Study of the Roles of SDF1 and CXCR4 in Hematopoiesis

Division Of Basic Sciences - Nci

Investigators

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Abstract

During the previous year, we have made the contributions to this research project described below. In the pursuit to discovery of scientifically-defined basis for advance in cancer treatment by targeting the endothelium we have essentially identified a set of angiogenic regulators that variously contribute to tumor angiogenesis. The systematic approach consisted in targeting the regulatory phosphatase SHP2 as an upstream regulator of of the vasculature. We have silenced or inactivated the SHP2 phosphatase in tumor cells that are themselves insensitive to SHP2 inhibition for propagation as tumors. We have then examined the effects of deleting SHP2 in tumors and characterized the tumor vasculature. We found that the tumor vessels are reduced in number but the persisting tumor vessels are functional. Furthermore, we have established that the tumor overall displays a new architecture, where the tumor cells cluster around the viable tumor vessels where they form islands of proliferating tumor, surrounded by areas whether the tumor cells are not viable. Kinetic analysis of this process found that initially tumor angiogenesis occurs, but soon thereafter a selection of vessels destined to survive or regress occurs and at the same time some of the tumor cells demonstrate "angiotropism" towards some of the vessels. Thus we have described a vessel-tumor process that combines angiogenesis and dependency to selected newly-generated vessels for survival. Importantly tumor residency in vessel islands generated a new sensitivity to targeting the MEK/ERK signaling pathway that could be exploited to markedly reduce tumor growth in experimental tumor models of colon carcinoma and melanoma. In ongoing experiments we are now testing structural and biochemical features of human melanoma and colon carcinoma to examine applicability of our preclinical studies to human treatment. Part of these studies have recently been published in the JCI. IN follow-up experiments, we are now examining the spatial "transcritome" of tumor endothelial cells when tumor cells are deprived of the phosphatase SHP2.