The AACR Judah Folkman Fellowship for Angiogenesis Research isopen to postdoctoral and clinical research fellows with a medical degree or a combined M.D./Ph.D., working at an academic, medical or research institution, who will be in the first five years of their postdoctoral training at the start of the grant term. Proposed research projects are restricted to basic, clinical, translational or epidemiological projects that substantially advance the field of angiogenesis research in cancer.
Fusanori Yotsumoto, M.D., Ph.D.
Postdoctoral Fellow, Sanford-Burnham Medical Research Institute, La Jolla, CA
Stromal Control of Brain Tumor Angiogenesis and Progression by NG2-PG
Establishment of a viable blood supply is thought to be required for the transition of hyperplastic foci to full-blown malignancies, a process often referred to as the angiogenic switch. This has led to a number of attempts to block tumor progression via anti-angiogenic therapy, mostly using the vascular endothelium as a target. Although anti-endothelial cell therapy has been partially successful against some types of tumors, it has been proposed that better results might be obtained by combined targeting of additional cell types involved in tumor vascularization. Pericytes are one obvious choice as an additional vascular target. Macrophages may be another good choice for targeting, based on their surprisingly strong role in tumor vascularization.
Work in the Stallcup laboratory has shown that the NG2 proteoglycan is expressed by both pericytes and macrophages in the stroma of developing tumors, even in cases where the tumor cells themselves do not express NG2. In addition, genetic ablation of NG2 in the host animal leads to large decreases in tumor progression, suggesting that stromal NG2 has an important role in promoting tumor growth. We are now using Cre-Lox technology to create cell type-specific ablations of NG2 (i.e. in pericytes and in macrophages). Our initial results indicate that while both the pericyte-specific and macrophage-specific NG2 null mice exhibit deficits in the structure and function of brain tumor blood vessels, brain tumor progression is reduced only in the macrophage-specific null mice. These findings suggest one of two things: (a) Functional deficits in macrophage-specific NG2 null tumor vessels are different from functional deficits in pericyte-specific NG2 null vessels, and only the macrophage-specific deficits affect tumor progression; or (b) Macrophage-specific ablation of NG2 affects other aspects of macrophage function that impair tumor growth independent of tumor vascularization.
"In order to evaluate these two alternatives, we will first characterize the details of brain tumor blood vessel structure and function in the pericyte-specific and macrophage-specific NG2 null mice. Analyses of vessel density, vessel diameter, and vessel tortuosity will be accompanied by analyses of the spatial relationships between endothelial cells, pericytes, and the vascular basement membrane. Functionally, we will evaluate vessel patency, vessel leakiness, and intratumoral hypoxia. Taken altogether, these parameters will allow us to determine whether pericyte-specific NG2 null tumor vessels have characteristics that are similar to or different from the characteristics of macrophage-specific NG2 null vessels."
"If vascular deficits are similar in the two lines of NG2 null mice, we will investigate a different aspect of macrophage function that appears to be affected by NG2 ablation; namely, macrophage invasion of tumors. After macrophages extravasate from the circulation into tumor tissue, they are able to interact with pericytes to guide their dissemination throughout the tumor. This behavior depends on the interaction of b2 integrins on the macrophage surface with ICAM-1 on the pericyte surface. Since it is known that NG2 promotes integrin-mediated interactions, we suspect that macrophage NG2 is important for optimizing the b2 integrin/ICAM-1 interaction. In support of this hypothesis, our preliminary results with several inflammatory pathologies note greatly decreased recruitment of b2 integrin-positive macrophages in NG2 null mice. We will expand on this theme by determining in detail the changes in spatial relationships between b2 integrin-positive macrophages and pericytes in brain tumors in the macrophage-specific NG2 null mouse, along with the resulting effects on macrophage recruitment to these tumors. We will also utilize in vitro methods to investigate the mechanisms by which NG2 mediates the macrophage-pericyte interaction, focusing on the ability of NG2 to promote b2 integrin binding to ICAM-1. "
"In a broad sense, we expect that these studies will identify the NG2 proteoglycan as a bifocal stromal target (pericytes and macrophages) for attacking tumors. At a more detailed level, we hope to elucidate specific NG2-dependent aspects of pericyte-mediated and macrophage-mediated activities that promote tumor progression. Development of effective therapeutic strategies will depend on achieving a better understanding of the molecular mechanisms underlying NG2-dependent processes. The support of the AACR Judah Folkman Fellowship for Angiogenesis Research will provide a tremendous boost for our pursuit of these important goals."
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