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. These aims will use the extensive set of human normal and prostate cancer samples in the Baylor University and University of Michigan 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.
Central question 1: What is the relationship between TAMs and the development of reactive stroma myofibroblasts?
Specific aim 1: Define the mechanisms by which TAMs promote myofibroblast differentiation and function. This aim will:
- 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.
- Determine the role of reactive stroma/myofibroblasts in the recruitment of macrophages using a human cancer/stromal recombination xenograft model.
- 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.
- To 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 intramarrow transplant approach.
Subaims will determine the effects of depleting TAMs on PCa tumorigenesis and PCa growth in bone, utilizing novel preclinical and transgenic models. We will deplete the tumor microenvironment of TAMs by blocking TAM chemoattraction through manipulation of the CCL2/CCR2 axis in primary and metastatic tumor models, including homozygous SCID/CCL2-/- and SCID/CCR2-/- mice as well as the transplanted vossicle model.
Central question 2: What is the composition of human prostate cancer reactive stroma?
Specific aim 2: To determine the composition of reactive stroma within prostate cancer bone metastases. This aim will determine:
- Which reactive stroma biomarkers co-evolve in a temporal and spatial pattern with prostate cancer bone metastases.
- How these biomarkers correlate with gene expression profiles from laser-captured reactive stroma.
- Whether these biomarkers correlate with reactive stroma markers of primary prostate cancer development.
- The effects of disruption of the CCL2 /TAM axis in primary prostate cancers and bone microenvironment on reactive stroma using novel models.