EGFR-Dependent Extracellular Matrix Protein Interactions Might Light a Candle in Cell Behavior of Non-Small Cell Lung Cancer

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.

Keywords: epidermal growth factor receptor (EGFR); extracellular matrix (ECM); glycoproteins; integrin receptors; matrix metalloproteinases (MMPs); non-small cell lung cancer (NSCLC); proteoglycans; tyrosine kinase inhibitors (TKIs)..

Figure 1

EGFR-mediated ECM remodeling during lung cancer progression. EGFR and ECM receptors, integrins, results in Akt, Erk, and Ras pathways’ activation that participate in increasing cell migration, invasion, survival, and motility and repressing cell apoptosis; (A) Normal ECM in healthy tissue; (B) Neoplastic cells with uncontrolled cell growth promote ECM remodeling during lung cancer progression; (C) Tumor migration and invasion are mediated by collagen alignment and ECM stiffness. Blue arrows point to stimulation, upright-directed red arrows point to increase effect, and dashed red arrows point to cellular effect.

Figure 2

Fibulins-mediated EGFR signaling pathways and matrix metalloproteinases in lung cancer. Fibulin (FBLN) family includes many types such as FBLN1,3&5 serve as tumor-suppressor proteoglycans. FBLN1 can inhibit EGFR activation and thus suppress cell proliferation. FBLN3 can compete with EGF and IGF-1 binding to their receptors; it also can inhibit transcription of oncogenic matrix metalloproteinases (MMP2& MMP9). FBLN3/5 can inhibit MMP7 and Erk pathway activation and thus inhibit cell invasion. Blue arrows for stimulation; dashed red arrows for cellular effect, and red “T” sign for inhibition.

Figure 3

Dual effect of ECM glycoproteins and proteoglycans in lung cancer. Tumor-promoting glycoproteins (e.g., laminin 5 and fibronectin); laminin expression enhances phospho-EGFR or phospho-Akt expression and loss of PTEN; fibronectin activates toll-like receptors (TLRs) to promote NF-κB activation as well as EGFR-dependent Akt/mTOR/p70S6K signaling pathway; and thus, it stimulates cell proliferation and differentiation in lung cancer. Tumor-promoting proteoglycans (e.g., GPC5) prompted cell migration and metastasis. Tumor-suppressing glycoproteins (e.g., fibulins1,3, and 5) compete with EGF and inhibit EGFR activation. Tumor-suppressing proteoglycans (e.g., GPC3 and SDC‐1) can regulate EGF and many intracellular signaling pathways inhibiting cell invasion and migration. Blue arrows for stimulation; dashed red arrows for cellular effect; and red “T” sign for inhibition.

Figure 4

ECM proteins and integrins regulate EGFR signaling pathways in lung cancer. The crosstalk between EGFR and integrins includes many signaling pathways: (A) ligand-independent pathway, where integrins can biochemically bind to EGFR leading to its activation. EGFR can interact with integrins via forming a multimeric complex (Src, FAK, and the adaptor protein p130Cas), leading to cell survival and proliferation, (B) ligand-dependent pathway, where integrin clustering enhances EGFR signaling cascades upon EGFR ligand binding, resulting in enhancing Akt, ERK, and Ras signaling pathways, and (C) integrin trafficking controls the membrane expression of EGFR. Blue arrows for stimulation; dashed red arrows for cellular effect, and red “T” sign for inhibition.