Lung cancer is the leading cause of cancer-related death worldwide. Lung cancer comprises two main histologic subtypes: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC, which includes large-cell carcinoma, squamous cell carcinoma, and adenocarcinoma, is the predominant form of lung cancer [1, 2]. Despite many advances in several fields of oncology, lung cancer treatment has not progressed significantly. Understanding the biological pathways involved in the cause of lung cancer is needed to recognize important biomolecules as diagnostic markers and new targeted therapies .
Discoidin domain receptors (DDRs) are kinds of tyrosine kinase receptors (RTKs) that have an extracellular discoidin homology domain for collagen binding and activation. DDR1 and DDR2 are two types of DDRs. The only RTKs that recognize specific amino acid motifs in collagen (binding motif: GVMGFO, six amino acid) and collagen activate them are the DDRs. The DDRs are important transmembrane regulators that, as part of extracellular matrix networks, regulate signaling and cell-matrix interactions. Therefore, the DDRs are involved in cancer progression by controlling the interactions between tumor cells and the collagen matrix around them [4–7].
Discoidin domain receptor 1 gene has 17 exons that are alternatively spliced to generate five DDR1 isoforms (a–e) that differ in the cytoplasmic region. DDR1 is widely distributed in the body but is expressed mainly in epithelial cells and is activated by fibrillar and non-fibrillar collagens. DDR1 signaling has been indicated to play a critical role in various cellular functions such as ECM remodeling, proliferation, survival, migration, immune response, differentiation, and wound healing. Different studies have shown DDR1 expression in a variety of human cancers such as renal clear cell carcinoma, breast cancer, non-small cell lung carcinoma, prostate cancer, esophageal cancer, and hepatocellular carcinoma indicating the function of DDR1 in tumor progression [7–12].
Angiogenesis is a vital process required for a variety of physiological and pathological functions, such as inflammation, metabolic diseases, wound repair, and tumor progression. As cancer progresses, angiogenesis is important to provide nutrition and remove waste products for tumor proliferation, survival and metastasis. Many different proteins have been discovered as proangiogenic and antiangiogenic molecules that regulate angiogenesis and their expression level determines the tumor cells invasion. Proangiogenic factors, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) have been identified as activators of angiogenesis [13, 14].
VEGF is one of the most effective angiogenic components that play a critical role in neovascularization. The VEGF family consists of six famous members. VEGF-A is a glycoprotein that has several molecular isoforms and is also called VEGF or VPE (vascular permeability factor). VEGF-stimulated signal activates various downstream proteins such as phospholipase Cγ, PI3-K, GAP, the Ras GTPase-activating protein, p38MAPK, ERK, p125FAK, and inducing cell progression. VEGF-A is a strong and particular mitogen for vascular endothelial cells that stimulates the angiogenesis pathways and is up-regulated in different tumors [15, 16].
FGF is another essential molecule that regulates angiogenesis. The FGF family includes nine sperate members. FGF-1 (acidic, aFGF) and FGF-2 (basic, bFGF) are indicated as potent activators of angiogenesis. FGF binds to specific receptors resulting in activation of downstream signal transduction cascade and play important roles in wound healing and embryonic development. Moreover, some FGF signaling promotes tumor angiogenesis and growth . Additionally, VEGF and bFGF act as antiapoptotic agents for the neovascularization, because they stimulate antiapoptotic molecules (like Bcl-2) expression and increase endothelial cell survival [18, 19].
In the current study, we evaluated the expression of DDR1 that induced by collagen type I and inhibited by siRNA in non-small cell lung cancer cells. Then, we investigated the expression of VEGF-A, FGF-1, and FGF-2 to find whether expression alteration in angiogenic factors were correlated with expression of DDR1 in NSCLC.