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HGF in the CAF matrix decreases sensitivity to PAC in SKOV3 and HO-8910 cells (a) SKOV3 or HO-8910 cells were treated with CM, combination of CM and 1.5 μM PAC (CM + PAC), the combination of PAC and CAF matrix (CAFs + PAC), the combination of PAC and HGF (HGF + PAC) or the combination of PAC, CAF matrix and c-Met inhibitor INCB28060 (CAFs + c-Met inhibitor + PAC) for 24h. Cell viability was monitored by MTT assay. (b) SKOV3 cells were treated with CM, CM + PAC, CAFs + PAC, HGF + PAC and CAFs + c-Met inhibitor + PAC for 24 h and then cells were stained with Annexin-V-FITC and propidium iodide. The apoptotic rate was determined by flow cytometry. (c) Quantificative analysis of SKOV3 apoptosis. The graph shows the summarized data. (d) HO-8910 cells were treated with CM, CM + PAC, CAFs + PAC, HGF + PAC and CAFs + c-Met inhibitor + PAC for 24 h and then cells were stained with Annexin-V-FITC and propidium iodide. The apoptotic rate was determined by flow cytometry. (e) Quantificative analysis of SKOV3 apoptosis. Each bar is a mean + − S.D. of three independent experiments; *, P<0.05; **, P<0.01; ***, P<0.001.
Source publication
The tumor microenvironment which is a highly heterogeneous entity plays crucial roles in cancer progression. As the most prominent stromal cell types, cancer-associated fibroblasts (CAFs) produce a variety of factors into the tumor microenvironment. In this study, we firstly isolated CAFs from tumor tissues of the patients with ovarian cancer and d...
Contexts in source publication
Context 1
... next examined the effect of CAF-derived HGF on chemoresistance. MTT assay showed that PAC decreased cell viability by approximately 65%, whereas the combination PAC with CAF matrix or HGF caused a significant increase in cell proliferation (approximately 2-fold) when compared with the cells treated with PAC alone (Figure 4a), suggesting that HGF in the CAF matrix attenuates the effect of PAC on cell proliferation. In addition, the c-Met inhibitor slightly blocked the rescue effect of CAFs, indicating that CAFs blocked PAC-induced apoptosis through activating c-Met (Figure 4a). ...
Context 2
... assay showed that PAC decreased cell viability by approximately 65%, whereas the combination PAC with CAF matrix or HGF caused a significant increase in cell proliferation (approximately 2-fold) when compared with the cells treated with PAC alone (Figure 4a), suggesting that HGF in the CAF matrix attenuates the effect of PAC on cell proliferation. In addition, the c-Met inhibitor slightly blocked the rescue effect of CAFs, indicating that CAFs blocked PAC-induced apoptosis through activating c-Met (Figure 4a). Moreover, Annexin-V-FITC/propidium iodide staining showed that PAC increased the cell apoptotic rate from approximately 6.5 to 39% in SKOV3 cells or from approximately 2 to 22% in HO-8910 cells respectively. ...
Context 3
... contrast, CAF matrix and HGF significantly rescued PAC-induced cell apoptosis in which the cell apoptotic rate reduced to approximately 20 and 13% in SKOV3 and HO-8910 cells respectively. But, when the c-Met inhibitor blocked the CAF signal, the rate of cell apoptosis increased both in SKOV3 and HO-8910 cells (Figure 4b-e). The quantificative data of Annexin-V-FITC/propidium iodide staining were shown in Figure 4c,e. ...
Context 4
... when the c-Met inhibitor blocked the CAF signal, the rate of cell apoptosis increased both in SKOV3 and HO-8910 cells (Figure 4b-e). The quantificative data of Annexin-V-FITC/propidium iodide staining were shown in Figure 4c,e. Taken together, these data indicated that HGF in the CAF matrix induced hyposensitivity to PAC in ovarian cancer cells and the effect of HGF was mediated through c-Met. ...
Citations
... Studies have highlighted the significance of transforming growth factor beta (TGF-β) signaling in promoting OC progression through its interaction with CAFs [10,11]. Activation of the c-Met/PI3K/Akt and GRP78 signaling pathways by CAFs-derived hepatocyte growth factor (HGF) promotes cell proliferation in OC cell lines [12]. The secretion of epidermal growth factor (EGF) by CAFs maintains ITGA5 expression and sustains aggregates formed by CAFs and ascites tumor cells [13]. ...
