Seeinstructions): 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. 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.
The Bone Core of the Program Project will provide shared facilities and services for processing and interpretation of tissues from the animal models utilized in all projects of the program. The overall goal of the core facility is to provide centralized histologic and image analysis support for investigators in the project. The following services will be provided: experimental design/consultation regarding endpoint analyses for histologic specimens, processing of osseous tissues for histologic analysis (decalcified and undecalcified sections, bone histomorphometric analysis of osseous sections (i.e. interpretation), and histologic analysis of soft tissue metastases or other soft tissue lesions with their pathologic diagnosis. In addition to histologic support, the core will provide services of FAXITRON microradiography and peripheral QCT. The bone core will continue providing expertise that includes the processing of soft tissue specimens and decalcified hard tissue specimens in paraffin in addition to processing undecalcified osseous specimens using plastic embedding techniques. Investigators will be provided with training and assistance in static and dynamic bone histomorphometric analysis. Core support of these services will promote efficiency of specimen analysis and facilitate interactions between projects through the similar model systems and their common analyses. A significant benefit to the program as a group will be a standardized format for analysis of specimens from the common animal models that will be using different experimental approaches/targets (e.g. CCL2, SDF-1 & CXCR4, wnts, Dkk-1, and PTHrP). This will provide valuable information that can be shared and compared across the projects in the program
