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The aldehyde dehydrogenase enzyme 7A1 is functionally involved in prostate cancer bone metastasis.

van den Hoogen C, van der Horst G, Cheung H, Buijs JT, Pelger RC, van der Pluijm G - Clin. Exp. Metastasis (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Leiden University Medical Centre, The Netherlands.

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(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.

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Differential expression of stem/progenitor markers and invasiveness-associated genes upon ALDH7A1 expression knockdown. a q-PCR analysis of stem/progenitor cell markers and EMT-associated genes (αv, α2, CD44, osteopontin, N-cadherin, snail, snail2, and twist). Relative expression levels in ALDH7A1-kd-Pro4luc cells were shown as compared to the NT-Pro4luc control cells. All values were normalized for GAPDH and presented as mean ± sem. b Relative E-cadherin/vimentin ratios of ALDH7A1-kd-Pro4luc and NT-Pro4luc control cells as measured by q-PCR analysis. Data are representative for two independent experiments
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Fig2: Differential expression of stem/progenitor markers and invasiveness-associated genes upon ALDH7A1 expression knockdown. a q-PCR analysis of stem/progenitor cell markers and EMT-associated genes (αv, α2, CD44, osteopontin, N-cadherin, snail, snail2, and twist). Relative expression levels in ALDH7A1-kd-Pro4luc cells were shown as compared to the NT-Pro4luc control cells. All values were normalized for GAPDH and presented as mean ± sem. b Relative E-cadherin/vimentin ratios of ALDH7A1-kd-Pro4luc and NT-Pro4luc control cells as measured by q-PCR analysis. Data are representative for two independent experiments

Mentions: Upon stable ALDH7A1 knockdown, a concomitant decrease in previously identified prostate cancer stem/progenitor cell surface markers was observed (Fig. 2a). Furthermore, ALDH7A1 knockdown in prostate cancer cells, led to reduced expression of E-cadherin transcriptional repressors (snail, snail2 and twist) and pro-metastatic factors including N-cadherin, twist, and osteopontin (OPN) (Fig. 2a) [34, 35]. In line with these observations, the E-cadherin/vimentin ratio increased upon ALDH7A1 knockdown, indicating the generation of a more epithelial and less invasive cell phenotype (Fig. 2b).Fig. 2


The aldehyde dehydrogenase enzyme 7A1 is functionally involved in prostate cancer bone metastasis.

van den Hoogen C, van der Horst G, Cheung H, Buijs JT, Pelger RC, van der Pluijm G - Clin. Exp. Metastasis (2011)

Differential expression of stem/progenitor markers and invasiveness-associated genes upon ALDH7A1 expression knockdown. a q-PCR analysis of stem/progenitor cell markers and EMT-associated genes (αv, α2, CD44, osteopontin, N-cadherin, snail, snail2, and twist). Relative expression levels in ALDH7A1-kd-Pro4luc cells were shown as compared to the NT-Pro4luc control cells. All values were normalized for GAPDH and presented as mean ± sem. b Relative E-cadherin/vimentin ratios of ALDH7A1-kd-Pro4luc and NT-Pro4luc control cells as measured by q-PCR analysis. Data are representative for two independent experiments
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198191&req=5

Fig2: Differential expression of stem/progenitor markers and invasiveness-associated genes upon ALDH7A1 expression knockdown. a q-PCR analysis of stem/progenitor cell markers and EMT-associated genes (αv, α2, CD44, osteopontin, N-cadherin, snail, snail2, and twist). Relative expression levels in ALDH7A1-kd-Pro4luc cells were shown as compared to the NT-Pro4luc control cells. All values were normalized for GAPDH and presented as mean ± sem. b Relative E-cadherin/vimentin ratios of ALDH7A1-kd-Pro4luc and NT-Pro4luc control cells as measured by q-PCR analysis. Data are representative for two independent experiments
Mentions: Upon stable ALDH7A1 knockdown, a concomitant decrease in previously identified prostate cancer stem/progenitor cell surface markers was observed (Fig. 2a). Furthermore, ALDH7A1 knockdown in prostate cancer cells, led to reduced expression of E-cadherin transcriptional repressors (snail, snail2 and twist) and pro-metastatic factors including N-cadherin, twist, and osteopontin (OPN) (Fig. 2a) [34, 35]. In line with these observations, the E-cadherin/vimentin ratio increased upon ALDH7A1 knockdown, indicating the generation of a more epithelial and less invasive cell phenotype (Fig. 2b).Fig. 2

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Leiden University Medical Centre, The Netherlands.

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(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.

Show MeSH
Related in: MedlinePlus