Extracellular matrix
The extracellular matrix (ECM) is the non-cellular component present
within all tissues and organs, and provides not only essential physical
scaffolding for the cellular constituents but also initiates crucial
biochemical and biomechanical cues that are required for tissue
morphogenesis, differentiation, and homeostasis[42]. The interaction
between NSCLC tumor cells with EGFR mutation and the ECM is crucial for
tumor development (Figure 1A). EGFR mutation can increase twist, snail,
and other gene expression in the process of tumor development, which
induced epithelial mesenchymal transition (EMT) and promoted tumor cell
invasion and metastasis, EGFR-TKIs can inhibit EMT and prevent tumor
cell invasion and metastasis[43, 44]. The activation of EGFR in
tumor cells can also increase the activity of matrix metalloproteinase-9
(MMP-9), which can promote the destruction of the ECM barrier and the
invasiveness of tumor cells[45, 46]. In recent years, many studies
have found that ECM is related to EGFR-TKIs resistance. The ECM of tumor
cells with EGFR-TKIs resistance highly expresses integrin-β1, which is a
collagen receptor, and produces a large amount of collagen around the
tumor cells. The sensitive cell lines showed EGFR-TKIs resistance after
co-cultured with Integrinβ-1 which was extracted from drug-resistant
cell lines, and inhibition of integrinβ-1 expression can reverse
EGFR-TKIs resistance[47].