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.
... The presence of fibrotic residual lesions has been widely observed following neo-adjuvant chemotherapy in OC patients and the chemotherapy response correlates with the amount of stroma [21][22][23] , indicating the potential role of CAFs in chemoresistance. Several mechanisms have been identified by which CAFs induce chemoresistance, including via secretion of IL-6/IL-8 44 , hepatocyte growth factor (HGF) 45 , and miR-522 46 . Here, we report a Wnt5a-mediated paracrine signaling mechanism that is necessary for the maintenance of OCSC population through increased symmetric division of CSCs or prevention of their differentiation and by dedifferentiation of a subpopulation of bulk OC cells. ...
Frequent relapse and chemoresistance cause poor outcome in ovarian cancer (OC) and cancer stem cells (CSCs) are important contributors. While most studies focus exclusively on CSCs, the role of the microenvironment in providing optimal conditions to maintain their tumor-initiating potential remains poorly understood. Cancer associated fibroblasts (CAFs) are a major constituent of the OC tumor microenvironment and we show that CAFs and CSCs are enriched following chemotherapy in patient tumors. CAFs significantly increase OC cell resistance to carboplatin. Using heterotypic CAF-OC cocultures and in vivo limiting dilution assay, we confirm that the CAFs act by enriching the CSC population. CAFs increase the symmetric division of CSCs as well as the dedifferentiation of bulk OC cells into CSCs. The effect of CAFs is limited to OC cells in their immediate neighborhood, which can be prevented by inhibiting Wnt. Analysis of single cell RNA-seq data from OC patients reveal Wnt5a as the highest expressed Wnt in CAFs and that certain subpopulations of CAFs express higher levels of Wnt5a. Our findings demonstrate that Wnt5a from CAFs activate a noncanonical Wnt signaling pathway involving the ROR2/PKC/CREB1 axis in the neighboring CSCs. While canonical Wnt signaling is found to be predominant in interactions between cancer cells in patients, non-canonical Wnt pathway is activated by the CAF-OC crosstalk. Treatment with a Wnt5a inhibitor sensitizes tumors to carboplatin in vivo. Together, our results demonstrate a novel mechanism of CSC maintenance by signals from the microenvironmental CAFs, which can be targeted to treat OC chemoresistance and relapse.
... HGF promotes OC tumor development and drug resistance [72], FGF-1, on the other hand, manages neoplasm growth through FGF-4, elevating Snail1 & MMP3 expression, whit engaging the pathway of MAPK/ERK [73]. Cancer-associated fibroblasts also aid in ovarian neoplasm dissemination via releasing VEGF-A and tenascin-c [74], as well as recruiting immune cells and interacting with a variety of immune components. ...
With poor prognosis for patients with advanced disease, ovarian cancer continues to be the most lethal gynecologic malignancy. Despite optimal treatment, the disease frequently recurs and develops chemoresistance. The tumor immune microenvironment has been predicted to play a special role in tumor development and treatment, by modifying immunosuppressive and cytotoxic responses in close proximity to tumor cells via metabolic reprogramming. A better understanding of the tumor microenvironment’s critical roles allows researchers to develop new therapeutic strategies, such as immunotherapy, to combat epithelial ovarian cancer chemoresistance. Unfortunately, the results of many clinical trials examining immune checkpoint blockade (ICB) have shown very low levels of efficacy for single-agent immune checkpoint inhibitors, and research on combination treatments has not yet identified any combinations with robust activity in a large number of epithelial ovarian cancer patients. The present research will begin with a review of the main concept of immune response inside the ovarian cancer microenvironment. Then, we’ll try to figure out what role various immune checkpoint inhibitors have in the ovarian cancer microenvironment. Finally, we’ll look into several exciting treatment options, such as immune checkpoint inhibition and the body’s anti-ovarian cancer immunological response.
... HGF overexpression was shown to activate MET signaling in an autocrine manner, which increased basal Met phosphorylation to promote cancer cell survival. In addition, HGF secreted from cancerassociated fibroblasts has been reported to protect breast, glioblastoma, lung, and ovarian cancer against classical chemotherapeutic-drug (camptothecin, cisplatin, and doxorubicin)induced apoptosis [184]. Moreover, dysregulated HGF/Met signaling could also activate various downstream effectors including the cellular Src kinase (c-Src), phosphotidylinsitol-3-OH kinase (PI3K), serine/threonine protein kinase (Akt), mitogen-activated protein kinase (MAPK), and the Wnt/β-catenin pathway to promote cell proliferation, invasiveness, morphogenesis, and angiogenesis. ...
