κB (NF-κB) pathway. On the other hand, CAFs cells could secrete C-X-C Motif Chemokine Ligand 8 (IL-8, IL-8), which promoted the malignant phenotype of GC cells. In this way, a feedback loop of mutual influence was constructed in the GC and tumor microenvironment (TME). Conclusions: Our research proved a novel model of GC-educated NFs. GC-IL-17-fibroblast-IL-8-GC axis might be a potential pathway of the interaction between GC and TME. [ABSTRACT FROM AUTHOR]

Abstract Background Radical surgery is the first line treatment for localized prostate cancer (PC), however, several studies have demonstrated that surgical procedures induce tumor cell mobilization from the primary tumor into the bloodstream. Methods The number and temporal fluctuations of circulating tumor cells (CTC), cancer associated fibroblasts (CAF) and CTC cluster present in each blood sample was determined. Results The results show that both CTC and CTC cluster levels significantly increased immediately following primary tumor resection, but returned to baseline within 2 weeks post-surgery. In contrast, the CAF level decreased over time. In patients who experienced PC recurrence within months after resection, CTC, CAF, and cluster levels all increased over time. Based on this observation, we tested the efficacy of an experimental TNF-related apoptosis-inducing ligand (TRAIL)-based liposomal therapy ex-vivo to induce apoptosis in CTC in blood. The TRAIL-based therapy killed approximately 75% of single CTCs and CTC in cluster form. Conclusion Collectively, these data indicate that CTC cluster and CAF levels can be used as a predictive biomarker for cancer recurrence. Moreover, for the first time, we demonstrate the efficacy of our TRAIL-based liposomal therapy to target and kill prostate CTC in primary patient blood samples, suggesting a potential new adjuvant therapy to use in combination with surgery.

Cancer-associated fibroblasts cells (CAFs) confer a rapid growth and metastasis ability of endometrial cancer (EC) via exosomes-mediated cellular communication. Long non-coding RNA nuclear enriched abundant transcript 1 (lncRNA NEAT1) drives the malignant phenotypes of EC cells. However, the role of exosomal NEAT1 from CAFs in EC progression remains ambiguous, which needs to be investigated. In our study, NEAT1 and YKL-40 were up-regulated, while miR-26a/b-5p was down-regulated in EC tissues. Moreover, NEAT1 expression was increased in CAF-exosomes compared with that in NF-exosomes. In addition, the exosomal NEAT1 derived from CAFs could transfer to EC cells and promote YKL-40 expression. Further exploration showed that exosomal NEAT1 enhanced YKL-40 expression via regulating miR-26a/b-5p-STAT3 axis in EC cells. More importantly, exosomal NEAT1 accelerated in vivo tumor growth via miR-26a/b-5p-STAT3-YKL-40 axis. Taken together, our study reveals that exosomal NEAT1 from CAFs contributes to EC progression via miR-26a/b-5p-mediated STAT3/YKL-40 pathway, which indicates the therapeutic potential of exosomal NEAT1 for treating EC.

There is evidence that demonstrates the effect of cannabinoid agonists inhibiting relevant aspects in lung cancer, such as proliferation or epithelial-to-mesenchymal transition (EMT). Most of these studies are based on evidence observed in in vitro models developed on cancer cell lines. These studies do not consider the complexity of the tumor microenvironment (TME). One of the main components of the TME is cancer-associated fibroblasts (CAFs), cells that are relevant in the control of proliferation and metastasis in lung cancer. In this work, we evaluated the direct effects of two cannabinoid agonists, tetrahydrocannabinol (THC) and cannabidiol (CBD), used alone or in combination, on CAFs and non-tumor normal fibroblasts (NFs) isolated from adenocarcinoma or from healthy lung tissue from the same patients. We observed that these compounds decrease cell density in vitro and inhibit the increase in the relative expression of type 1 collagen (COL1A1) and fibroblast-specific protein 1 (FSP1) induced by transforming growth factor beta (TGFβ). On the other hand, we studied whether THC and CBD could modulate the interactions between CAFs or NFs and cancer cells. We conditioned the culture medium with stromal cells treated or not with THC and/or CBD and cultured A549 cells with them. We found that culture media conditioned with CAFs or NFs increased cell density, induced morphological changes consistent with EMT, inhibited cadherin-1 (CDH1) gene expression, and induced an increase in the relative expression of cadherin-2 (CDH2) and vimentin (VIM) genes in A549 cells. These changes were inhibited or decreased by THC and CBD administered alone or in combination. In another series of experiments, we conditioned culture media with A549 cells treated or not with THC and/or CBD, in the presence or absence of TGFβ. We observed that culture media conditioned with A549 in the presence of TGFβ induced an increase in the expression of COL1A1 and VIM, both in CAFs and in non-tumor NFs. Both THC and CBD ameliorated these effects. In summary, the results presented here reinforce the usefulness of cannabinoid agonists for the treatment of some relevant aspects of lung cancer pathology, and demonstrate in a novel way their possible effects on CAFs as a result of their relationship with cancer cells. Likewise, the results reinforce the usefulness of the combined use of THC and CBD, which has important advantages in relation to the possibility of using lower doses, thus minimizing the psychoactive effects of THC. [ABSTRACT FROM AUTHOR]

