Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in tumor stroma, are important modifiers of tumor progression. However, the mechanisms underlying stromal fibroblast activation and their promotion of tumor growth remain largely unknown in gastric cancer. Here, we show that normal fibroblasts (NFs) from non-cancerous regions of gastric cancer exhibit the traits of CAFs when grown together with gastric cancer cells in vivo. Activation of NFs can be induced by co-culture with gastric cancer cells, while deprivation of hepatocyte growth factor (HGF) using a neutralizing antibody inhibits the activation of NFs. Moreover, we identify HGF as an important factor from CAFs that acts in a paracrine manner to promote tumorigenesis in vitro and in vivo. Taken together, these results suggest that HGF may play a pivotal role in the regulatory circuit between gastric cancer cells and stromal fibroblasts, and neutralization of HGF inhibits both activation and tumor-promoting properties of CAFs.

Cancer associated fibroblasts (CAFs) is one of the most crucial components of the tumor microenvironment which promotes the growth and invasion of cancer cells by various mechanisms. CAFs demonstrate a high degree of heterogeneity due to their various origins; however, many distinct morphological features and physiological functions of CAFs have been identified. It is becoming clear that the crosstalk between the cancer cells and the CAFs plays a key role in the progression of cancer, and understanding this mutual relationship would eventually enable us to treat cancer patients by targeting CAFs. In this review, we will discuss the latest findings on the role of CAFs in tumorigenesis and metastasis as well as potential therapeutic implication of CAFs.

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.

AbstractCancer-associated fibroblasts (CAFs) comprise a heterogeneous population of stromal cells within the tumour microenvironment. CAFs exhibit both tumour-promoting and tumour-suppressing functions, making them exciting targets for improving cancer treatments. A careful identification and characterisation of the CAF heterogeneity is thus necessary before implementing CAF-targeted strategies in cancer. With that in mind, we developed a flow cytometry strategy based on exclusion of non-CAF cells and successfully employed it to explore the temporal heterogeneity of CAFs in two models of triple-negative breast cancer (4T1 and 4T07). Analysing 128 murine tumours we identified 5-6 main CAF subpopulations and numerous minor ones based on the analysis of alpha smooth muscle actin, fibroblast activation protein alpha, platelet derived growth factor receptor alpha and beta, CD26/DPP4 and podoplanin. All markers showed temporal changes, and CD26+ CAFs emerged as a large novel subpopulation. These results form the foundation needed for the future elucidation of tumour-promoting CAF subpopulations.

Cancer-associated fibroblasts (CAFs), as a central component of the tumor microenvironment in primary and metastatic tumors, profoundly influence the behavior of cancer cells and are involved in cancer progression through extensive interactions with cancer cells and other stromal cells. Furthermore, the innate versatility and plasticity of CAFs allow their education by cancer cells, resulting in dynamic alterations in stromal fibroblast populations in a context-dependent manner, which highlights the importance of precise assessment of CAF phenotypical and functional heterogeneity. In this review, we summarize the proposed origins and heterogeneity of CAFs as well as the molecular mechanisms regulating the diversity of CAF subpopulations. We also discuss current strategies to selectively target tumor-promoting CAFs, providing insights and perspectives for future research and clinical studies involving stromal targeting.

Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment and mediate tumor progression in various cancers. A previous study demonstrated that TRAF6 promotes the malignant phenotype of melanoma cells. However, the role of TRAF6 in melanoma CAFs remains unclear. In this study, we found that TRAF6 was significantly upregulated in CAFs adjacent to melanoma cells. Functional assays showed that TRAF6 promoted fibroblast proliferation and migration as well as MMP and α-SMA expression. Moreover, the expression of TRAF6 in fibroblasts promoted the malignant phenotype of melanoma cells invitro and invivo. Meanwhile, the intervention of TRAF6 expression in melanoma cells affected the activation of CAFs. We found that FGF19 was a key cytokine regulated by TRAF6 through NF-κB1 using luciferase assay and chromatin immunoprecipitation in melanoma cells. Because plasma FGF19 levels are elevated in patients with melanoma, it may significantly induce fibroblast activation invitro and invivo. Taken together, our results support that TRAF6 is a key molecule that mediates the interaction between melanoma cells and stromal fibroblasts, suggesting that TRAF6 is a potentially promising target in melanoma therapy.