The Met protein is a cell surface receptor tyrosine kinase predominantly expressed in epithelial cells. Aberrant regulation of MET is manifested by numerous mechanisms including amplification, mutations, deletion, fusion of the MET proto-oncogene, and protein overexpression. They represent the common causes of drug resistance to conventional and targeted chemotherapy in numerous cancer types. There is also accumulating evidence that MET/HGF signaling drives an immunosuppressive tumor microenvironment and dampens the efficacy of cancer immunotherapy. Substantial research effort has been invested in designing Met-targeting drugs with different mechanisms of action. In this review, we summarized the current preclinical and clinical research about the development of Met-targeting drugs for cancer therapeutics. Early attempts to evaluate Met-targeted therapies in clinical trials without selecting the appropriate patient population did not produce satisfactory outcomes. In the era of personalized medicine, cancer patients harboring MET exon 14 alterations or MET amplification have been found to respond well to Met-inhibitor therapy. The application of Met inhibitors to overcome drug resistance in cancer patients is discussed in this paper. Given that kinases play critical roles in cancer development, numerous kinase-mediated signaling pathways are attractive targets for cancer therapy. Existing kinase inhibitors have also been repurposed to new kinase targets or new indications in cancer. On the other hand, non-oncology drugs have also been repurposed for treating cancer through kinase inhibition as one of their reported anticancer mechanisms.
... CAF-derived CXCL12 also induces EMT via the CXCR4/Wnt/b-catenin pathway; CXCL12 expression was associated with cisplatin chemoresistance in OC patients (123). These findings, together with other evidence, propose CAFs as a modulator cell type with a decisive role in generating chemoresistance, angiogenesis, remodeling, and immunomodulating the TME and the PMN (124)(125)(126). ...
Molecular and cellular components of the tumor microenvironment are essential for cancer progression. The cellular element comprises cancer cells and heterogeneous populations of non-cancer cells that satisfy tumor needs. Immune, vascular, and mesenchymal cells provide the necessary factors to feed the tumor mass, promote its development, and favor the spread of cancer cells from the primary site to adjacent and distant anatomical sites. Cancer-associated fibroblasts (CAFs) are mesenchymal cells that promote carcinogenesis and progression of various malignant neoplasms. CAFs act through the secretion of metalloproteinases, growth factors, cytokines, mitochondrial DNA, and non-coding RNAs, among other molecules. Over the last few years, the evidence on the leading role of CAFs in gynecological cancers has notably increased, placing them as the cornerstone of neoplastic processes. In this review, the recently reported findings regarding the promoting role that CAFs play in gynecological cancers, their potential use as therapeutic targets, and the new evidence suggesting that they could act as tumor suppressors are analyzed and discussed.
... HGF's activity is mediated by c-MET receptor tyrosine kinase [32]. The HGF/MET axis was reported as a potential key contributor to promoting chemoresistance in cancer cells [62]. In our study, exposure to increasing concentrations of HGF resulted in increased proliferation and increased platinum resistance, as evidenced by the reduction in cPARP levels ( Figure 5A). ...
Ovarian cancer (OC) ranks as the second most common type of gynecological malignancy, has poor survival rates, and is frequently diagnosed at an advanced stage. Platinum-based chemother-apy, such as carboplatin, represents the standard-of-care for OC. However, toxicity and acquired resistance to therapy have proven challenging for the treatment of patients. Chemoresistance, a principal obstacle to durable response in OC patients, is attributed to alterations within the cancer cells, and it can also be mediated by the tumor microenvironment (TME). In this study, we report that conditioned medium (CM) derived from murine and human stromal cells, MS-5 and HS-5, respectively , and tumor-activated HS-5, was active in conferring platinum chemoresistance to OC cells. Moreover, CM derived from differentiated murine pre-adipocyte (3T3-L1), but not undifferentiated pre-adipocyte cells, confers platinum chemoresistance to OC cells. Interestingly, CM derived from tumor-activated HS-5 was more effective in conferring chemoresistance than was CM derived from HS-5 cells. Various OC cells exhibit variable sensitivity to CM activity. Exploring CM content revealed the enrichment of a number of soluble factors in the tumor-activated HS-5, such as soluble uPAR (Su-PAR), IL-6, and hepatocyte growth factor (HGF). FDA-approved JAK inhibitors were mildly effective in restoring platinum sensitivity in two of the three OC cell lines in the presence of CM. Moreover, Crizotinib, an ALK and c-MET inhibitor, in combination with platinum, blocked HGF's ability to promote platinum resistance and to restore platinum sensitivity to OC cells. Finally, exposure to 2-hydroxyestardiol (2HE2) was effective in restoring platinum sensitivity to OC cells exposed to CM. Our results showed the significance of soluble factors found in TME in promoting platinum chemoresistance and the potential of combination therapy to restore chemosensitivity to OC cells.
