The idea that tumors could be eradicated by destroying tumor-associated blood vessels was first proposed over 30 years ago. Today there are about 11 anti-angiogenic drugs in clinical trials. But the results of most clinical studies to date have so far been disappointing. The idea behind anti-angiogenesis (anti-endothelial) therapy is that the endothelial cells lining tumor blood vessels are homogeneous, normal, are not mutable, and wlll not develop drug resistance in contrast to tumor cells. However, that basic assumption has been challenged by recent studies showing morphological and molecular changes (e.g. ectopic calcification) and striking heterogeneity in tumor-specific endothelial cells. Endothelial cells conscripted by a growing tumor may evade anti-angiogenic strategies through diverse, acquired mechanisms. For example, tumor-specific endothelial cells may be derived from multiple cell types. Including sprouting endothelium, bone marrowderived vascular progenitors, trans-differentiated myeloid cells, and multi-potent mesodermal stem cells. It is surprising, then, that most anti-angiogenic therapies today are routinely tested on normal endothelial cell lines in the laboratory. To address this problem, our goals are: 1) To use transgenic mouse models of breast and prostate carcinoma to isolate and characterize tumor-specific endothelial cells from breast and prostate tumors. 2) To determine the relationship between tumor blood vessel calcification and tumor progression and metastasis. 3) To determine the tumor-specific """"""""homing"""""""" and vascular differentiation potential of adult mesenchymal stem cells in tumor-bearing mice. 4) And to use laser capture micro-dissection and microarrays to identify a molecular signature in tumor-specific endothelial cells as tumors progress from the earliest neoplasia to adenocarcinoma. It Is not known why anti-angiogenic therapies, which hold great promise in the treatment of cancer, have not succeeded in the clinic. Our study seeks to better understand the biology of tumor-specific endothelial cells through rigorous characterization of freshly Isolated cells and high-throughput gene analysis to identify novel genes and gene networks. The long-term goal Is to use this new knowledge for the rational design of more effective anti-angiogenic strategies.

Public Health Relevance

Anti-angiogenesis is based on the principle that tumors can be shrunk by using drugs to target the blood vessels feeding them with blood, oxygen, and nutrients. But our basic knowledge of tumor blood vessels Is severely limited. Our study will better characterize the biology of tumor-specific blood vessels with the longterm goal of using this new knowledge towards the rational design of anti-angiogenic therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
5R00CA140708-06
Application #
8526412
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mohla, Suresh
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
6
Fiscal Year
2013
Total Cost
$234,060
Indirect Cost
$75,912
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Xiao, Lin; Kim, Dae Joong; Davis, Clayton L et al. (2015) Tumor Endothelial Cells with Distinct Patterns of TGF?-Driven Endothelial-to-Mesenchymal Transition. Cancer Res 75:1244-54
Xiao, Lin; Harrell, J Chuck; Perou, Charles M et al. (2014) Identification of a stable molecular signature in mammary tumor endothelial cells that persists in vitro. Angiogenesis 17:511-8
Dunleavey, James M; Xiao, Lin; Thompson, Joshua et al. (2014) Vascular channels formed by subpopulations of PECAM1+ melanoma cells. Nat Commun 5:5200
Wagner, Marek; Dudley, Andrew C (2013) A three-party alliance in solid tumors: Adipocytes, macrophages and vascular endothelial cells. Adipocyte 2:67-73
Dunleavey, James M; Dudley, Andrew C (2012) Vascular Mimicry: Concepts and Implications for Anti-Angiogenic Therapy. Curr Angiogenes 1:133-138
Dudley, Andrew C (2012) Tumor endothelial cells. Cold Spring Harb Perspect Med 2:a006536
Wagner, Marek; Bjerkvig, Rolf; Wiig, Helge et al. (2012) Inflamed tumor-associated adipose tissue is a depot for macrophages that stimulate tumor growth and angiogenesis. Angiogenesis 15:481-95
Di Vizio, Dolores; Morello, Matteo; Dudley, Andrew C et al. (2012) Large oncosomes in human prostate cancer tissues and in the circulation of mice with metastatic disease. Am J Pathol 181:1573-84
Panigrahy, Dipak; Edin, Matthew L; Lee, Craig R et al. (2012) Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice. J Clin Invest 122:178-91
Melero-Martin, Juan M; Dudley, Andrew C (2011) Concise review: Vascular stem cells and tumor angiogenesis. Stem Cells 29:163-8

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