5098

CXCL-8, a member of the CXC chemokine family, is constitutively expressed in malignant melanoma and functions as an autocrine/paracrine growth, invasive and angiogenic factor. Two high affinity receptors of CXCL-8, CXCR1 and CXCR2, are differentially expressed on melanoma cells as well as on endothelial cells. We have demonstrated that CXCR1 is constitutively expressed in all the melanoma cases irrespective of stage and grade, however, CXCR2 expression is restricted to aggressive melanoma tumors, with higher metastatic potential. The precise functional role of these receptors in melanoma growth and angiogenesis remains unclear. To gain insight into their functional role, we stably overexpressed CXCR1 or CXCR2 in A375P (tumorigenic, low metastatic) and A375SM (tumorigenic and highly metastatic) melanoma cells. Cells over-expressing CXCR1 or CXCR2 exhibited significant increase in CXCL-8-mediated proliferation and survival as compared to control (vector-transfected) cells. Moreover, we observed that overexpression of CXCR1 or CXCR2 significantly enhanced chemotaxis and chemo-invasion, which also correlated with cytoskeletal changes, (F-actin reorganization) and nuclear localization of β-catenin. In vivo studies demonstrated an enhanced tumor growth and angiogenesis in CXCR1- or CXCR2-overexpressing melanoma cells as compare to control cells. In addition, there was a significant increase in proliferating cells and decrease in number of apoptotic cells in tumors over-expressing CXCR1 or CXCR2 as compare to control tumors. We did not observe significant difference in cellular phenotypes associated with tumor growth and metastasis between melanoma cells over-expressing CXCR1 or CXCR2. Together these data demonstrate that activation of CXCR1 or CXCR2 by CXCL-8 in malignant melanoma is important and have overlapping role in regulating the cellular proliferation, migration, invasion and tumor growth.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

American Association for Cancer Research
2008