Clonogenicity of Cultured Prostate Cancer Cells Is Controlled by Dormancy: Significance and Comparison with Cell Culture Models of Breast Cancer Cell Dormancy

Abstract

The metastatic disease determines the cancer-specific death of most patients suggesting that decreasing the rate of metastasis should translate into increased cancer-specific survival. Several experiments in mice suggest that a major limiting step of the metastatic process is the ability of single cancer cells to proliferate at distant sites. Most dispersed cancer cells disseminated in distant organs seem to remain dormant for long period before eventually dying or resuming cell proliferation to give rise to micrometastases. The study of these dispersed dormant cells is made difficult by their rarity and the difficulty to isolate them into a viable cell population. Our recently published work shows that a dormant state can be easily induced in prostate cancer cells ex vivo in cell culture. Indeed, if and only if cells are cultured at low clonal density, slightly hypertonic conditions will induce a dormant state leading to an almost 1,000-fold reduction in clonogenicity. Our data suggest that a full dormant state is a stable anergic state actively generated in dispersed cells in response to specific growth conditions, and which may require special growth stimuli to be reversed. Here we compare this model with two examples of breast cancer cell dormancy induced in vitro in order to highlight their convergences and discuss the link between dormancy, epithelial-mesenchymal transition and stemness. We suggest that despite some ­similarities with stem cell dormancy, dormancy of epithelial cancer cells may be related to a reversible differentiation-like process. We also discuss the applications of the culture model of prostate cancer cell dormancy with emphasis on the development of new tools to fight the metastatic disease at the clonogenic step.