Abstract
Angiogenesis is a critical factor in the growth and dissemination of solid tumors. Indeed, tumor vasculature is abnormal and contributes to the development and spread of malignancies by creating a hostile microenvironment. The alternative SDF-1/CXCL12 receptor, CXCR7, is frequently and specifically expressed in tumor-associated vessels. In this study, we examine the role of endothelium-expressed CXCR7 in tumor vascular dysfunction by specifically examining the contribution of CXCR7 to endothelial cell (EC) proliferation. We demonstrate that CXCR7 expression is sufficient to drive post-confluent growth in EC cultures. Further, we provide a novel mechanism for CXCR7-mediated proliferation via proteasomal degradation of the tumor suppressor protein Rb. These findings identify a heretofore unappreciated role for CXCR7 in vascular dysfunction and confirm this receptor as a plausible target for anti-tumor therapy.
Highlights
Angiogenesis is the process by which new vessels form from existing vascular networks in both the blood and lymphatic circulatory systems
In order to determine whether adenovirus-expressed CXCR7 is displayed at the cell surface, we performed FACS analysis of cultures transduced with increasing doses of CXCR7, gating stringently on intact cells via propidium iodide exclusion
We chose to do our experiments in primary human lymphatic Endothelial cells (EC) because this lineage displays more robust growth in static culture compared to primary blood vascular lineage EC and has uniformly low levels of baseline CXCR7 expression compared to primary umbilical vein EC, in which we observe sporadic induction of CXCR7 in single cells
Summary
Angiogenesis is the process by which new vessels form from existing vascular networks in both the blood and lymphatic circulatory systems. This highly regulated process is critical for wound healing and tissue regeneration but is co-opted in a variety of pathogenic processes including angioproliferative diseases and the growth of aberrant vasculature into tumors [1]. EC are long-lived, quiescent cells that are highly dependent upon cell-cell and cell-substrate adhesion for their survival and function Angiogenesis requires both EC migration into an angiogenic niche and EC proliferation in order to form new vascular structures [2]. Tumor vascular dysfunction exacerbates the development and spread of cancer by selecting for tumor cells that can survive and proliferate under these adverse conditions, thereby enhancing malignancy and driving the development of metastases [3]
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