Cancer-associated fibroblasts
Cancer-associated fibroblasts are one of the important components of the tumor microenvironment, which are activated by growth factors, direct intercellular communication, adhesion molecules, and other factors. Different from normal fibroblasts, CAFs are perpetually activated, do not return to normal phenotype and apoptosis, also promote tumor progression[48]. CAFs play an important role in the malignant progression of cancer by releasing growth factors and cytokines which stimulate angiogenesis, cell proliferation, invasion, and metastasis[48]. The function of CAFs in EGFR-TKIs sensitive lung cancer is different from that in EGFR-TKIs resistant lung cancer (Figure 1B). In vitro and in vivo experiments showed that CAFs in EGFR-TKIs resistant lung cancer increased the expression and phosphorylation of ANXA2 by secretion of growth factors HGF and IGF-1 and by activation of the corresponding receptors c-met and IGF-1R, which induced EMT of tumor cells and promoted EGFR-TKIs resistance[49]. In addition, CD200-positive CAFs in tumor tissues can augment the sensitivity of EGFR mutant tumor cells to EGFR TKI[50]. Another study found that podoplanin-positive CAFs promoted tumor cells to EGFR-TKIs resistance and inhibition of the expression of podoplanin in CAFs can reverse the drug resistance[51]. A recent study found that mesenchymal cells isolated from EGFR mutant lung cancer can differentiate into CAFs which can promote tumor invasion and metastasis[52].