Reciprocal interactions between cancer cells and stromal cells in the tumor microenvironment (TME) are essential for full-blown tumor development. Carcinoma-associated fibroblasts (CAFs) are a key component of the TME together with a wide variety of stromal cell types including vascular, inflammatory, and immune cells in the extracellular matrix. CAFs not only promote tumor growth, invasion, and metastasis, but also dampen the efficacy of various therapies including immune checkpoint inhibitors. CAFs are composed of distinct fibroblast populations presumably with diverse activated fibroblastic states and tumor-promoting phenotypes in a tumor, indicating intratumor heterogeneity in these fibroblasts. Given that CAFs have been implicated in both disease progression and therapeutic responses, elucidating the functional roles of each fibroblast population in CAFs and the molecular mechanisms mediating their phenotypic stability and plasticity in the TME would be crucial for understanding tumor biology. We herein discuss how distinct fibroblast populations comprising CAFs establish their cell identities, in terms of cells-of-origin, stimuli from the TME, and the phenotypes characteristic of activated states.

Cancer-associated fibroblasts (CAFs) are important, highly heterogeneous components of the tumor extracellular matrix that have different origins and express a diverse set of biomarkers. Different subtypes of CAFs participate in the immune regulation of the tumor microenvironment (TME). In addition to their role in supporting stromal cells, CAFs have multiple immunosuppressive functions, via membrane and secretory patterns, against anti-tumor immunity. The inhibition of CAFs function and anti-TME therapy targeting CAFs provides new adjuvant means for immunotherapy. In this review, we outline the emerging understanding of CAFs with a particular emphasis on their origin and heterogeneity, different mechanisms of their regulation, as well as their direct or indirect effect on immune cells that leads to immunosuppression.

Cancer is a systemic disease encompassing multiple components of both tumor cells themselves and host stromal cells. It is now clear that stromal cells in the tumor microenvironment play an important role in cancer development. Molecular events through which reactive stromal cells affect cancer cells can be defined so that biomarkers and therapeutic targets can be identified. Cancer-associated fibroblasts (CAFs) make up the bulk of cancer stroma and affect the tumor microenvironment such that they promote cancer initiation, angiogenesis, invasion, and metastasis. In breast cancer, CAFs not only promote tumor progression but also induce therapeutic resistance. Accordingly, targeting CAFs provides a novel way to control tumors with therapeutic resistance. This review summarizes the current understandings of tumor stroma in breast cancer with a particular emphasis on the role of CAFs and the therapeutic implications of CAFs. In addition, the effects of other stromal components such as endothelial cells, macrophages, and adipocytes in breast cancer are also discussed. Finally, we describe the biologic markers to categorize patients into a specific and confirmed subtype for personalized treatment.

In tumor tissues, activated stromal fibroblasts, termed cancer-associated fibroblasts (CAFs), exhibit similar characteristics to myofibroblasts. CAFs promote cancer cell differentiation and invasion by releasing various factors, such as growth factors, chemokines, and matrix-degrading proteases, into neighboring tumor cells. However, the roles of tumor microenvironment in case of radiation-induced carcinogenesis remain poorly understood. We recently revealed that mitochondrial oxidative stress causestumormicroenvironment formation associated with radiation-induced cancer. Repeated low-dose fractionated radiation progressively damages fibroblast mitochondria and elevates mitochondrial reactive oxygen species (ROS) levels. Excessive mitochondrial ROS activate transforming growth factor-beta (TGF-β) signaling, thereby inducing fibroblasts activation and facilitating tumor microenvironment formation. Consequently, radiation affects malignant cancer cells directly and indirectly via molecular alterations in stromal fibroblasts, such as the activation of TGF-β and angiogenic signaling. This review summarizes for the first time the roles of mitochondrial oxidative stress in microenvironment formation associated with radiation-induced cancer. This review may help us understand the risks of exposure to low-dose radiation. The cross talk between cancer cells and stromal fibroblasts contributes to the development and progression of radiation-induced cancer.