Procollagen 11A1 (COL11A1) is a central component of the extracellular matrix in many carcinomas, which is considered to be mainly produced by cancer associated fibroblasts (CAFs). As COL11A1 expression correlates with adverse prognosis and is implicated in chemoresistance, it is a promising putative target. For the first time, we used RNA in-situ hybridization to systematically identify the cells that produce COL11A1 in the ten most prevalent carcinoma types, lymphomas (n = 275) and corresponding normal tissue (n = 55; panCancer cohort). Moreover, as most salivary gland carcinomas (SGC) display distinct stromal architectures, we also analysed 110 SGC. The corresponding protein formation of COL11A1 was determined by MALDI-TOF–MS-Imaging. We report that colon, breast and salivary duct carcinomas are highly infiltrated by COL11A1 positive CAFs (CAFsCOL11A1) and might thus be promising candidates for antidesmoplastic or COL11A1-targeted therapies. The amount of CAFsCOL11A1 correlated significantly with tumour grade, tumour stage and nodal spread in the panCancer cohort. Significant associations between CAFsCOL11A1 and vascular invasion, perineural spread and nodal spread were observed in the SGC cohort. Also, we discovered that tumour cells of intercalated duct derived SGC and CAFs produce COL11A1 in a mutually exclusive manner. Our findings represent a novel mode of extracellular matrix production in carcinomas and could be highly relevant in the future. Our findings elucidate the mode of COL11A1 expression in very different carcinoma types and may aid to categorise tumours in the setting of possible future COL11A1-related therapies. [ABSTRACT FROM AUTHOR]

Insulin-like growth factors binding protein-6 (IGFBP-6) is involved in a relevant number of cellular activities and represents an important factor in the immune response, particularly in human dendritic cells (DCs). Over the past several years, significant insights into the IGF-independent effects of IGFBP-6 were discovered, such as the induction of chemotaxis, capacity to increase oxidative burst and neutrophils degranulation, ability to induce metabolic changes in DCs, and, more recently, the regulation of the Sonic Hedgehog (SHH) signaling pathway during fibrosis. IGFBP-6 has been implicated in different human diseases, and it plays a rather controversial role in the biology of tumors. Notably, well established relationships between immunity, stroma activity, and fibrosis are prognostic and predictive of response to cancer immunotherapy. This review aims at describing the current understanding of mechanisms that link IGFBP-6 and fibrosis development and at highlighting the multiple roles of IGFBP-6 to provide an insight into evolutionarily conserved mechanisms that can be relevant for inflammation, tumor immunity, and immunological diseases. [ABSTRACT FROM AUTHOR]

Backgrounds: Hepatocellular carcinoma (HCC) is a malignant cancer with high mortality. Previous studies have reported that RAB42 is associated with prognosis and progression in glioma. However, the role of RAB42 in HCC is still unknown. Therefore, we aimed to elucidate the value of RAB42 in the predicting prognosis of HCC, and its relationship with immune cells infiltration.Methods: UALCAN, HCCDB, and MethSurv databases were used to examine the expression and methylation levels of RAB42 in HCC and normal samples. cBioPortal and MethSurv were used to identify genetic alterations and DNA methylation of RAB42, and their effect on prognosis. The correlations between RAB42 and the immune cells and cancer-associated fibroblasts infiltration were analyzed by TIMER, TISIDB, and GEPIA database. The LinkedOmics database was used to analyze the enriched pathways associated with genes co-expressed with RAB42. EdU assay was used to evaluate the proliferation ability of liver cancer cells, and transwell assay was used to detect the invasion and migration ability of liver cancer cells.Results: The expression levels of RAB42 were increased in HCC tissues than that in normal tissues. Highly expressed RAB42 was significantly correlated with several clinical parameters of HCC patients. Moreover, increased RAB42 expression clearly predicted poor prognosis in HCC. Furthermore, multivariate Cox regression analysis showed that RAB42 was an independent prognostic factor in HCC. The RAB42 genetic alteration rate was 5%. RAB42 DNA methylation in HCC tissues was lower than that in normal tissues. Among the 7 DNA methylation CpG sites, two were related to the prognosis of HCC. The results of gene set enrichment analysis (GSEA) showed that RAB42 was associated with various immune cells and cancer-associated fibroblasts infiltration in HCC. Meanwhile, we found RAB42 methylation was strongly correlated with immune infiltration levels, immunomodulators, and chemokines. Experiments in vitro indicated that knockdown of RAB42 inhibited the proliferation, invasion, and migration of liver cancer cells.Conclusions: Our study highlights the clinical importance of RAB42 in HCC and explores the effect of RAB42 on immune infiltration in the tumor microenvironment, and RAB42 may act as a pro-oncogene that promotes HCC progression.

