Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Modelling all aspects of prostate cancer metastases in bone (#64)

Allison Pettit 1
  1. Mater Research Institute, Woolloongabba, QLD, Australia

Metastatic prostate cancer (PCa) has a high propensity to metastasise to bone where it usurps the normal functions of bone and bone marrow (BM) driving tumour growth and a mixed osteoblastic-osteolytic bone pathology. Both the malignancy and current treatments, including androgen deprivation, compromise skeletal structural integrity, requiring active management to alleviate pain and reduce the risk of pathological fractures. Identification of the key cellular and molecular mechanisms driving the dynamic interplay between PCa cells and cells of the bone-BM environment is needed to develop effective treatment options. Xenograft PCa models using human PCa cell lines have been commonly used to investigate the sequential stages of PCa bone metastasis: invasion, colonization, dormancy and growth. They have also been manipulated to test mechanisms of hormone resistance, examine specific molecular pathways and/or novel therapeutic strategies. However these Xenograft models require an immunosuppressed host and therefore occur in the absence of tumour-immune system interactions. The recent boom in onco-immunology, including emergence of immune-checkpoint inhibitor therapies, has reiterated the importance of the endogenous immune system in tumour spontaneous regression, dormancy, immune-evasion and conventional therapy success. PCa bone metastasis models need to encompass this important part of the metastatic evolutionary process. We recently optimized a murine PCa bone metastatic growth model in immune-competent mice that recapitulates the mixed osteoblastic-osteolytic characteristics of human PCa. We confirmed that immune-PCa dynamic is an important aspect of disease with the osteoblastic pathology dependent on co-opted osteal macrophages. However, this model required intratibial delivery and is not useful for study of all aspects of the PCa metastatic cycle. New and improved models are needed with humanized mouse models using donor matched PCa cells and immune reconstitution clearly on the horizon. These matched with improved intra-vital imaging capabilities and unprecedented molecular tools provide great promise for improving treatment options in PCa bone metastasis.