Abstract
Cell dormancy constitutes a limiting step of the metastatic process by preventing the proliferation of isolated cancer cells disseminated at distant sites from the primary tumor. The study of cancer cell dormancy is severely hampered by the lack of biological samples so that the mechanisms that regulate cell dormancy have not been extensively explored. In this work, we describe the rapid induction in vitro of a dormant state in prostate cancer cells by exposure to a slightly hypertonic growth medium. This quiescence is observed only when cells are seeded at low density and, once established, requires additional stimuli besides osmotic pressure to be reversed. Media conditioned by cells grown at high density can partially prevent or reverse dormancy, a phenomenon which can be reproduced with citric acid. In addition to this role of small metabolites, inactivation of the p53 and smad pathways also counters the entry into dormancy, whereas exposure to activin A induces it to some extent. Thus, this easily inducible dormancy reproduces several features associated with the dormancy of stem cells and cancer cells in vivo.
Highlights
Dormancy of disseminated cancer cells is a limiting step of cancer metastasis
Cloning Efficiency of Prostate Cancer Cells Is Inversely Correlated to Osmotic Pressure of the Culture Medium—In the course of analyzing the in vitro growth potential of prostate cancer cell lines, we used the LNCaP* cells, a cell population derived from LNCaP cells by transfection with a vector expressing the ecotropic receptor for murine leukemia retroviruses followed by phleomycin selection
We observed that LNCaP* cells cultured in DMEM-FCS had a markedly reduced cloning efficiency when compared with LNCaP cells grown in RPMI-FCS (Fig. 1A)
Summary
Dormancy of disseminated cancer cells is a limiting step of cancer metastasis. Results: A dormant state controls clonogenicity of dispersed prostate cancer cells in culture and is modulated by osmotic pressure, p53, and the activin A signaling pathways. We describe the rapid induction in vitro of a dormant state in prostate cancer cells by exposure to a slightly hypertonic growth medium This quiescence is observed only when cells are seeded at low density and, once established, requires additional stimuli besides osmotic pressure to be reversed. Media conditioned by cells grown at high density can partially prevent or reverse dormancy, a phenomenon which can be reproduced with citric acid In addition to this role of small metabolites, inactivation of the p53 and smad pathways counters the entry into dormancy, whereas exposure to activin A induces it to some extent. Several studies have shown that patients with prostate or breast cancer but no clinical metastases can harbor numerous cancer cells in their blood circulation for years
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