Bone-Marrow-Derived Mesenchymal Stem Cells in Prostate Cancer-Induced Bone Remodeling

Bone metastasis and skeletal complications are the major contributing factors to prostate cancer (PCa) morbidity and mortality. Prostate cancer bone metastasis tends to induce predominantly osteoblastic (bone forming) lesions, although osteolytic (bone lysing) lesions are also observed. The PCa-induced bone remodeling is due to factors secreted by PCa cells that modulate tumor stroma in a paracrine fashion. The stroma cells, mainly osteoblasts and osteoclasts, in the bone microenvironment have been shown to play critical roles in the progression of PCa in bone. Recently, bone marrow-derived mesenchymal stem cells (BM-MSCs) have been found to interact with tumor cells and play a role in tumor progression. In the bone marrow, MSCs are multipotential progenitors for osteoblasts and adipocytes. It has been proposed that during age-related osteoporosis, the balance between the osteoblast and adipocyte lineages is tilted towards increased adipocytes and decreased osteoblasts, leading to fatty bone marrow with bone loss. As the similarity of pathogenesis in osteoporosis and osteolytic metastases, the correlation between the switch from osteogenesis to adipogenesis in BM-MSCs and the ability of their associated prostate cancer cell lines to induce osteolytic lesions implies that interactions between prostate cancer and BM-MSCs could be a critical determinant of skeletal pathogenesis. In light of our previous study that BM-MSCs that were associated with osteolytic PCa not only exhibited a stronger ability to promote prostate cancer cell migration and invasion, but also acquired a higher potential for adipogenic differentiation, we hypothesize that unbalance osteogenic/adipogenic differentiation of BM-MSCs in tumor microenvironment provides an important but understudied pathway by which PCa cells regulate bone remodeling. The goal of this proposal aim to understand the inextricable relationship between BM-MSC and PCa cells in controlling pathological remodeling of the bone, and to devise a safely strategy for targeting this altered bone balance for controlling prostate cancer metastasis. To achieve the goal, three Specific Aims are proposed. Aim 1: To characterize the role of PCa-associated BM-MSCs in bone remodeling. Aim 2: To identify the BM-MSC-derived factors that responsible for pathogenic lesion of prostate cancer bone metastases. Aim 3: To design a therapy strategy targeting BM-MSC niche for prostate cancer bone metastasis. The completion of the proposed studies will not only provide key insights into the molecular basis of tumor-stroma interactions, but also pave the way for potential new diagnosis and treatment strategy for prostate cancer bone metastasis.