Simple Summary: Lung cancer is the leading cause of cancer related deaths and non-small cell lung cancer (NSCLC) is its most relevant subtype. Here, we present data on p53 co-playing 5′-Nucleotidase Domain-Containing Protein 2 (NT5DC2) protein- and gene-expression and its clinical implication and prognostic value. NT5DC2 overexpression was associated with advanced lymphonodal spread and reduced survival in patients with adenocarcinoma of the lung. Moreover, dysregulated p53 in combination with overexpressed NT5DC2 might promote malignancy by interaction with cancer associated fibroblasts. Via immunohistochemistry (IHC) on tissue micro arrays (TMA) clinical and prognostic impact of p53 co-playing 5′-Nucleotidase Domain-Containing Protein 2 (NT5DC2) protein expression was evaluated in 252 NSCLC patients. Confirmatory, gene expression database. mRNA levels of NT5DC2 were studied in 1925 NSCLC patients. High protein expression of NT5DC2 resulted in reduced median overall survival (OS) of patients with stage I-III adenocarcinoma (ADC) (Log Rank p = 0.026, HR 2.04 (1.08–3.87)), but not in squamous cell carcinoma (SCC) (p = 0.514, HR 0.87 (0.57–1.33)). Findings on OS were reproduced via gene expression analysis in ADC (p < 0.001, HR 1.64 (1.30–2.08)) and SCC (p = 0.217, HR 0.86 (0.68–1.09)). Yet, NT5DC2 mRNA levels were higher in SCC compared to ADC (p < 0.001) and in pN2 tumors compared to pN0/1 tumors (p = 0.001). Likewise, NT5DC2 protein expression associated with high-grade SCC. Moreover, NT5DC2 expression was positively correlated with p53 protein (p = 0.018) and TP53 gene expression (p < 0.001) and its survival effect was p53 dependent. While p53 expression was negatively associated with the presence of CD34+ cancer associated fibroblasts (CAFs), NT5DC2 expression insignificantly tended to higher levels of SMA+ CAFs (p = 0.065). [ABSTRACT FROM AUTHOR]

Fibroblasts in the tumor microenvironment have been proven to actively participate in tumor progression; they can be "educated" by cancer cells acquiring an activated state and, as such, are identified as cancer-associated fibroblasts (CAFs); CAFs, in turn, remodel tumor stroma to be more advantageous for cancer progression by modulating several processes, including angiogenesis, immunosuppression, and drug access, presumably driving the chemoresistance. That is why they are believed to hamper the response to clinical therapeutic options. The communication between cancer cells and fibroblasts can be mediated by extracellular vesicles (EVs), composed of both exosomes (EXOs) and microvesicles (MVs). To verify the role of different subpopulations of EVs in this cross-talk, a nearly pure subpopulation of EXO-like EVs and the second one of mixed EXO- and MV-like EVs were isolated from ovarian cancer cells and administered to fibroblasts. It turned out that EVs can activate fibroblasts to a CAF-like state, supporting their proliferation, motility, invasiveness, and enzyme expression; EXO-like EV subpopulation seems to be more efficient in some of those processes, suggesting different roles for different EV subpopulations. Moreover, the secretome of these "activated" fibroblasts, composed of both soluble and EV-associated molecules, was, in turn, able to modulate the response of bystander cells (fibroblasts, tumor, and endothelial cells), supporting the idea that EVs sustain the mutual cross-talk between tumor cells and CAFs. [ABSTRACT FROM AUTHOR]

Nuclear transport factor 2 (NUTF2) is a GDP-binding protein that participates in the nucleocytoplasmic transport process. The role of NUTF2 in cancer development is largely unknown and lacks systemic assessment across human cancers. In this study, we performed a pan-cancer analysis of NUTF2 in human cancers. Out of 33 types of cancers, 19 types had significantly different expression of NUTF2 between tumor and normal tissues. Meanwhile, survival analysis showed that NUTF2 could be an independent prognostic factor in several tumor types. Further analysis suggested that the expression of NUTF2 expression was correlated with the infiltration of immune cells, such as CD8+ T cells, effector memory CD4+ T cells, and cancer-associated fibroblasts in kidney renal clear cell carcinoma. Moreover, co-expression analysis showed the positive association between NUTF2 and cell proliferation biomarkers (MKI67and PCNA) and epithelial–mesenchymal transition markers (VIM, TWIST1, SNAI1, SNAI2, FN1, and CDH2), suggesting that NUTF2 plays important roles in regulating cancer proliferation and metastasis. This pan-cancer analysis of NUTF2 provides a systemic understanding of its oncogenic role across different types of cancers. [ABSTRACT FROM AUTHOR]

