High
aldehyde dehydrogenase (ALDH) activity can be used to identify
tumor-initiating and
metastasis-initiating cells in various human
carcinomas, including
prostate cancer. To date, the functional importance of ALDH
enzymes in prostate
carcinogenesis, progression and
metastasis has remained elusive. Previously we identified strong expression of ALDH7A1 in human
prostate cancer cell lines, primary
tumors and matched bone
metastases. In this study, we evaluated whether ALDH7A1 is required for the acquisition of a metastatic stem/progenitor cell phenotype in human
prostate cancer. Knockdown of ALDH7A1 expression resulted in a decrease of the α2(hi)/αv(hi)/CD44(+) stem/progenitor cell subpopulation in the human
prostate cancer cell line PC-3M-Pro4. In addition, ALDH7A1 knockdown significantly inhibited the clonogenic and migratory ability of human
prostate cancer cells in vitro. Furthermore, a number of genes/factors involved in migration, invasion and
metastasis were affected including
transcription factors (snail, snail2, and twist) and
osteopontin, an ECM molecule involved in
metastasis. Knockdown of ALDH7A1 resulted in decreased intra-bone growth and inhibited experimentally induced (bone)
metastasis, while intra-prostatic growth was not affected. In line with these observations, evidence is presented that TGF-β, a key player in
cancer invasiveness and bone
metastasis, strongly induced ALDH activity while BMP7 (an antagonist of TGF-β signaling) down-regulated ALDH activity. Our findings show, for the first time, that the ALDH7A1
enzyme is functionally involved in the formation of bone
metastases and that the effect appeared dependent on the microenvironment, i.e., bone versus prostate.