Prostate cancer is the second leading cause of death from cancer in men in the U.S. and mortality from prostate cancer is invariably due to tumor metastasis. Our overall goals for the first competitive renewal application therefore continue to be to understand prostate cancer invasion and hematogenous metastasis. We have gleaned several insights from the previous four years of studying the role of vascularization and the physiological environment in promoting prostate cancer invasion and dissemination. This has led us to formulate five new hypotheses: (1) invasion is necessary but not sufficient, without vascularization, for hematogenous prostate cancer metastasis; (2) there are combinations of co-registered vascular, physiological and metabolic regions within solid tumors, which are most permissive for invasion and metastasis; (3) anti-angiogenic treatments attenuate or prevent metastasis; (4) there will be a reduction in the """"""""permissive"""""""" vascular, physiological and metabolic regions following treatment with anti-angiogenicagents; (5) endothelial cell - cancer cell interactions play a significant role in promoting invasion and metastasis from stressed physiological conditions of hypoxia and acidic pH found in solid tumors. We will continue to work with the human prostate cancer xenografts we selected during our first funding period. We will increase vascularization in solid tumors by creating transgenic cell lines over expressing VEGF A or bFGF, and reduce vascularization by treating solid tumors with the anti-angiogenic agents TNP-470 and endostatin. The technical advances we have made, such as obtaining co-registered maps of vascular volume, permeability, extracellular pH and metabolites will be applied to gain further insight into prostrate cancer metastasis. Our """"""""Metabolic Boyden Chamber"""""""" assay that was developed and optimized during the previous funding period now has an additional facet of a layer of endothelial cells incorporated between the matrigel layer and the cellular layer. This will allow, for the first time, the noninvasive investigation of the interaction between vascular endothelial cells and prostate cancer cells under various physiological conditions, simulating conditions found in solid tumors. The proposed studies will continue to identify vascular, physiological and metabolic characteristics that promote invasion and metastasis. This information is critical for developing strategies to prevent metastasis from prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073850-06
Application #
6624299
Study Section
Special Emphasis Panel (ZRG1-SRB (33))
Program Officer
Menkens, Anne E
Project Start
1997-06-11
Project End
2007-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
6
Fiscal Year
2003
Total Cost
$327,409
Indirect Cost
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Bharti, Santosh K; Mironchik, Yelena; Wildes, Flonne et al. (2018) Metabolic consequences of HIF silencing in a triple negative human breast cancer xenograft. Oncotarget 9:15326-15339
Chen, Zhihang; Krishnamachary, Balaji; Penet, Marie-France et al. (2018) Acid-degradable Dextran as an Image Guided siRNA Carrier for COX-2 Downregulation. Theranostics 8:1-12
Penet, Marie-France; Kakkad, Samata; Pathak, Arvind P et al. (2017) Structure and Function of a Prostate Cancer Dissemination-Permissive Extracellular Matrix. Clin Cancer Res 23:2245-2254
Krishnamachary, Balaji; Stasinopoulos, Ioannis; Kakkad, Samata et al. (2017) Breast cancer cell cyclooxygenase-2 expression alters extracellular matrix structure and function and numbers of cancer associated fibroblasts. Oncotarget 8:17981-17994
Shah, Tariq; Wildes, Flonne; Kakkad, Samata et al. (2016) Lymphatic endothelial cells actively regulate prostate cancer cell invasion. NMR Biomed 29:904-11
Jin, Jiefu; Krishnamachary, Balaji; Mironchik, Yelena et al. (2016) Phototheranostics of CD44-positive cell populations in triple negative breast cancer. Sci Rep 6:27871
Penet, Marie-France; Jin, Jiefu; Chen, Zhihang et al. (2016) Magnetic Resonance Imaging and Spectroscopy in Cancer Theranostic Imaging. Top Magn Reson Imaging 25:215-221
Winnard Jr, Paul T; Bharti, Santosh K; Penet, Marie-France et al. (2016) Detection of Pancreatic Cancer-Induced Cachexia Using a Fluorescent Myoblast Reporter System and Analysis of Metabolite Abundance. Cancer Res 76:1441-50
Penet, Marie-France; Chen, Zhihang; Mori, Noriko et al. (2016) Magnetic Resonance Spectroscopy of siRNA-Based Cancer Therapy. Methods Mol Biol 1372:37-47
Chen, Zhihang; Penet, Marie-France; Krishnamachary, Balaji et al. (2016) PSMA-specific theranostic nanoplex for combination of TRAIL gene and 5-FC prodrug therapy of prostate cancer. Biomaterials 80:57-67

Showing the most recent 10 out of 63 publications