PTHrP, osteoblasts and hematopoietic cells in the skeletal metastatic niche The microenvironment of the skeletal metastatic lesion of prostate carcinoma (PCa) is rich in cells that support tumor growth. Prostate carcinoma engages this niche in an unstable cascade with deregulated bone resorption and formation. Numerous factors in the bone microenvironment have been implicated that support tumor growth but interest is now turning to PCa derived factors that impact the hematopoietic cell population and contribute to the unstable cascade. Parathyroid hormone related protein (PTHrP) is a tumor-derived factor that increases angiogenesis and enriches the bone marrow complement of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). Prostate carcinoma is not a normal inhabitant of bone and its presence disrupts the equilibrium of the marrow, but little is known of the crosstalk between prostate carcinoma, cells of the marrow and bone. The osteoblast/stromal cell is likely a central component as a director of the hematopoietic component, a regulator of angiogenesis, and as the mediator of the osseous lesion. The overall hypothesis is that prostate cancer-derived PTHrP acts through cells of the osteoblast lineage to support hematopoietic cell expansion which in turn supports angiogenesis, and tumor growth in the bone marrow microenvironment. The reciprocal impact of PCa cells and hematopoietic cell populations will be determined early during tumor localization in the skeletal microenvironment. The impact of metastatic prostate carcinoma on angiogenesis in the bone marrow and the role of PTHrP in supporting the angiogenesis critical for tumor growth will be determined. Finally the requirement of osteoblasts/stromal cells for the PTHrP impact on hematopoietic cells and angiogenesis will be elucidated. These studies will answer outstanding questions such as what is the relationship between PCa and hematopoietic cells in the skeletal metastatic lesion? What is the contribution of PTHrP to angiogenesis in skeletal metastasis? Are PTHrP-driven hematopoietic cells and angiogenic mechanisms inter-related? Do hematopoietic and angiogenic promoting effects support an osteoblastic phenotype? These findings will provide valuable strategies to develop therapeutic interventions in patients with primary prostate carcinoma to prevent tumor residency in the skeleton and its devastating consequences.

Public Health Relevance

(Seeinstructions): Bone marrow cells impact the tumor cells and visa versa, but little is actually known of such interactions. This project will determine the role of the prostate cancer protein, PTHrP, in the bone marrow and how it affects tumor growth. A better understanding of PTHrP and its role in the tumor microenvironment has strong potential for designing therapies that prevent tumor occupation of the skeleton.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Ann Arbor
United States
Zip Code
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
Chalfin, Heather J; Glavaris, Stephanie A; Malihi, Paymaneh D et al. (2018) Prostate Cancer Disseminated Tumor Cells are Rarely Detected in the Bone Marrow of Patients with Localized Disease Undergoing Radical Prostatectomy across Multiple Rare Cell Detection Platforms. J Urol 199:1494-1501
Axelrod, Haley D; Pienta, Kenneth J; Valkenburg, Kenneth C (2018) Optimization of Immunofluorescent Detection of Bone Marrow Disseminated Tumor Cells. Biol Proced Online 20:13

Showing the most recent 10 out of 228 publications