Background: Cancer-associated fibroblasts (CAFs) are critically involved in gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanism by which CAFs promote chemotherapy resistance remains unexplored. Here, we explored the role of circRNAs in CAF-induced GEM resistance in PDAC. Methods: circRNA sequencing and quantitative real-time PCR (qRT–PCR) were utilized to screen CAF-specific circRNAs. The effects of CAF circFARP1 expression on GEM resistance in tumor cells were assessed in vitro and in vivo. RNA-seq, RNA pulldown, RNA immunoprecipitation, and luciferase reporter assays were used to screen the downstream target and underlying mechanism of circFARP1. Results: circFARP1 (hsa_circ_0002557), a CAF-specific circRNA, was positively correlated with GEM chemoresistance and poor survival in an advanced PDAC cohort. Silencing or overexpressing circFARP1 in CAFs altered the ability of CAFs to induce tumor cell stemness and GEM resistance via leukemia inhibitory factor (LIF). Mechanistically, we found that circFARP1 directly binds with caveolin 1 (CAV1) and blocks the interaction of CAV1 and the E3 ubiquitin-protein ligase zinc and ring finger 1 (ZNRF1) to inhibit CAV1 degradation, which enhances LIF secretion. In addition, circFARP1 upregulated LIF expression by sponging miR-660-3p. Moreover, high circFARP1 levels were positively correlated with elevated serum LIF levels in PDAC and poor patient survival. Decreasing circFARP1 levels and neutralizing LIF significantly suppressed PDAC growth and GEM resistance in patient-derived xenograft models. Conclusions: The circFARP1/CAV1/miR-660-3p/LIF axis is critical for CAF-induced GEM resistance in PDAC. Hence, circFARP1 may be a potential therapeutic target for PDAC. [ABSTRACT FROM AUTHOR]

The role of fibroblast APC mutation in carcinogenesis is not clear. Apc+/− colon fibroblasts have been previously characterized: however, little is known about their behavior at very early‐stage of colon carcinogenesis. We cultured colon mucosa fibroblasts (PCF, Apc+/−) of Pirc rats (F344/NTac‐Apcam1137) at an early stage of tumorigenesis, in absence of preneoplastic lesions, and of age‐matched wt (WCF): DNA damage levels, inflammatory phenotype and the expression of known markers of CAFs were analyzed. The latter were also assessed by microarray analysis on colon normal mucosa of Pirc and wt animals. PCF exhibited higher proliferative rates (P <.001) and delayed replicative senescence onset (P <.05) compared to WCF, along with a lower level of oxidative DNA damage (P <.05). Furthermore, a constitutively higher expression of COX‐2 and sensitivity to inflammatory stimuli was found in PCF compared to WCF (P <.05), accompanied by higher invasive capability (P <.05) and presence of cytoplasmic chromatin foci (cytoplasmic chromatin foci, P <.05). However, they neither expressed CAFs markers (α‐SMA, IL‐6) nor responded to CAFs activating stimuli (TGF‐β). Accordingly, CAFs markers and activating stimuli resulted down‐regulated in Pirc normal mucosa compared to wt, whereas DNA damage response and tolerance pathways were overexpressed. These data show for the first time that a proliferative and inflammatory phenotype characterizes Apc+/− colon fibroblasts since very early stages of colon tumorigenesis, and indicate a role of Apc mutation in driving fibroblast phenotypic alterations that could support the establishment of a protumorigenic environment. Early pharmacological targeting of these dysfunctions might impact on tumor prevention in FAP patients. What's new? Heterozygous mutations in APC represent the earliest event in sporadic colorectal carcinogenesis onset and cause familial adenomatous polyposis syndrome. However, the role of APC‐mutated fibroblasts remains unclear. Here, Apc+/‐ fibroblasts isolated from apparently‐normal colon tissue of Pirc rats showed proliferative, inflammatory features and resistance to oxidative DNA damage, although they did not show cancer‐associated fibroblast features. These data suggest that, at the very early stages of colon tumourigenesis, Apc‐mutated colon fibroblasts favour the establishment of a pro‐tumourigenic environment for pre‐neoplastic lesion development. Early pharmacological targeting of these dysfunctions might be valuable for tumour prevention in familial adenomatous polyposis patients. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to investigate the effect of overexpression of transforming growth factor β1 (TGF-β1) and stromal cell-derived factor 1 (SDF-1) in cervical cancer-associated fibroblasts (CAFs) on regulating cell growth, invasion and migration. Methods: CAF cells and normal fibroblast cells (NFs) were obtained from patients with cervical squamous cell carcinoma and multiple uterine leiomyomas, respectively. Immunofluorescence assay and western blot were used to determine the expression of Vimentin and α-smooth muscle actin (α-SMA). CCK-8 assay was used to detect cell viability. Giemsa dyer was used to detect the colony formation. Flow cytometry was used to detect the growth state of cells. Transwell assays were used to detect the migration and invasion. Results: Vimentin and α-SMA expression in CAFs were significantly increased than those in NFs. In addition, TGF-β1 and SDF-1 expression were notably increased, and transforming growth factor beta receptor 2 (TβRII) expression was markedly decreased in CAF cells than those in NFs. Similarly, TGF-β1 and SDF-1 expression in the co-culture of CAFs and Hela cells were significantly increased, and cell proliferation, migration, invasion, colony formation and cell cycle progression were also promoted, while cell apoptosis was decreased. Those phenomena were reversed in the co-culture system with neutralizing antibodies to TGF-β1 and SDF-1. Furthermore, exogenous TGF-β1 and SDF-1 enhanced proliferation, colony formation, cell cycle progression, migration and invasion while decreased apoptosis of cells. These phenomena were also reversed by the addition of neutralizing antibodies to TGF-β1 and SDF-1. Conclusion: Overexpression of TGF-β1 and SDF-1 in CAFs can promote the growth, invasion and migration of cervical cancer cells. [ABSTRACT FROM AUTHOR]

