Molecular mechanism underlying the tumor-promoting functions of carcinoma-associated fibroblasts

Abstract

Tumor microenvironment is composed of all the untransformed elements in the vicinity of tumor, mainly including a large number of stromal cells and extracellular matrix proteins, which play an active role in most solid tumor initiation and progression. Carcinoma-associated fibroblasts (CAFs), one of the most common stromal cell types in the tumor microenvironment, have been demonstrated to be involved in tumor growth, invasion, and metastasis. Therefore, they are becoming a promising target for anti-cancer therapies. In this review, we firstly summarize the current understandings of CAFs' molecular biology, including the heterogeneous cellular origins and molecular markers, and then, we focus on reviewing their various tumor-promoting phenotypes involved in complex mechanisms, which can be summarized to the CAF-conveyed paracrine signals in tumor cells, cancer stem cells, and metastasis-initiating cancer cells, as well as the CAF-enhanced extrinsic tumor-promoting processes including angiogenesis, extracellular matrix remodeling, and tumor-related inflammation; finally, we describe the available directions of CAF-based target therapy and suggest research areas which need to be further explored so as to deepen the understanding of tumor evolution and provide new therapeutic targets for cancer treatment.

MicroRNAs in the Communication between Cancer Associated Fibroblasts (CAF) and Cancer Cells

“…Deregulation of miRs in fibroblasts in general appears to induce as major effects smooth muscle α-actin (α-SMA) upregulation and modulated secretion of cytokines including: increased IL-6 and CXCL12, activation of the TGF-ß and inhibition of various signaling pathways, such as the PI3K-AKT pathways. [2,3,20] Various miRs interfere with multiple cellular functions and therefore be found at different point in the subsequent listing.…”

“…[2] MiR-146b inhibition is sufficient to transactivate NFs into CAFs, which promote EMT transition in breast cancer cells in a paracrine manner. [40] In a similar manner miR-148a targets genes of the WNT family, WNT1 and WNT10b with comparable cellular effects.…”

“…[1] For example, CAFs can promote tumorigenesis, growth, invasion and metastasis of cancer, whereas NFs are thought to suppress tumor progression. [2] As one key event CAF activation appears to induce alternative production and secretion of extracellular matrix (ECM) proteins resulting in ECM remodeling and cancer cell invasion. [3] Resulting desmoplasia is not only attributed to CAFs but also to surrounding stellate cells, which are believed to play critical roles in conferring cancer aggressiveness.…”

Stromal expression of matrix metalloproteinase 2 in cancer-associated fibroblasts is strongly related to human epidermal growth factor receptor 2 status in invasive breast carcinoma

“…Over several years, the majority of studies on breast carcinoma have focused only on the epithelial component; however, the tumor-associated stroma and particularly the cancer-associated fibroblasts (CAFs) have been found to play a crucial role in cancer pathogenesis (1,2).…”

Application of post-genomic techniques in dog cancer research

“…Carcinoma-associated fibroblasts provide the main cancer stromal structure. 48 Gene expression studies of cancer cell lines co-cultured with carcinoma-associated fibroblasts have demonstrated that 100 genes were upregulated in cancer cells as compared to individual cell lines. 49 This group of genes codes for proteins involved in cell adhesion, such as chondroadherin, CLEC7A, protocadherin-19, desmoplakin, and VCAM-1, and angiogenesis, such as EMT.…”