Research: 2018 – Ottawa (Addison)

Project Title:
The Role of Beta1 Integrin Signaling in promote bone metastatic prostate cancer growth.
Investigators:
Christina Addison, Ottawa Hospital Research Institute
 
Christina Addison holds a Ph.D. in Molecular Biology and Cancer Research from McMaster University, and did her Post-Doctoral Training at the University of Michigan. She is presently a Senior Scientist at the Ottawa Hospital Research Institute in the Cancer Therapeutics Program, and an Associate Professor at the University of Ottawa. Her main research interests are centered on the role of the tumor microenvironment on tumor angiogenesis, growth, metastasis and response to therapy. This work is mostly focused on the development and treatment of cancer metastasis to the bone. This includes identifying and understanding novel pathways that control bone metastasis progression and attempts to block these pathways in a a therapeutic setting. Other ongoing work in the lab involves analysis of putative biomarkers of patient response or disease recurrence.
Project Abstract:
Prostate cancer most commonly spreads to bone. Despite newer therapies which prolong the survival of patients with bone metastasis, they remain incurable. Patients newly diagnosed with prostate cancer can already have tumor cells in their bones, but some of these patients never develop bone metastasis, while others do develop tumor growth in their bone but many years later. This suggests that the bone environment normally does not permit tumor cells to grow and keeps prostate cells in a ‘dormant state’. Certain types of cells or biological processes in the bone may talk to prostate tumor cells and keep them ‘dormant’ thereby preventing their growth. However, prostate tumors eventually bypass these blocks in part by activating processes such as new blood vessel growth to feed the growing tumor, activating bone degradation to release factors that support tumor cell growth, and by retraining immune cells so they cannot recognize and kill tumor cells. We have identified a pathway in prostate tumor cells that may regulate this cell communication and reprograming in the bone, and we will test how this pathway allows prostate tumor cells to ‘reprogram’ the bone environment to support tumor growth.
Scientific Abstract:
Bone is the predominant site of prostate cancer metastasis, and once there it is incurable. Metastasis to bone is a complex multi-step process and once in the bone, disseminated tumor cells (DTC) must overcome microenvironmental induced ‘dormancy’ to grow. Dormancy occurs when DTC enter a state of reversible G0/G1 quiescence or expansion of micrometastases are restricted. This latter process usually involves lack of bone remodeling or angiogenesis and establishment of anti-tumor immunity. Tumors must overcome these inhibitory blocks for bone metastases to grow. We have found that depletion of β1 integrin, a receptor for extracellular matrix (ECM) proteins such as collagen found in the bone, resulted in impaired ability for PC3 prostate tumor cells to grow in bone. We further found that β1 integrin depleted cells had decreased ability to induce proliferation of endothelial cells, suggesting an impaired ability to promote tumor angiogenesis. We thus hypothesize that the integrin signaling pathway contributes to the ability of prostate tumor cells to ‘reprogram’ the bone microenvironment and facilitate tumor growth and current experiments will assess the cellular cross-talk between tumor and bone resident cells in this context.
Impact on prostate cancer patients:
Although this project is at the preclinical stage of testing, the results could have important implications for the treatment management of prostate cancer patients in the future. As prostate cancer becomes incurable once it spreads to the bone, if we could identify therapeutic strategies that might prevent prostate cell growth in the bone, we could have significant impact on the incidence and outcomes of these patients.