Abstract Background In bone-invasive oral squamous cell carcinoma (OSCC), cancer-associated fibroblasts (CAFs) infiltrate into bony tissue ahead of OSCC cells. In the present study, we aimed to investigate the role of the Axin2-Snail axis in the biological behaviour of CAFs and bone invasion in OSCC. Methods The clinicopathological significance of Axin2 and Snail expression was investigated by immunohistochemistry in an OSCC cohort containing 217 tissue samples from patients with long-term follow-up. The influence of the Axin2-Snail axis on the biological behaviour of OSCC cells and CAFs was further investigated both in vitro and in vivo. Results Axin2 expression was significantly associated with Snail expression, the desmoplasia status, and bone invasion in patients with OSCC. In multivariate analysis, lymph node metastasis, desmoplasia, Axin2 expression, and Snail expression were independent poor prognostic factors in our cohort. Consistent with these findings, OSCC cells demonstrated attenuated oncogenic activity as well as decreased expression of Snail and various cytokines after Axin2 knockdown in vitro. Among the related cytokines, C-C motif chemokine ligand 5 (CCL5) and interleukin 8 (IL8) demonstrated a strong influence on the biological behaviour of CAFs in vitro. Moreover, both the desmoplastic reaction and osteolytic lesions in the calvaria were predominantly decreased after Axin2 knockdown in OSCC cells in vivo using a BALB/c athymic nude mouse xenograft model. Conclusions Oncogenic activities of the Axin2-Snail axis are not limited to the cancer cells themselves but rather extend to CAFs via regulation of the cytokine-mediated cancer-stromal interaction, with further implications for bone invasion as well as a poor prognosis in OSCC.

Abstract Tumor microenvironment (TME) is the internal environment in which tumor cells survive, consisting of tumor cells, fibroblasts, endothelial cells, and immune cells, as well as non-cellular components, such as exosomes and cytokines. Exosomes are tiny extracellular vesicles (40-160nm) containing active substances, such as proteins, lipids and nucleic acids. Exosomes carry biologically active miRNAs to shuttle between tumor cells and TME, thereby affecting tumor development. Tumor-derived exosomal miRNAs induce matrix reprogramming in TME, creating a microenvironment that is conducive to tumor growth, metastasis, immune escape and chemotherapy resistance. In this review, we updated the role of exosomal miRNAs in the process of TME reshaping.

