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Project 1

Physicochemical Transducer Networks and Their Role in Regulating the Angiogenic Switch Across Multiple Scales

Participants


This project integrates physical sciences and cancer biology approaches to enhance understanding of the cellular and molecular mechanisms that underlie tumor vascularization. Tumor vascularization is ediated in large part by the microenvironmentally controlled angiogenic potential of tumor cells and not only plays a critical role in the growth of primary tumors, but also the metastasis of cancer to distant organs. Our current understanding of tumor vascularization indicates that blood vessel invasion is stimulated by reduced oxygen tension  (i.e., hypoxia) in growing tumors, which acts to induce pro-angiogenic factors, and, finally, endothelial cell sprouting from nearby blood vessels. However, new experimental evidence indicates that bone marrow-derived endothelial (EPCs) and hematopoietic progenitor cells (HPCs) play an important role in this process. These bone marrow cells contribute significantly to tumor neo-angiogenesis, and selective targeting to impair their recruitment to, and incorporation within the developing tumor vasculature has broad implications for the development of antiangiogenic cancer therapies. However, therapeutic modalities targeting the tumor vasculature have relied primarily on a “candidate gene” approach; our proposal, to identify in an unbiased manner extracellular mediators and intracellular signaling pathways of bone marrow cell recruitment represents a major advance.