Metastasis-associated fibroblasts: an emerging target for metastatic cancer

Abstract

Metastasis suggests a poor prognosis for cancer patients, and treatment strategies for metastatic cancer are still very limited. Numerous studies have shown that cancer-associated fibroblasts (CAFs), a large component of the tumor microenvironment, contribute to tumor metastasis. Stromal fibroblasts at metastatic sites are different from CAFs within primary tumors and can be termed metastasis-associated fibroblasts (MAFs), and they also make great contributions to the establishment of metastatic lesions and the therapeutic resistance of metastatic tumors. MAFs are capable of remodeling the extracellular matrix of metastatic tumors, modulating immune cells in the tumor microenvironment, promoting angiogenesis and enhancing malignant tumor phenotypes. Thus, MAFs can help establish premetastatic niches and mediate resistance to therapeutic strategies, including immunotherapy and antiangiogenic therapy. The results of preclinical studies suggest that targeting MAFs can alleviate the progression of metastatic cancer and mitigate therapeutic resistance, indicating that MAFs are a promising target for metastatic cancer. Here, we comprehensively summarize the existing evidence on MAFs and discuss their origins, generation, functions and related therapeutic strategies in an effort to provide a better understanding of MAFs and offer treatment perspectives for metastatic cancer.

Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs)

“…The role of tumor stromal cells, particularly CAFs, in the induction of migration in carcinoma cells has been shown previously [29]. To study the potential of PFD in reducing invasive properties of carcinoma cells, we first co-cultured MCF7 carcinoma cells known as low-vimentin expressers with CAF-CM for 48 h and then treated cells with a low concentration of PFD (40 µM) for 72 h (Figure 4A).…”

Tumor metastasis: Mechanistic insights and therapeutic interventions

“…Fibroblasts distributed in the metastatic site are called metastasis‐associated fibroblasts (MAFs), which promote angiogenesis and the formation of immunosuppressive microenvironment in pre‐metastatic niche. 138 The main difference between MAFs and primary tumor‐related fibroblasts is that MAFs have a stronger ability to inhibit the anti‐tumor effect of immune cells, which is reflected explicitly in the higher levels of CC motif chemokines ligand 2 (CCL2), CXCL12, and interferon‐related genes secreted by MAFs. 139 Additionally, in metastatic liver cancer and gastric cancer, it was found that the decrease of CD3+ infiltrating lymphocytes and the increase of TAM cells were related to the high levels of MAFs, partly due to the chemokine CXC receptor 4 (CXCR4) signal transduction in α‐smooth muscle actin (α‐SMA)+ MAFs.…”

“…69 As presented earlier, immune cells (e.g., TAMs, Treg, and neutrophil), stromal cells (e.g., CAFs, MSCs, and TECs), chemokines, cytokines, and growth factors in TME, are involved in a complex crosstalk with tumor cells that affects tumor growth and metastasis. 69 , 79 , 138 , 406 Furthermore, recent studies have emphasized the role of autophagy, lipid metabolism, and lncRNA in tumor metastasis. 212 , 240 , 255 …”

Contradictory roles of lipid metabolism in immune response within the tumor microenvironment

“…Except for immune cells, cancer-associated fibroblasts (CAFs) represent a dominant component of the tumor stroma and contribute significantly to the formation of the TME. CAFs can facilitate the malignant phenotype of tumor cells, reinforce therapy resistance, and modulate other tumor-infiltrating immune cells by depositing and remodeling the extracellular matrix, and secreting cytokines or direct cell–cell contact [ 14 ].…”