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].