NIH/NCI Program Project

Prostate cancer bone metastasis: biology and targeting

PI: Leland W.K. Chung, Ph.D.

Project 1

Biology of Tumor-Stroma Interaction
Project Director: Leland W.K. Chung, Ph.D.
Cedars-Sinai Medical Center

Project 2

Heparan Sulfate Proteoglycans in Prostate Cancer Bone Metastasis
Project Director: Mary C. Farach-Carson, Ph.D.
Rice University

Project 3

Mitochondrial DNA Mutations in Prostate Tumorigenesis and Stromal-Epithelial
Interaction
Project Director: John A. Petros, M.D.
Emory University

Core A

Administrative and Service Core
Core Director: Leland W. K. Chung, Ph.D.
Cedars-Sinai Medical Center

Core B

Bioinformatics, Biostatistics and Translational (BBT) Core
Core Director: Andre Rogatko, Ph.D.
Cedars-Sinai Medical Center

Core C

Pathology and Laboratory Support Core
Core Director: Majd Zayzafoon, M.D., Ph.D.
University of Alabama at Birmingham

Project Summary

The overarching theme of this Program Project is that prostate cancer (PCa) bone metastasis is driven by progressive changes acquired through tumor-stroma interaction in the bone and prostate microenvironment. Genes activated in prostate and bone stroma confer growth and survival advantages to cancer cells and encode gene products that serve as novel predictive biomarkers for PCa progression. Our discoveries defining intra- and extra-cellular reactive oxygen species (ROS) show that ROS can mediate increased expression of perlecan (Pln), a key heparin sulfate proteoglycan (HSPG), and _2-Microglobulin (_2-M) expression by PCa cells. There appears to be a tight signaling relationship among _2-M, Pln, and ROS by which the expression of these signaling molecules is coordinated and regulated. PCa cells with mitochondrial DNA mutations produced increased levels of ROS, _2-M and Pln. We investigated the clinical translation of these molecular biomarkers in primary and bone metastatic human PCa tissues. Results showed significant correlation of LIV-1 (p<0.001), a driver of epithelial to mesenchymal transition (EMT), cytoplasmic but not nuclear BDNF (p<0.001), _2-M (p=0.006), focal adhesion kinase (FAK) (p=0.010), a target gene of ROS in human prostate cancer cells, and heparanase, a Pln degradative enzyme (p<0.001) with the progression of PCa from normal, benign, PIN, and localized cancer to bone metastasis. In the first Program Project funding period, we made remarkable progress with paradigm-shifting discoveries, collaborative publications, and successful mentoring of the next generation of prostate cancer researchers.

The Projects successfully accomplished all of the proposed aims, reflected in 82 publications, 37 of which were considered to be high impact. In this competitive renewal, Project 1 focuses on characterization of _2-M-mediated growth and signaling pathways in prostate cancer bone metastasis. Project 2 focuses on the characterization of multiple Pln domains known to interact with soluble growth factors in extracellular matrices to ultimately affect cancer growth and metastasis. Project 3 focuses on the characterization of ROS-mediated gene expression and signaling in prostate epithelial cells in response to bone stromal interaction. The Projects and Cores will continue to define the biology and targeting potential of tumorstromal interaction, validate biomarkers in tissue and serum specimens and ultimately translate these discoveries into clinical practice.