... HGF contributes to desmoplasia as well as to the acidification of the TME through the regulation of tumor metabolism. In ovarian cancer cells, HGF secreted by CAFs increased the therapeutic resistance and cell proliferation [75]. In HNSCC, HGF induces glycolysis, which facilitates the secretion of tumor-derived lactate [4]. ...
Simple Summary
Cancer cells rely on the surrounding environment to grow and spread. This environment contains structural components, secreted factors, immune cells, and other types of cells. Among these, cancer-associated fibroblasts (CAFs) play an important role in tumor cell growth, invasion, and metastasis. CAFs are heterogenous within tumor tissue and across cancer types. Given the plasticity, CAFs are the master tumor microenvironment modifier: an architect and a coordinator. Specifically, they produce and remodel the tumor microenvironment. They also communicate with immune cells, aiding the cancer in evading immune detection. This review highlights the factors and signaling pathways by which CAFs act.
Abstract
Cancer cells rely on the tumor microenvironment (TME), a composite of non-malignant cells, and extracellular matrix (ECM), for survival, growth, and metastasis. The ECM contributes to the biomechanical properties of the surrounding tissue, in addition to providing signals for tissue development. Cancer-associated fibroblasts (CAFs) are stromal cells in the TME that are integral to cancer progression. Subtypes of CAFs across a variety of cancers have been revealed, and each play a different role in cancer progression or suppression. CAFs secrete signaling molecules and remodel the surrounding ECM by depositing its constituents as well as degrading enzymes. In cancer, a remodeled ECM can lead to tumor-promoting effects. Not only does the remodeled ECM promote growth and allow for easier metastasis, but it can also modulate the immune system. A better understanding of how CAFs remodel the ECM will likely yield novel therapeutic targets. In this review, we summarize the key factors secreted by CAFs that facilitate tumor progression, ECM remodeling, and immune suppression.
... For instance, CAFs serve as synthetic machines that release large quantities of factors to involve in tumor proliferation, angiogenesis, tumor metastasis. TGFβ, Fibroblast growth factor 2 (FGF2), matrix metalloproteases 2 (MMP2) and hepatocyte growth factor (HGF) derived from CAF endow tumor cells with stronger proliferative behavior [1,[11][12][13]. Many other factors from CAFs, such as VEGF, PDGF SFRP2, osteopontin, can drive tumor angiogenesis [1,14]. ...
As one of the most essential components of the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) interact extensively with cancer cells and other stromal cells to remodel TME and participate in the pathogenesis of cancer, which earmarked themselves as new promising targets for cancer therapy. Numerous studies have highlighted the heterogeneity and versatility of CAFs in most cancer types. Thus, the identification and appropriate use of CAF-related genes (CAFGenes) in the context of specific cancer types will provide critical insights into disease mechanisms and CAF-related therapeutic targets. In this study, we collected and curated 5421 CAFGenes identified from small- or large-scale experiments, encompassing 4982 responsors that directly or indirectly participate in cancer malignant behaviors managed by CAFs, 1069 secretions that are secreted by CAFs and 281 regulators that contribute in modulating CAFs in human and mouse, which covered 24 cancer types. For these human CAFGenes, we performed gene expression and prognostic marker-based analyses across 24 cancer types using TCGA data. Furthermore, we provided annotations for CAF-associated proteins by integrating the knowledge of protein-protein interaction(s), drug-target relations and basic annotations, from 9 public databases. CAFrgDB (CAF related Gene DataBase) is free for academic research at http://caf.zbiolab.cn and we anticipate CAFrgDB can be a useful resource for further study of CAFs.
