Dissertation/Thesis Abstract

Tumor Angiogenesis is all Tied up in Tie2-Expressing Macrophages
by Forget, Mary A., Ph.D., The Ohio State University, 2012, 212; 10630962
Abstract (Summary)

The impact of the immune system on solid tumor formation and malignant disease has been the focus of much study over the last several decades. Elimination of macrophages from mouse models for malignancy result in decreased in tumor angiogenesis, progression and malignancy. Further migration of myeloid cells following standard chemo and radiation therapies results in tumor resistance and further progression of disease. Tie2-expressing monocytes (TEMs) are a distinct subset of pro-angiogenic monocytes selectively recruited to breast tumors in both mouse models of cancer and breast cancer patients. Because of the hypoxic nature of tumors, we investigated if oxygen regulated the trafficking of these cells into tumors or differentiated once inside the tumor microenvironment. In part one of this study, we demonstrate that the Tie2 receptor is up regulated under hypoxia and that macrophage knockout of, HIF-1α, inhibits Tie2 receptor expression at both the protein and mRNA levels. Given this data and that hypoxia commonly occurs during the tumor development, we next investigated the effect of macrophage-specific deletion of HIF-1α in a PyMT mouse model for breast cancer. Here genetic oblation of HIF-1α from macrophages decreased the rate of tumor growth, angiogenesis and tumor metastasis.

M-CSF is known to promote tumor vessel growth and progression through the production of angiogenic factors like VEGF. In the second part of this study, we demonstrate that M-CSF can modulate Tie2 receptor expression on macrophages both in vitro and in vivo. Under ambient oxygen conditions, we found that M-CSF increased Tie2 receptor on macrophages. This up regulation synergistically increased migration of monocytes towards Angiopoietin-2 (Ang-2) and resulted in greater branch formation in an in vitro endothelial tube formation assay. A neutralizing antibody against the M-CSF receptor abrogated this activity as did knockdown of the Tie2 receptor through the use of a siRNA targeting the Tie2 receptor. In a PyMT mouse model of breast cancer, recombinant M-CSF increased the TEM population while the total number of F4/80+ macrophages did not change between M-CSF and vehicle control treatment groups. In this model, M-CSF administration enhanced tumor angiogenesis, while having no significant effect on tumor size. No metastatic effects were examined. Given the observations that both HIF-1α and M-CSF could effect Tie2 receptor expression on macrophages, we investigated the mechanism underlying these events. We found that a PI3 kinase/Akt inhibitor suppressed the generation of TEMs in culture in response to M-CSF. Further, we found that HIF-1α and M-CSF synergistically act to regulate the generation of TEMs.

These studies highlight the role of TEM modulation in tumor angiogenesis and progression. First, our results show that HIF-1α regulates TEM differentiation in the hypoxic environment of the solid tumor. M-CSF, to the contrary, expanded the TEM population not only in the tumor, but in the peripheral blood as well. This along with the increases in Ang-2 and SDF-1/CXCL12 concentrations in M-CSF-treated tumors suggests a role for M-CSF in the recruitment of TEMs. These studies highlight role of TEMs specifically, and not total F4/80 macrophages, in tumor growth, angiogenesis and progression.

Indexing (document details)
Advisor: Marsh, Clay
Commitee: Bisaro, Dave, Tridandapani, Susheela, Wewers, Mark
School: The Ohio State University
Department: Molecular, Cellular and Developmental Biology
School Location: United States -- Ohio
Source: DAI-B 78/11(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Immunology
Keywords: Breast cancer, Macrophage, Tumors
Publication Number: 10630962
ISBN: 9780355012804
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