Advanced prostate cancer (PCa) frequently leads to bone metastasis, which is a major cause of morbidity and mortality from this malignancy. Our limited knowledge of the molecular interactions underpinning the colonization, survival, and proliferation of cancer cells in the bone microenvironment has prevented the development of curative therapies. In the proposed study, we will examine the role of interaction between the bone marrow stroma and androgen receptor (AR) positive and negative disseminated tumor cells (DTCs) in the establishment of bone metastases. Our previous work has shown that IL-1? is overexpressed in both high-Gleason score primary tumors and PCa bone metastases, and that IL-1? is a major mediator of bone-metastatic behavior of AR(-) human prostate cancer cells in SCID mice. Recent data indicates not only that IL-1? signaling dictates the metastatic potential of PCa cells, but also that IL-1? secreted from highly bone-metastatic PCa cells can establish cross-talk with bone stromal cells, prompting them to acquire a carcinoma-associated fibroblast (CAF) phenotype. Speculating that CAFs may support growth of DTC types that would normally be unable to initiate a metastatic niche, we co-inoculated metastatic PCa cells with AR(+) or AR(-) non-metastatic PCa cells via the intracardiac route. We subsequently found skeletal lesions composed of both cell types, indicating that metastasis-initiating cells could support colonization by cancer cells that normally fail to survive in the bone. These data suggest a crucial interaction between the microenvironment and cancer cells of various phenotypes in the initial stages of metastatic colonization. This project aims to characterize the mechanism of this prostate cancer cell cooperation in the bone metastatic niche, which we hypothesize to be mediated by IL-1?. If exploited clinically, the signaling pathways identified here may lead to a substantial reduction in metastatic burden and concomitant increase in quality of life for patients with advanced prostate cancer, and ultimately to therapies with the potential to preclude the development of bone metastatic disease from prostate cancer.
This project employs a new model system to study the way in which proteins secreted by aggressive cancer cells force normal tissue at metastatic sites to support the cancer, enabling the development of large and ultimately fatal metastatic tumors. Through this research, we hope to identify crucial factors in this process which can be targeted with both new and existing drugs in order to limit or prevent the development of metastasis, thereby providing improved survival and quality of life for patients with advanced prostate cancer.
| Shahriari, K; Shen, F; Worrede-Mahdi, A et al. (2017) Cooperation among heterogeneous prostate cancer cells in the bone metastatic niche. Oncogene 36:2846-2856 |
