The specific mechanisms of how the microenvironment regulates prostate cancer progression remain poorly understood. The combined previous studies of Drs. Pienta and Rowley have revealed that tumor associated macrophages (TAMs) and reactive stroma both promote prostate cancer progression. Dr. Pienta has demonstrated a major role for CCL2 in prostate tumor growth and metastasis through its regulatory role in mediating monocyte / macrophage infiltration into the tumor microenvironment and stimulating a phenotypic change to TAMs within these immune cells to promote tumor growth. Dr. Rowley has demonstrated that human prostate cancer reactive stroma is composed of myofibroblasts that initiate during PIN and continually co-evolve with adjacent carcinoma during organ-confined progression. The overall hypothesis of this application is that TAMs and reactive stroma serve as complementary coregulators of each other and together promote prostate cancer growth in primary and metastatic sites.
Specific Aim 1 (Pienta): Define the mechanisms by v/hich TAMs promote myofibroblast differentiation and function.
This Aim will: 1). Define the temporal relationship between the presence of TAMs, the development of reactive stroma, and the development of primary and metastatic prostate cancers using novel transgenic mouse models. 2). Determine the role of reactive stroma / myofibroblasts in the recruitment of macrophages using a human cancer / stromal recombination xenograft model. 3). Compare and contrast the factors that are secreted by TAMs that affect the differentiation of myofibroblasts in primary and metastatic prostate cancer sites using a novel vossicle implant model. 4). Assess the effects of disruption of the CCL2 /TAM axis in the bone microenvironment on PCa cell homing, growth in bone and bone destruction using a novel intra-marrow transplant approach.
Specific Aim 2 (Rowley): Determine the composition of reactive stroma in prostate cancer bone metastases.
This Aim will: 1). Determine for the first time the relationship between the induction of reactive stroma and the induction of TAMs in both primary and metastatic prostate cancers. 2). Compare results obtained in animal models with human disease. Our goal is to define new biomarkers and therapeutic targets for prostate cancer. All of these Aims will use the prostate cancer samples in the Baylor University and U of M SPORE Tissue Banks, including samples obtained through the rapid autopsy program and samples from the mouse models of prostate cancer growth in primary prostate and bone.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA143055-02
Application #
8139125
Study Section
Special Emphasis Panel (ZCA1-SRLB-X (M2))
Program Officer
Mohla, Suresh
Project Start
2010-09-07
Project End
2015-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$552,256
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zarif, Jelani C; Yang, Weiming; Hernandez, James R et al. (2017) The Identification of Macrophage-enriched Glycoproteins Using Glycoproteomics. Mol Cell Proteomics 16:1029-1037
Parsana, Princy; Amend, Sarah R; Hernandez, James et al. (2017) Identifying global expression patterns and key regulators in epithelial to mesenchymal transition through multi-study integration. BMC Cancer 17:447
San Martin, Rebeca; Pathak, Ravi; Jain, Antrix et al. (2017) Tenascin-C and Integrin ?9 Mediate Interactions of Prostate Cancer with the Bone Microenvironment. Cancer Res 77:5977-5988
Decker, A M; Cackowski, F C; Jung, Y et al. (2017) Biochemical Changes in the Niche Following Tumor Cell Invasion. J Cell Biochem 118:1956-1964
Amend, Sarah R; Roy, Sounak; Brown, Joel S et al. (2016) Ecological paradigms to understand the dynamics of metastasis. Cancer Lett 380:237-42
Jung, Younghun; Decker, Ann M; Wang, Jingcheng et al. (2016) Endogenous GAS6 and Mer receptor signaling regulate prostate cancer stem cells in bone marrow. Oncotarget 7:25698-711
Zarif, Jelani C; Hernandez, James R; Verdone, James E et al. (2016) A phased strategy to differentiate human CD14+monocytes into classically and alternatively activated macrophages and dendritic cells. Biotechniques 61:33-41
Valkenburg, Kenneth C; Amend, Sarah R; Pienta, Kenneth J (2016) Murine Prostate Micro-dissection and Surgical Castration. J Vis Exp :
Yumoto, Kenji; Eber, Matthew R; Wang, Jingcheng et al. (2016) Axl is required for TGF-?2-induced dormancy of prostate cancer cells in the bone marrow. Sci Rep 6:36520
Lee, Eunsohl; Wang, Jingcheng; Yumoto, Kenji et al. (2016) DNMT1 Regulates Epithelial-Mesenchymal Transition and Cancer Stem Cells, Which Promotes Prostate Cancer Metastasis. Neoplasia 18:553-66

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