Prostate cancer (CaP) is a common neoplasm and the second leading cause of cancer deaths in American males. Despite numerous advances, once the tumors metastasize, prostate cancer is almost invariably fatal. The high mortality rate is principally due to the spread of malignant cells to many tissues including bone. Because of these facts, there is a growing interest in the early detection and screening of men for prostate cancer, and for a greater understanding of the mechanisms that lead to metastasis. Hematopoietic stem cells also ?home? to bone during fetal life and marrow transplantation. In this context, a CXC chemokine stromal-derived factor-1 (SDF-1) and its receptor, CXCR4 appear to be critical molecular determinants for these events. This has been substantiated in several ways, but most convincingly with SDF-1 or CXCR4 gene knockouts, where marrow engraftment by hematopoietic cells is not observed. Moreover, osteoblasts and marrow endothelial cells express SDF-1 protein that function as a chemoattractant for human hematopoietic progenitor cells. Our overall hypothesis is that metastatic CaPs also use the SDF-1/CXCR4 as a pathway to localize to the bone marrow. Our investigations will test this hypothesis by determining the mechanisms whereby SDF-1 supports the adhesion and invasion of CaPs cells into the marrow (Aim 1), whether autocrine production of SDF-1 confers upon CaPs a selective advantage by either promoting proliferation or survival in the marrow microenvironment (Aim 2) and delineate whether CXCR4 and SDF-1 are responsible for homing of CaP carcinomas to bone using animal models. These investigations will provide important new information pertaining to the molecular basis of how tumors ?home? to bone which we believe will facilitate the development of new strategies for preventing or minimizing prostate metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA093900-01A2
Application #
6990045
Study Section
Subcommittee G - Education (NCI)
Project Start
2004-06-05
Project End
2009-04-30
Budget Start
2004-06-05
Budget End
2005-04-30
Support Year
1
Fiscal Year
2004
Total Cost
$131,053
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Hill, Elliott E; Kim, Jin Koo; Jung, Younghun et al. (2018) Integrin alpha V beta 3 targeted dendrimer-rapamycin conjugate reduces fibroblast-mediated prostate tumor progression and metastasis. J Cell Biochem 119:8074-8083
Axelrod, Haley D; Valkenburg, Kenneth C; Amend, Sarah R et al. (2018) AXL Is a Putative Tumor Suppressor and Dormancy Regulator in Prostate Cancer. Mol Cancer Res :
de Groot, Amber E; Pienta, Kenneth J (2018) Epigenetic control of macrophage polarization: implications for targeting tumor-associated macrophages. Oncotarget 9:20908-20927
Roca, Hernan; Jones, Jacqueline D; Purica, Marta C et al. (2018) Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone. J Clin Invest 128:248-266
Wu, Amy; Liao, David; Kirilin, Vlamimir et al. (2018) Cancer dormancy and criticality from a game theory perspective. Cancer Converg 2:1
Park, Sun H; Keller, Evan T; Shiozawa, Yusuke (2018) Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis. Calcif Tissue Int 102:152-162
Singhal, Udit; Wang, Yugang; Henderson, James et al. (2018) Multigene Profiling of CTCs in mCRPC Identifies a Clinically Relevant Prognostic Signature. Mol Cancer Res 16:643-654
Lee, Eunsohl; Wang, Jingcheng; Jung, Younghun et al. (2018) Reduction of two histone marks, H3k9me3 and H3k27me3 by epidrug induces neuroendocrine differentiation in prostate cancer. J Cell Biochem 119:3697-3705
van der Toom, Emma E; Axelrod, Haley D; de la Rosette, Jean J et al. (2018) Prostate-specific markers to identify rare prostate cancer cells in liquid biopsies. Nat Rev Urol :
Roca, Hernan; McCauley, Laurie K (2018) Efferocytosis and prostate cancer skeletal metastasis: implications for intervention. Oncoscience 5:174-176

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