Discoidin Domain Receptor 1 Expression in Colon Cancer: Roles and Prognosis Impact

Abstract

Extracellular matrix components such as collagens are deposited within the tumor microenvironment at primary and metastatic sites and are recognized to be critical during tumor progression and metastasis development. This study aimed to evaluate the clinical and prognostic impact of Discoidin Domain Receptor 1 (DDR1) expression in colon cancers and its association with a particular molecular and/or morphological profile and to evaluate its potential role as a prognosis biomarker. Immunohistochemical expression of DDR1 was evaluated on 292 colonic adenocarcinomas. DDR1 was highly expressed in 240 (82.2%) adenocarcinomas. High DDR1 immunostaining score was significantly associated, on univariate analysis, with male sex, left tumor location, BRAF wild type status, KRAS mutated status, and Annexin A10 negativity. High DDR1 immunohistochemical expression was associated with shorter event free survival only. Laser capture microdissection analyses revealed that DDR1 mRNA expression was mainly attributable to adenocarcinoma compared to stromal cells. The impact of DDR1 expression on cell invasion was then evaluated by modified Boyden chamber assay using cell types with distinct mutational profiles. The invasion capacity of colon adenocarcinoma is supported by DDR1 expression. Thus, our results showed that DDR1 was highly expressed in most colon adenocarcinomas and appears as an indicator of worse event free survival.

Clinical significance of immunohistochemical expression of DDR1 and β-catenin in colorectal carcinoma

“…DDR1 was evaluated in all studied cases (carcinoma, adenoma, and control cases). Interpretation of immunostaining included evaluation of expression (positive expression should be considered if any cytoplasmic or membranous brownish staining of cells) [ 22 ] localization (cytoplasmic or membranous), intensity (mild, moderate, and strong), extent (% percent of positivity), and calculation of H-score (calculated based on a linear combination of the percentage of weakly stained cytoplasm/nucleus (WSN)), the percentage of moderately stained cytoplasm/nucleus (MSN), and the percentage of strongly stained cytoplasm/nucleus (SSN) according to the equation: H-score = 1 × WSN + 2 × MSN + 3 × SSN . The final score has a numerical value range from 1 to 300 [ 23 ].…”

“…Discoidin domain receptors (DDRs) are collagen receptors with tyrosine kinase activity with a suggested role in cellular proliferation, tumor invasion, and metastasis [ 5 ]. DDR1 was highly expressed in several tumors including the prostate [ 6 ], lung [ 7 ], breast [ 8 ] ovary [ 9 ], pancreas [ 10 ], liver [ 11 ], and stomach [ 12 ].…”

“…DDR1 was highly expressed in several tumors including the prostate [ 6 ], lung [ 7 ], breast [ 8 ] ovary [ 9 ], pancreas [ 10 ], liver [ 11 ], and stomach [ 12 ]. In CRC, DDR1 expression was recently observed to be associated with more stromal infiltration, upregulation of epithelial-mesenchymal transition genes, transforming growth factor-β (TGF-β) signaling, angiogenesis, matrix remodelling pathways, and complement-mediated inflammation [ 5 ]. On the other hand, a growing body of evidence suggests that DDRs promote apoptosis and suppress tumor progression in various human cancers [ 13 ].…”

The Insulin-like Growth Factor System and Colorectal Cancer

“…DDR1 is expressed in colon mucosa and to a greater extent in cancer than in normal tissue. The association of its expression and tumor prognosis, however, awaits further evaluation [ 193 ].…”

Clinical, Pathological, and Molecular Characteristics in Colorectal Cancer

“…The expression of discoidin domain receptors (DDRs), i.e., collagen receptors with tyrosine kinase activity, was furthermore investigated in a large cohort of CRC patients [ 4 ]. DDRs were found highly expressed in colon adenocarcinoma and associated with a molecular profile that could be integrated within the CMS4 group.…”