Tumor growth, angiogenesis, and invasion depends on the recruitment and coordinated activity of different cell types populating the tumor stroma, such as endothelial cells, fibroblasts, pericytes, and infiltrating inflammatory cells. Although tumor associated vessels share similar components to normal vessels, including endothelial cells, basement membranes and pericytes, these vessels are abnormal, tortuous and leaky. While the functional role of endothelial cells in the context of tumor angiogenesis and vasculogenesis is extensively studied, the contribution of pericytes/perivascular cells in cancer progression and metastasis is poorly understood. Several studies suggest that targeting pericytes can control the rate of angiogenesis and growth of late stage tumors;however it is imperative to perform functional studies to evaluate the consequence of anti-pericyte therapy before moving these agents into clinical testing phase. In this regard, NG2, a novel cell surface chondroitin sulfate proteoglycan, is shown to be a reliable marker of pericytes/perivascular cells, along with the PDGF receptor 2 (PDGFR2). This grant proposes to perform functional studies utilizing these markers in transgenic mice setting to elucidate the role of pericytes in breast cancer progression and lung metastasis. This application will test the central hypothesis that "pericytes associated with primary breast tumors determine the rate of cancer progression and emergence lung metastasis". The proposal will functionally explore therapeutic targeting of pericytes using novel genetic mouse models in combination with novel pharmacological interventions using targeted therapy.
The specific aims i n this proposal are: 1) To determine the functional contribution of pericytes in primary breast cancer progression and lung metastasis, 2) To investigate the contribution of epithelial to mesenchymal transition in hypoxia induced lung metastasis, and 3) To determine the role of PDGFR2 in lung metastasis.

Public Health Relevance

About 80% of cancer deaths are associated with systemic disease, also known as 'metastasis'. Many studies suggest that the genetic alterations that accumulate in the cancer cells define, in part, the metastatic potential. Nevertheless, components of the tumor stroma, such as fibroblasts, endothelial cells, and pericytes, may play a role in metastasis. Several studies suggest pericytes as new potential therapeutic targets to inhibit tumor angiogenesis and subsequently tumor growth. Our proposal is designed to functionally determine the contribution of pericytes in primary tumor growth and metastasis, and identify new therapies to inhibit metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA155370-02
Application #
8210865
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Mohla, Suresh
Project Start
2011-01-01
Project End
2012-10-31
Budget Start
2012-01-01
Budget End
2012-10-31
Support Year
2
Fiscal Year
2012
Total Cost
$361,050
Indirect Cost
$153,550
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
LeBleu, Valerie S; O'Connell, Joyce T; Gonzalez Herrera, Karina N et al. (2014) PGC-1? mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol 16:992-1003, 1-15
Melo, Sonia A; Sugimoto, Hikaru; O'Connell, Joyce T et al. (2014) Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26:707-21
Charytan, David M; Padera, Robert; Helfand, Alexander M et al. (2014) Increased concentration of circulating angiogenesis and nitric oxide inhibitors induces endothelial to mesenchymal transition and myocardial fibrosis in patients with chronic kidney disease. Int J Cardiol 176:99-109
Özdemir, Berna C; Pentcheva-Hoang, Tsvetelina; Carstens, Julienne L et al. (2014) Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25:719-34
Carstens, Julienne L; Lovisa, Sara; Kalluri, Raghu (2014) Microenvironment-dependent cues trigger miRNA-regulated feedback loop to facilitate the EMT/MET switch. J Clin Invest 124:1458-60
Tampe, Björn; Tampe, Desiree; Müller, Claudia A et al. (2014) Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis. J Am Soc Nephrol 25:905-12
Zeisberg, Michael; Tampe, Björn; LeBleu, Valerie et al. (2014) Thrombospondin-1 deficiency causes a shift from fibroproliferative to inflammatory kidney disease and delays onset of renal failure. Am J Pathol 184:2687-98
Kahlert, Christoph; Melo, Sonia A; Protopopov, Alexei et al. (2014) Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem 289:3869-75
Plaks, Vicki; Rinkenberger, Julie; Dai, Joanne et al. (2013) Matrix metalloproteinase-9 deficiency phenocopies features of preeclampsia and intrauterine growth restriction. Proc Natl Acad Sci U S A 110:11109-14
LeBleu, Valerie S; Taduri, Gangadhar; O'Connell, Joyce et al. (2013) Origin and function of myofibroblasts in kidney fibrosis. Nat Med 19:1047-53

Showing the most recent 10 out of 18 publications