Background: Inhibin, beta A (INHBA) is a member of the transforming growth factor-β superfamily and is associated with carcinogenesis and cancer progression in several types of human cancers. However, its significance in breast cancer has not been evaluated. Here, we investigated the prognostic value of INHBA and its correlation with tumor-infiltration immune cells in the microenvironment of breast cancer.Methods: In this study, we analyzed the INHBA expression profile in the Oncomine database and Tumor Immune Estimation Resource 2.0 (TIMER2.0) site. Using Breast Cancer Gene-Expression Miner (bc-GenExMiner v4.7) tool and the UALCAN cancer database, we further evaluated the correlation of INHBA expression with clinicopathological factors in breast cancer. Then, we assessed the clinical prognostic value of INHBA using Kaplan–Meier Plotter and the PrognoScan databases. The correlations between INHBA and tumor-infiltrating immune cells were investigated via TIMER2.0. In addition, correlations between INHBA expression and gene markers of immune infiltrates were analyzed by TIMER2.0 and Gene Expression Profiling Interactive Analysis 2.Results: Compared with the level in normal tissues, the INHBA mRNA expression was upregulated in different subtypes of breast cancer, and its expression was positively correlated with progesterone receptor, human epidermal growth factor receptor-2 status, and PAM50 subtypes but negatively related to age and basal-like status. The INHBA protein was also highly expressed in primary breast cancer and closely related to the pathological stage. Patients with high INHBA expression levels showed worse overall survival, relapse-free survival, and distant metastasis-free survival. Also, high INHBA expression was significantly associated with worse overall survival and relapse-free survival in positive lymph nodes. Of interest, INHBA expression was negatively correlated with infiltrating levels of activated NK cells, NKT, and CD4+ T cells but was positively correlated with tumor infiltration of CD8+ T cells, neutrophils, especially macrophages and cancer-associated fibroblasts. Moreover, INHBA expression showed strong correlations with various markers of monocytes/macrophages and cancer-associated fibroblasts.Conclusion: High INHBA expression is correlated with poor prognosis and the infiltration of immune cells in the tumor microenvironment. These findings suggest that INHBA may be involved in immune escape and can serve as a potential biomarker of prognosis and tumor-infiltrating immune cells.

Fibroblasts in the tumor microenvironment have been proven to actively participate in tumor progression; they can be “educated” by cancer cells acquiring an activated state and, as such, are identified as cancer-associated fibroblasts (CAFs); CAFs, in turn, remodel tumor stroma to be more advantageous for cancer progression by modulating several processes, including angiogenesis, immunosuppression, and drug access, presumably driving the chemoresistance. That is why they are believed to hamper the response to clinical therapeutic options. The communication between cancer cells and fibroblasts can be mediated by extracellular vesicles (EVs), composed of both exosomes (EXOs) and microvesicles (MVs). To verify the role of different subpopulations of EVs in this cross-talk, a nearly pure subpopulation of EXO-like EVs and the second one of mixed EXO- and MV-like EVs were isolated from ovarian cancer cells and administered to fibroblasts. It turned out that EVs can activate fibroblasts to a CAF-like state, supporting their proliferation, motility, invasiveness, and enzyme expression; EXO-like EV subpopulation seems to be more efficient in some of those processes, suggesting different roles for different EV subpopulations. Moreover, the secretome of these “activated” fibroblasts, composed of both soluble and EV-associated molecules, was, in turn, able to modulate the response of bystander cells (fibroblasts, tumor, and endothelial cells), supporting the idea that EVs sustain the mutual cross-talk between tumor cells and CAFs.

Nuclear transport factor 2 (NUTF2) is a GDP-binding protein that participates in the nucleocytoplasmic transport process. The role of NUTF2 in cancer development is largely unknown and lacks systemic assessment across human cancers. In this study, we performed a pan-cancer analysis of NUTF2 in human cancers. Out of 33 types of cancers, 19 types had significantly different expression of NUTF2 between tumor and normal tissues. Meanwhile, survival analysis showed that NUTF2 could be an independent prognostic factor in several tumor types. Further analysis suggested that the expression of NUTF2 expression was correlated with the infiltration of immune cells, such as CD8+ T cells, effector memory CD4+ T cells, and cancer-associated fibroblasts in kidney renal clear cell carcinoma. Moreover, co-expression analysis showed the positive association between NUTF2 and cell proliferation biomarkers (MKI67and PCNA) and epithelial–mesenchymal transition markers (VIM, TWIST1, SNAI1, SNAI2, FN1, and CDH2), suggesting that NUTF2 plays important roles in regulating cancer proliferation and metastasis. This pan-cancer analysis of NUTF2 provides a systemic understanding of its oncogenic role across different types of cancers.

Tumor cells grow in a microenvironment with a lack of nutrients and oxygen. Cancer-associated fibroblasts (CAFs) as one major component of tumor microenvironment have strong ability to survive under stressful conditions through metabolic remodelling. Furthermore, CAFs are educated by tumor cells and help them adapt to the hostile microenvironment through their metabolic communication. By inducing catabolism, CAFs release nutrients into the microenvironment which are taken up by tumor cells to satisfy their metabolic requirements. Furthermore, CAFs can recycle toxic metabolic wastes produced by cancer cells into energetic substances, allowing cancer cells to undergo biosynthesis. Their metabolic crosstalk also enhances CAFs' pro-tumor phenotype and reshape the microenvironment facilitating tumor cells' metastasis and immune escape. In this review, we have analyzed the effect and mechanisms of metabolic crosstalk between tumor cells and CAFs. We also analyzed the future perspectives in this area from the points of CAFs heterogeneity, spatial metabonomics and patient-derived tumor organoids (PDOs). These information may deepen the knowledge of tumor metabolism regulated by CAFs and provide novel insights into the development of metabolism-based anti-cancer strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xiong, Xu, Zhou, Tong and Yu.)