... HGF's activity is mediated by c-MET receptor tyrosine kinase [35]. The HGF/MET axis was reported as a potential key contributor to promoting chemoresistance in cancer cells [63]. In our study, exposure to increasing concentrations of HGF resulted in increased proliferation and increased platinum resistance, as evidenced by the reduction of cPARP levels (Fig. 5A). ...
Ovarian cancer (OC) ranks as the second most common type of gynecological malignancy, has poor survival rates, and is frequently diagnosed at an advanced stage. Platinum-based chemotherapy, such as carboplatin, represents the standard-of-care for OC. However, toxicity and acquired resistance to therapy have proven challenging in the treatment of patients, most of who will experience relapse, mainly due to chemoresistance. Chemoresistance, a principal obstacle to durable response in OC patients, is attributed to alterations within the cancer cells, and can also be mediated by the tumor microenvironment (TME).
In this study, we report that conditioned medium (CM) derived from murine and human stromal cells, MS-5 and HS-5 respectively, and tumor-activated HS-5, was active in conferring platinum chemoresistance to OC cells. Moreover, CM derived from differentiated murine pre-adipocyte (3T3-L1), but not undifferentiated pre-adipocyte cells, confers platinum chemoresistance to OC cells. Interestingly, CM derived from tumor-activated HS-5 was more effective in conferring chemoresistance than was CM derived from HS-5 cells.
Various OC cells exhibit variable sensitivity to CM activity. Moreover, exposure of OC to CM affected ERK1/2 phosphorylation in a non-consistent pattern and in a cell-specific manner, and does not correlate with platinum chemoresistance. Exploring CM content revealed the enrichment of a number of soluble factors in the tumor-activated HS-5, such as soluble uPAR (SuPAR), IL-6, and hepatocyte growth factor (HGF). FDA-approved JAK inhibitors were mildly effective in restoring platinum sensitivity in two of the three OC cell lines in the presence of CM. Exposure to increasing concentrations of HGF resulted in increased proliferation and reduced platinum sensitivity. Crizotinib, an ALK and c-MET inhibitor, in combination with platinum, blocked HGF’s ability to promote platinum resistance and restore platinum sensitivity to OC cells. Finally, exposure to 2-hydroxyestardiol (2HE2) was effective in restoring platinum sensitivity to OC cells exposed to CM.
Our results showed the significance of soluble factors found in TME in promoting platinum chemoresistance and the potential of combination therapy to restore chemosensitivity to OC cells.
... The hepatocyte growth factor (HGF) is a key growth factor derived from CAFs. HGF stimulates OC cell growth and drug resistance by activating the c-Met/PI3K/Akt and GRP78 pathways (84). Fibroblast growth factor-1 (FGF-1) is another crucial factor in CAFs. ...
With encouraging antitumor effects, immunotherapy represented by immune checkpoint blockade has developed into a mainstream cancer therapeutic modality. However, only a minority of ovarian cancer (OC) patients could benefit from immunotherapy. The main reason is that most OC harbor a suppressive tumor immune microenvironment (TIME). Emerging studies suggest that M2 tumor-associated macrophages (TAMs), T regulatory cells (Tregs), myeloid-derived suppressor cells (MDSCs), and cancer-associated fibroblasts (CAFs) are enriched in OC. Thus, reversing the suppressive TIME is considered an ideal candidate for improving the efficiency of immunotherapy. Nanoparticles encapsulating immunoregulatory agents can regulate immunocytes and improve the TIME to boost the antitumor immune response. In addition, some nanoparticle-mediated photodynamic and photothermal therapy can directly kill tumor cells and induce tumor immunogenic cell death to activate antigen-presenting cells and promote T cell infiltration. These advantages make nanoparticles promising candidates for modulating the TIME and improving OC immunotherapy. In this review, we analyzed the composition and function of the TIME in OC and summarized the current clinical progress of OC immunotherapy. Then, we expounded on the promising advances in nanomaterial-mediated immunotherapy for modulating the TIME in OC. Finally, we discussed the obstacles and challenges in the clinical translation of this novel combination treatment regimen. We believe this resourceful strategy will open the door to effective immunotherapy of OC and benefit numerous patients.
