Developmental Research Pilot Project

Norman Greenberg PhD, Fred Hutchinson Cancer Research Center

"Prostate Cancer Stem Cells"

Abstract

Our central hypothesis is that androgen dependent (AD) prostate cancer and androgen independent (AI) prostate cancer emerge from distinct prostate cancer stem cell populations (P-CSC) that arise stochastically in primary tumors through a combination of genetic predisposition and spontaneous somatic events. In a modification of the standard "stem cell hypothesis" we suppose: (i) that any single somatic immortal P-CSC has the ability to initiate an independent prostate tumors; (ii) that prostate tumor heterogeneity results when transit-amplifying progeny of a P-CSC become blocked at various stages of differentiation; and (iii) that AI prostate cancer emerges from a P-CSC that is normally quiescent in the presence of androgen but displays selective survival and growth advantage following hormone withdrawal therapy. Given our supporting preliminary data, we propose to isolate distinct and resolvable P-CSC populations in autochthonous primary tumors that give rise to either AD (P-CSC^AD) or AI (P-CSC^AI) disease. To this end we will isolate P-CSC populations from primary tumors arising spontaneously in cohorts of intact and castrated genetically engineered mouse (GEM) models and test the ability of these P-CSC populations to initiate tumors in intact or castrated NOD/SCID recipient mice. If our hypothesis is correct then we expect to isolate more P-CSC^AI than P-CSC^AD in a castrated GEM mouse and that fewer P-CSC^AI than P-CSC^AD would be required to form tumors in recipient castrated mice. An immediate goal will be to elucidate gene expression profiles that distinguish P-CSC^AD from P-CSC^AI to identify new targets for prevention and intervention therapy.