The aldehyde dehydrogenase enzyme 7A1 is functionally involved in prostate cancer bone metastasisReport as inadecuate




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Clinical and Experimental Metastasis

, Volume 28, Issue 7, pp 615–625

First Online: 07 June 2011Received: 05 February 2011Accepted: 23 May 2011DOI: 10.1007-s10585-011-9395-7

Cite this article as: van den Hoogen, C., van der Horst, G., Cheung, H. et al. Clin Exp Metastasis 2011 28: 615. doi:10.1007-s10585-011-9395-7

Abstract

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-αv-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.

KeywordsProstate cancer Bone metastasis ALDH EMT Tumor-initiating cells AbbreviationsALDHAldehyde dehydrogenase

BLIWhole body bioluminescent reporter imaging

BMPBone morphogenetic protein

CSCCancer stem cell

EMTEpithelial-to-mesenchymal transition

GAPDHGlyceraldehyde-3′-phosphate dehydrogenase

OPNOsteopontin

SDS-PAGESodium dodecyl sulphate-polyacrylamide gel electrophoresis

shRNAShort hairpin RNA

TGF-βTransforming growth factor-β

Electronic supplementary materialThe online version of this article doi:10.1007-s10585-011-9395-7 contains supplementary material, which is available to authorized users.

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Author: Christel van den Hoogen - Geertje van der Horst - Henry Cheung - Jeroen T. Buijs - Rob C. M. Pelger - Gabri van der Pl

Source: https://link.springer.com/







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