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., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

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., (© 2024 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

Background: The tumor microenvironment (TME) plays an important role in the progression of renal cell carcinoma (RCC). Cancer-associated fibroblasts (CAFs) are considered to constitute a major component of the TME and participate in various tumor-promoting molecular events. We have previously confirmed that CD248 represents a promising biomarker of CAFs, which may provide insight into CAF-based tumor-promoting effects. However, CAF-mediated tumor progression and the potential mechanism of CD248 remain largely unknown in RCC patients. Methods: Expression profiling and clinical data of RCC patients were obtained from The Cancer Genome Atlas (TCGA) database. An MCP-counter algorithm and Kaplan–Meier survival analysis were performed to explore the prognostic value of CAFs and CD248, respectively. A Pearson correlation coefficient test and Student's t -test were employed to evaluate the relationship between immunosuppressive TME and CD248 or CAFs. Immunohistochemistry and immunofluorescence staining were performed to confirm CD248 expression within CAFs. CD248-specific siRNA was used to investigate the potential function of CD248 in CAF tumor promotion. Differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), and enrichment analysis were conducted to clarify the function of CD248+ CAFs in RCC progression and the associated regulatory mechanism. Results: CD248 overexpression and CAF infiltration could predict poor RCC prognosis, which may involve the immunosuppressive TME. CD248 may serve as a promising CAFs biomarker and be involved with the tumor-promoting effect of CAFs. Moreover, CD248+ CAF infiltration may contribute to RCC progression and an immunosuppressive TME through cell-extracellular matrix (ECM) interactions and metabolism regulation. Conclusion: CD248+ CAFs participate in the regulation of RCC progression and immunosuppressive TME, which may represent a novel prognostic and therapeutic target for RCC. [ABSTRACT FROM AUTHOR]

To identify novel cancer therapies, the tumor microenvironment (TME) has received a lot of attention in recent years in particular with the advent of clinical successes achieved by targeting immune checkpoint inhibitors (ICIs). The TME consists of multiple cell types that are embedded in the extracellular matrix (ECM), including immune cells, endothelial cells and cancer associated fibroblasts (CAFs), which communicate with cancer cells and each other during tumor progression. CAFs are a dominant and heterogeneous cell type within the TME with a pivotal role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis and chemotherapy resistance. CAFs mediate their effects in part by remodeling the ECM and by secreting soluble factors and extracellular vesicles. Exosomes are a subtype of extracellular vesicles (EVs), which contain various biomolecules such as nucleic acids, lipids, and proteins. The biomolecules in exosomes can be transmitted from one to another cell, and thereby affect the behavior of the receiving cell. As exosomes are also present in circulation, their contents can also be explored as biomarkers for the diagnosis and prognosis of cancer patients. In this review, we concentrate on the role of CAFs-derived exosomes in the communication between CAFs and cancer cells and other cells of the TME. First, we introduce the multiple roles of CAFs in tumorigenesis. Thereafter, we discuss the ways CAFs communicate with cancer cells and interplay with other cells of the TME, and focus in particular on the role of exosomes. Then, we elaborate on the mechanisms by which CAFs-derived exosomes contribute to cancer progression, as well as and the clinical impact of exosomes. We conclude by discussing aspects of exosomes that deserve further investigation, including emerging insights into making treatment with immune checkpoint inhibitor blockade more efficient. [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) still represents a mainstay of treatment in clinical oncology. Traditionally, the effectiveness of radiotherapy has been attributed to the killing potential of ionizing radiation (IR) over malignant cells, however, it has become clear that therapeutic efficacy of RT also involves activation of innate and adaptive anti-tumor immune responses. Therapeutic irradiation of the tumor microenvironment (TME) provokes profound cellular and biological reconfigurations which ultimately may influence immune recognition. As one of the major constituents of the TME, cancer-associated fibroblasts (CAFs) play central roles in cancer development at all stages and are recognized contributors of tumor immune evasion. While some studies argue that RT affects CAFs negatively through growth arrest and impaired motility, others claim that exposure of fibroblasts to RT promotes their conversion into a more activated phenotype. Nevertheless, despite the well-described immunoregulatory functions assigned to CAFs, little is known about the interplay between CAFs and immune cells in the context of RT. In this review, we go over current literature on the effects of radiation on CAFs and the influence that CAFs have on radiotherapy outcomes, and we summarize present knowledge on the transformed cellular crosstalk between CAFs and immune cells after radiation. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) have important roles in promoting cancer development and progression. We previously reported that high expression of sex-determining region Y (SRY)-box9 (SOX9) in oral squamous cell carcinoma (OSCC) cells was positively correlated with poor prognosis. This study developed three-dimensional (3D) in vitro models co-cultured with OSCC cells and CAFs to examine CAF-mediated cancer migration and invasion in vitro and in vivo. Moreover, we performed an immunohistochemical analysis of alpha-smooth muscle actin and SOX9 expression in surgical specimens from 65 OSCC patients. The results indicated that CAFs promote cancer migration and invasion in migration assays and 3D in vitro models. The invading OSCC cells exhibited significant SOX9 expression and changes in the expression of epithelial–mesenchymal transition (EMT) markers, suggesting that SOX9 promotes EMT. TGF-β1 signalling inhibition reduced SOX9 expression and cancer invasion in vitro and in vivo, indicating that TGF-β1-mediated invasion is dependent on SOX9. In surgical specimens, the presence of CAFs was correlated with SOX9 expression in the invasive cancer nests and had a significant impact on regional recurrence. These findings demonstrate that CAFs promote cancer migration and invasion via the TGF-β/SOX9 axis.

