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].