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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZCA1-SRLB-X (M2))
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Mohla, Suresh
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Johns Hopkins University
Schools of Medicine
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Roca, Hernan; Pande, Manjusha; Huo, Jeffrey S et al. (2014) A bioinformatics approach reveals novel interactions of the OVOL transcription factors in the regulation of epithelial - mesenchymal cell reprogramming and cancer progression. BMC Syst Biol 8:29
Axelrod, Haley; Pienta, Kenneth J (2014) Axl as a mediator of cellular growth and survival. Oncotarget 5:8818-52
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Roca, Hernan; Hernandez, James; Weidner, Savannah et al. (2013) Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition in human cancer. PLoS One 8:e76773
Cheng, Heather H; Mitchell, Patrick S; Kroh, Evan M et al. (2013) Circulating microRNA profiling identifies a subset of metastatic prostate cancer patients with evidence of cancer-associated hypoxia. PLoS One 8:e69239
Ng, Yee Seng; Roca, Hernan; Fuller, David et al. (2012) Chemical transfection of dye-conjugated microRNA precursors for microRNA functional analysis of M2 macrophages. J Cell Biochem 113:1714-23
Patel, Lalit R; Camacho, Daniel F; Shiozawa, Yusuke et al. (2011) Mechanisms of cancer cell metastasis to the bone: a multistep process. Future Oncol 7:1285-97
Lonigro, Robert J; Grasso, Catherine S; Robinson, Dan R et al. (2011) Detection of somatic copy number alterations in cancer using targeted exome capture sequencing. Neoplasia 13:1019-25

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