Will the Stroma-derived Factor-1α (CXCL12)/CXCR4 Pathway Become a Major Concern for Advanced Colorectal Cancer?

Abstract

See Article on Page 27-34 The chemokine stroma-derived factor (SDF-1α/CXCL12) is a homeostatic chemokine. The major function of this chemokine is to regulate hematopoietic cell trafficking and secondary lymphoid tissue architecture [1]. SDF-1α is also widely expressed in various organs. Including the heart, liver, brain, kidney, skeletal muscle, and lymphoid organs, and it plays multiple roles in tumor pathogenesis. SDF-1α has been demonstrated to promote tumor growth, enhance tumor angiogenesis, participate in tumor metastasis, and contribute to immunosuppressive networks within the tumor microenvironment. SDF-1α expression is reported in ovarian cancer, breast cancer [2], colorectal cancer, pancreatic cancer, prostate cancer, thyroid cancer, and many other human tumors. SDF-1α can increase the invasiveness and the migration of cancer cells, and its levels are correlated with node involvement and long-term survival in patients with breast cancer. SDF-1 may, therefore, have potential value in assessing clinical outcomes of patients with breast cancer [3]. Although colorectal cancer (CRC) tissues contain SDF-1α-positive stromal cells, immunohistochemistry clearly demonstrated that the cancerous cells in more than 50% of the CRC samples examined had much stronger expression of SDF-1α than their neighboring normal colonic epithelial cells. Accordingly, as with CXCR4 overexpression, the SDF-1α/CXCR4 pathway appears to play important roles in the progression of CRC [4]. In this study, the authors merely measured the SDF-1α expression level in the normal colonic mucosa and in colorectal cancer tissue. If this study had included the SDF-1α specific receptor CXCR4 expression level, the authors would have obtained better results. Nevertheless, the results are quite impressive. SDF-1α expression was highly correlated with pericolic lymph-node metastasis, distant metastasis, tumor-node-metastasis stage and lymphovascular invasion. Strong SDF-1α expression was inversely related with patients' survival, suggesting suggest SDF-1α could be a prognostic factor. Further study evaluating the distinctive value of SDF-1α expression in clinical practice may be warranted. According to the literature, it is evident that manipulation of this pathway represents a new strategy for cancer treatment. CXCR4 antagonists, such as Plerixafor (AMD3100) and T140 analogues (TN14003/BKT140), and blocking antibodies toward CXCR4 or SDF-1α are being investigated in various cancer settings. In an in vitro study using a colorectal cancer cell line, results indicate that a CXCR4-antagonistic therapy might prevent tumor cell dissemination and metastasis in CRC patients, consequently improving survival [5]. Of course, we need to bear in mind that although targeting CXCR4/CXCL12 is an attractive option in treating human tumors, it is certain that to gain effective, reliable, and consistent clinical efficacy, a definitive combinatorial therapeutic regimen should be found.