Gail P Risbridger
Renea A Taylor, Roxanne Toivanen and Gail P Risbridger
Prostate cancer is a hormone-dependent, epithelial-derived tumor, resulting from uncontrolled growth of genetically unstable transformed cells. Stem cells are therapeutic targets for prostate cancer, but as disease progression occurs over decades, the imperative is to identify and target the cancer-repopulating cell (CRC) that maintains malignant clones. In order to achieve this goal, we will review the current knowledge of three specific types of cells, their origins, and their differentiation potential. The first is the normal stem cell, the second is the cancer cell of origin, and the third is the CRC. Specifically, we review three proposed models of stem cell differentiation in normal tissues, including linear, bidirectional, and independent lineages. We consider evidence of the cancer cell of origin arising from both basal and luminal cells. Finally, we discuss the limited data available on the identity and characterization of CRCs in localized and castrate-resistant prostate cancer, which is where we believe the focus of future research efforts should be directed. Ultimately, understanding the intrinsic or extrinsic influences that dictate the behavior of these unique cells will be instrumental in facilitating the development of new therapeutic targets for prostate cancer.
Marianna Volpert, Luc Furic, Jinghua Hu, Anne E O’Connor, Richard J Rebello, Shivakumar Keerthikumar, Jemma Evans, D Jo Merriner, John Pedersen, Gail P Risbridger, Peter McIntyre and Moira K O’Bryan
Identifying the factors stimulating prostate cancer cells migration and invasion has the potential to bring new therapeutic targets to the clinic. Cysteine-rich secretory protein 3 (CRISP3) is one of the most highly upregulated proteins during the transition of a healthy human prostatic epithelium to prostate cancer. Here we show using a genetically engineered mouse model of prostate cancer that CRISP3 production greatly facilitates disease progression from carcinoma in situ to invasive prostate cancer in vivo. This interpretation was confirmed using both human and mouse prostate cancer cell lines, which showed that exposure to CRISP3 enhanced cell motility and invasion. Further, using mass spectrometry, we show that CRISP3 induces changes in abundance of a subset of cell-cell adhesion proteins, including LASP1 and TJP1 both in vivo and in vitro. Collectively, these data identify CRISP3 as being pro-tumorigenic in the prostate and validate it as a potential target for therapeutic intervention.