Abstract
Lung cancer remains the leading cause of cancer-related death and is associated with a poor prognosis. Lung cancer is divided into 2 main types: the major in incidence is non-small cell lung cancer (NSCLC) and the minor is small cell lung cancer (SCLC). Although NSCLC progression depends on driver mutations, it is also affected by the extracellular matrix (ECM) interactions that activate their corresponding signaling molecules in concert with integrins and matrix metalloproteinases (MMPs). These signaling molecules include cytoplasmic kinases, small GTPases, adapter proteins, and receptor tyrosine kinases (RTKs), particularly the epidermal growth factor receptor (EGFR). In NSCLC, the interplay between ECM and EGFR regulates ECM stiffness, angiogenesis, survival, adhesion, migration, and metastasis. Furthermore, some tumor-promoting ECM components (e.g., glycoproteins and proteoglycans) enhance activation of EGFR and loss of PTEN. On the other hand, other tumor-suppressing glycoproteins and -proteoglycans can inhibit EGFR activation, suppressing cell invasion and migration. Therefore, deciphering the molecular mechanisms underlying EGFR and ECM interactions might provide a better understanding of disease pathobiology and aid in developing therapeutic strategies. This review critically discusses the crosstalk between EGFR and ECM affecting cell behavior of NSCLC, as well as the involvement of ECM components in developing resistance to EGFR inhibition.
Highlights
Lung cancer is the foremost cause of cancer-related death, accounting for 2.09 million cases and 1.76 million deaths in 2018, according to GLOBOCAN [1]
The increased Postn expression in the nonsmall cell lung cancer (NSCLC) A549 cells is one form of cellular response to chemical-mimic hypoxia stress, and this effect can be controlled by hypoxia-inducible growth factors like TGF-a and bFGF, which trigger the receptor tyrosine kinases (RTKs)/PI3-K pathway leading to upregulation of Postn, and in turn, facilitating the survival of A549 cells in a hypoxic microenvironment via the Akt/PKB pathway [89]
extracellular matrix (ECM) proteins associated with poor NSCLC prognosis via crosstalk with epidermal growth factor receptor (EGFR), including COLs, matrix metalloproteinases (MMPs)-9, MUC1, MUC5AC, Ln 5, and GPC5
Summary
Lung cancer is the foremost cause of cancer-related death, accounting for 2.09 million cases and 1.76 million deaths in 2018, according to GLOBOCAN [1]. ECM is composed of a non-cellular network of proteins, proteoglycans, glycoproteins, and polysaccharides that constitute the interstitial matrix (IM) and the basement membrane (BM) [17] The latter is a well-structured membrane, underlining epithelial and endothelial cells under healthy conditions to separate them from the IM, which constitutes the main stroma and plays a significant role in cell adhesion, cell migration, tissue development, angiogenesis, and repair [18]. It is well-known that carcinogenesis is multistep genetic and epigenetic variations, resulting in oncogenes overexpression and downregulation of tumor suppressor genes [19]. We highlight the different types of ECM proteins and their roles in mediating EGFR signaling to pinpoint their significance in NSCLC as biomarkers for diagnosis and prognosis and their potential as druggable targets
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