BackgroundThe tumor microenvironment (TME) plays an important role in the progression of renal cell carcinoma (RCC). Cancer-associated fibroblasts (CAFs) are considered to constitute a major component of the TME and participate in various tumor-promoting molecular events. We have previously confirmed that CD248 represents a promising biomarker of CAFs, which may provide insight into CAF-based tumor-promoting effects. However, CAF-mediated tumor progression and the potential mechanism of CD248 remain largely unknown in RCC patients.MethodsExpression profiling and clinical data of RCC patients were obtained from The Cancer Genome Atlas (TCGA) database. An MCP-counter algorithm and Kaplan–Meier survival analysis were performed to explore the prognostic value of CAFs and CD248, respectively. A Pearson correlation coefficient test and Student’s t-test were employed to evaluate the relationship between immunosuppressive TME and CD248 or CAFs. Immunohistochemistry and immunofluorescence staining were performed to confirm CD248 expression within CAFs. CD248-specific siRNA was used to investigate the potential function of CD248 in CAF tumor promotion. Differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), and enrichment analysis were conducted to clarify the function of CD248+ CAFs in RCC progression and the associated regulatory mechanism.ResultsCD248 overexpression and CAF infiltration could predict poor RCC prognosis, which may involve the immunosuppressive TME. CD248 may serve as a promising CAFs biomarker and be involved with the tumor-promoting effect of CAFs. Moreover, CD248+ CAF infiltration may contribute to RCC progression and an immunosuppressive TME through cell-extracellular matrix (ECM) interactions and metabolism regulation.ConclusionCD248+ CAFs participate in the regulation of RCC progression and immunosuppressive TME, which may represent a novel prognostic and therapeutic target for RCC.

In this collectively drafted Commentary, we offer some reflections on the past year for CAFS (Canadian Association for Food Stuides), and the state of food studies in general. Note: this is a modified version of the 2021 CAFS Presidential Address, given at the joint CAFS/ASFS/AFHVS/SAFN Conference Just Food: Because it never it just Food on June 10th, 20201.

Currently, exosomes derived from Cancer-associated fibroblast (CAF) have reportedly been involved in regulating hepatocellular carcinoma (HCC) tumour microenvironment (TME). LIM domain and actin binding 1 (LIMA1) is an actin-binding protein that is involved in controlling the biological behaviour and progression of specific solid tumours. We aimed to determine the effect of LIMA1 and exosome-associated miR-20a-5p in HCC development. LIMA1 and miR-20a-5p expression levels were examined by real-time quantitative PCR (qRT-PCR), western blotting or immunohistochemistry (IHC). Functional experiments, including Cell Counting Kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU) assays, colony formation assays, wound healing assays, and Transwell invasion assays, were performed to investigate the effect of LIMA1 and miR-20a-5p. A dual-luciferase reporter gene assay was performed to confirm the interaction of miR-20a-5p and LIMA1. Exosomes were characterised by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting. We noted that LIMA1 was downregulated in human HCC tissues and cells and remarkably correlated with overall survival (OS) and recurrence-free survival (RFS). LIMA1 overexpression suppressed HCC cell proliferation and metastasis in vitro and in vivo, while LIMA1 knockdown had the opposite effects. A mechanistic investigation showed that LIMA1 inhibited the Wnt/β-catenin signalling pathway by binding to BMI1 and inducing its destabilisation. Additionally, we found that LIMA1 expression in HCC cells could be suppressed by transferring CAF-derived exosomes harbouring oncogenic miR-20a-5p. In summary, LIMA1 is a tumour suppressor that inhibits the Wnt/β-catenin signalling pathway and is downregulated by CAF-derived exosomes carrying oncogenic miR-20a-5p in HCC.