The overall poor outcomes in ESCC are thought because of
The overall poor outcomes in ESCC are thought because of a combination of late diagnosis, aggressiveness of the disease, and a lack of effective treatment strategies for systemic disease. Several molecular pathways, such as epidermal growth factor receptor, vascular endothelial growth factor, and p53, have been investigated to comprehend the underlying biology of the disease and improve treatment strategies.7, 8 However, these investigations have been unsuccessful in developing and effective targeted therapy. Moreover, molecular biomarkers capable of predicting recurrence of localized disease have not yet been developed, thus relegating treatment decisions regarding systemic therapy to a later time after patients present with recurrence.
In this study, we turned our attention to whether the discoidin domain receptor-1 (DDR1) could be a potential prognostic biomarker in ESCC. DDR1 is a tyrosine kinase receptor which is activated by collagen and is expected to play a key role in cancer progression by promoting the interactions of cancer PKI-402 receptor with the surrounding collagens. DDR1 shares homology of the N-terminal domain with a related kinase receptor, DDR2, and its expression was accidentally discovered through a screen for tyrosine kinase proteins in human malignancies. Although increased expression of DDR1 has been reported in many types of aggressive tumors, the potential importance of DDR1 in upper aerodigestive squamous cell cancers was suggested because increased levels of phosphorylated DDR1 (pDDR1) were found predominantly in squamous cell lung cancers. Because little is known about the role of DDR1 in ESCC, we retrospectively explored levels of total DDR1 (tDDR1) and pDDR1 in ESCC, to examine whether or not DDR1 can be a biomarker to evaluate long-term outcome.
Materials and methods
Discussion DDR1 is a receptor protein kinase that is activated by collagen which also interacts with epithelial cells to regulate cell polarity and differentiation. Collagen in the extracellular matrix demonstrates a barrier to prevent tumor cells to invade into adjacent normal tissues. In malignant transformation, the interactions of epithelial cells with the surrounding extracellular matrix are fundamentally altered.17, 18 Almost all human cancers display dysregulated expression and function of one or more receptor tyrosine kinases, and the DDR family of kinases are unique in terms of response to collagen as a ligand. DDRs have been shown to be key regulators of aggressive characteristics such as cellular proliferation, migration, and invasion. The increased expression of these collagen-related receptor tyrosine kinases in various human cancers suggests that they may be involved in proliferation of cancer cells.12, 20 Supporting that DDRs play a role in tumorigenesis, experiments have shown that inhibiting DDR1 by small interfering RNA suppresses tumor development and progression, and these findings have supported the possibility of DDR1 as a molecular target for anticancer drugs. The relationship of DDR1 expression to tumor aggressiveness or patient outcome has been investigated for other types of cancer, but these other investigations have typically only considered expression of tDDR1 protein. For example, Quan et al. reported that the DDR1 protein was highly expressed in 69% (46/67) of serous ovarian cancer tissue samples, and that its expression was correlated with pathologic grade of the tumor and clinical disease stage at the time of surgery. In colorectal cancer, Hu et al. found that increased DDR1 and decreased miR-199a-5p expression coexisted in colorectal cancer and suggested that upregulation of DDR1 induced by miR-199a-5p downregulation may contribute to activation of epithelial-mesenchymal transition and progression of colorectal cancer. Jian et al. found that DDR1 mRNA expression (by microarray analysis) was significantly higher in hepatocellular cancers with early recurrence compared with those without early recurrence using microarray technology and confirmed an association of evaluated DDR1 protein levels to early outcome using IHC. Immunohistochemical measurements of increased DDR1 protein in tumors have also been shown to correlate with poor survival for patients with bone metastasis in lung cancer, higher frequency of lymph node metastases in non–small cell lung cancer, and more frequent recurrences. Interestingly, ameloblastoma is generally classified as a benign neoplasm, and even in this situation, high expression of DDR1 protein correlates with aggressive clinical behavior.