A Novel Immune-Intact Mouse Model of Prostate Cancer Bone Metastasis: Mechanisms of Chemotaxis and Bone Colonization
Abstract
Rationale of the Proposed Study: Bone metastasis is the predominant cause of death and loss of quality of life in advanced prostate cancer patients. Currently, no effective therapy exists. The cascade of events leading to bone metastasis in human prostate cancer can be visualized as three steps: (1) prostate tumor cells undergo epithelial-to-mesenchymal transition, escape the primary tumor and enter the blood circulation; (2) tumor cells travel in the blood stream and lodge in the bone by chemotaxis induced by soluble factors such as CXCL12 and its receptor CXCR4 on the tumor cell surface; and (3) prostate tumor cells, after homing to the bone, interact with cells in the bone microenvironment and release factors that trigger a vicious cycle of further bone destruction and new bone formation, causing excruciating bone pain and bone fractures in prostate cancer patients. RANKL/RANK is a predominant ligand/receptor pathway in the interaction between metastasized prostate cancer cells and osteoclasts that increases bone turnover. Current drugs that target human prostate cancer bone metastasis include denosumab, which targets RANKL to prevent prostate cancer cell interaction in the bone niche, thus delaying cancer-induced skeletal events. Chemokines are factors produced by the bone that signal and attract prostate tumor cells to lodge in the bone. A large number of studies in recent years have shown that the chemokine CXCL12 secreted by the bone plays a pivotal role in attracting prostate cancer cells that express the cognate receptor CXCR4. Therefore, the CXCL12/CXCR4 ligand/receptor pathway is widely recognized to play a critical role in the homing of prostate cancer cells to the bone. Preclinical mouse models are invaluable tools to study prostate cancer biology and therapy. One of the major obstacles in current prostate cancer research, however, is that there is no suitable mouse model that mimics all the events in human prostate cancer bone metastasis including the presence of an intact host immune system -- a crucial component of the human physiology that is now recognized to play a seminal role in prostate cancer progression and bone metastasis. To overcome this major limitation, we made a significant effort to develop a novel mouse model to study prostate cancer bone metastasis within the context of an intact immune system. Both CXCL12/CXCR4 and RANKL/RANK pathways have been reported to be overexpressed/dysregulated in human prostate cancer bone metastatic samples. Data generated utilizing our immune-intact mouse model show that the CXCL12/CXCR4 and RANKL/RANK pathways cooperate with each other in prostate cancer bone metastasis. Our hypothesis is that the CXCL12/CXCR4 pathway plays a major role in the homing of prostate cancer cells to the bone (step 2 of the cascade), the RANKL/RANK pathway plays a predominant role in bone destruction step that takes place after the prostate cancer cells have reached the bone (step 3 of the cascade), and therefore, to effectively target human prostate cancer bone metastasis, it is crucial to target both pathways. This double-pronged approach would be more holistic and effective strategy than the current largely ineffective single-pronged clinical approach targeting prostate cancer cell growth after it has metastasized to the bone. Further, studies have shown that targeting the CXCL12/CXCR4 and RANKL/RANK pathways individually affects the immune system, thus making our new immune-intact mouse model an indispensable tool for studying the cooperation between these two critical pathways in human prostate cancer bone metastasis. Objective of the Proposed Study: In Aim 1, we will further delineate the cooperation between the CXCL12/CXCR4 and RANKL/RANK pathways through genetic modulation of the two pathways together or individually in prostate cancer cells, and determine the effect of this modulation on bone metastasis in our immune-intact model. In Aim 2, we will assess
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610174
Entities
People
- Srinivas Nandana
Organizations
- Cedars-Sinai Medical Center
- United States Army