Date of Completion

8-9-2013

Embargo Period

8-6-2014

Keywords

CD13, Tumor Vasculature

Major Advisor

Linda H Shapiro, PhD

Associate Advisor

Kevin Claffey

Associate Advisor

Ann Cowan

Associate Advisor

Guo-Hua Fong

Associate Advisor

Hector Aguila

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Campus Access

Abstract

Optimal tumor growth relies on the integration of inflammation and angiogenesis such that a number of molecules are critical regulators of both processes contributing to the overall orchestration of cancer growth and progression. The cell-surface peptidase CD13 is expressed on myeloid cells and activated endothelium where it acts as both a homotypic adhesion molecule regulating inflammatory myeloid cell migration and a regulator of angiogenesis. Naïve wild type or CD13-deficient mice showed identical baseline immune profiles, but displayed significant differences in the number and ratio of myeloid subsets recruited to sites of ischemic injury as well as effects on angiogenesis, prompting our investigation into the contribution of CD13 to angiogenesis and inflammation in tumors. Surprisingly, and in contrast to injury models, tumor allografts grown in CD13-deficient mice were larger and showed increased numbers of infiltrating monocytes, dendritic cells and macrophages resulting in increased levels of inflammatory and angiogenic cytokines. Paradoxically, the capillary density of these larger tumors in CD13-deficient animals was markedly decreased with significant improvement in the percentage of blood vessels stabilized by pericytes, suggesting CD13 contributes to dysregulated tumor angiogenesis. Mechanistically, the junctional localization of VE-cadherin was significantly enhanced in endothelial monolayers treated with CD13 blocking antibodies, which would predict improved pericyte-endothelial contacts in vivo. Therefore, this work illustrates that loss of CD13 contributes to immune cell infiltration and angiogenesis to promote solid tumor progression identifying CD13 as a novel target for normalization of tumor blood vessels, a contemporary therapeutic goal in tumor treatment.

CD13 Destabilizes Vasculature in Tumors

8/6/13

Kaitlyn Margaret Vernier B.S. Randolph-Macon College

Ph.D. University of Connecticut

Directed by: Linda H Shapiro Ph.D.

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