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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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ALDH7A1 knockdown in prostate cancer cells differentially affects orthotopic and intra-bone growth in preclinical models. a The left panel demonstrates representative images of one mouse 14, 21, and 28 days after orthotopic injection in the prostate with either 100,000 ALDH7A1-kd-Pro4luc or NT-Pro4 prostate cancer cells. The right panel reveals total tumor burden for the mice injected with the ALDH7A1-kd-Pro4luc knockdown population (closed circles) or the NT-Pro4luc control population (open circles) (n = 8/group). b Representative images of mice intra-osseously inoculated with either ALDH7A1-kd-Pro4luc or NT-Pro4luc cells (100,000) at different days after inoculation. Total tumor burden of the mice injected with ALDH7A1-kd-Pro4luc (closed circles) or NT-Pro4luc cells (open circles) subpopulation (n = 8/group *P < 0.05)
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Fig3: ALDH7A1 knockdown in prostate cancer cells differentially affects orthotopic and intra-bone growth in preclinical models. a The left panel demonstrates representative images of one mouse 14, 21, and 28 days after orthotopic injection in the prostate with either 100,000 ALDH7A1-kd-Pro4luc or NT-Pro4 prostate cancer cells. The right panel reveals total tumor burden for the mice injected with the ALDH7A1-kd-Pro4luc knockdown population (closed circles) or the NT-Pro4luc control population (open circles) (n = 8/group). b Representative images of mice intra-osseously inoculated with either ALDH7A1-kd-Pro4luc or NT-Pro4luc cells (100,000) at different days after inoculation. Total tumor burden of the mice injected with ALDH7A1-kd-Pro4luc (closed circles) or NT-Pro4luc cells (open circles) subpopulation (n = 8/group *P < 0.05)

Mentions: When implanted orthotopically in the mouse prostate, no significant differences were observed in tumor growth between both groups (Fig. 3a). Strikingly, we observed marked differences in tumorigenicity and metastatic ability in bone/bone marrow using our preclinical models of intra-bone growth [4, 32, 36]. Tumor take and intra-bone tumor growth were significantly decreased in the ALDH7A1-kd-Pro4luc group versus NT-Pro4luc control cells (Fig. 3b).Fig. 3


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)

ALDH7A1 knockdown in prostate cancer cells differentially affects orthotopic and intra-bone growth in preclinical models. a The left panel demonstrates representative images of one mouse 14, 21, and 28 days after orthotopic injection in the prostate with either 100,000 ALDH7A1-kd-Pro4luc or NT-Pro4 prostate cancer cells. The right panel reveals total tumor burden for the mice injected with the ALDH7A1-kd-Pro4luc knockdown population (closed circles) or the NT-Pro4luc control population (open circles) (n = 8/group). b Representative images of mice intra-osseously inoculated with either ALDH7A1-kd-Pro4luc or NT-Pro4luc cells (100,000) at different days after inoculation. Total tumor burden of the mice injected with ALDH7A1-kd-Pro4luc (closed circles) or NT-Pro4luc cells (open circles) subpopulation (n = 8/group *P < 0.05)
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Related In: Results  -  Collection

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Fig3: ALDH7A1 knockdown in prostate cancer cells differentially affects orthotopic and intra-bone growth in preclinical models. a The left panel demonstrates representative images of one mouse 14, 21, and 28 days after orthotopic injection in the prostate with either 100,000 ALDH7A1-kd-Pro4luc or NT-Pro4 prostate cancer cells. The right panel reveals total tumor burden for the mice injected with the ALDH7A1-kd-Pro4luc knockdown population (closed circles) or the NT-Pro4luc control population (open circles) (n = 8/group). b Representative images of mice intra-osseously inoculated with either ALDH7A1-kd-Pro4luc or NT-Pro4luc cells (100,000) at different days after inoculation. Total tumor burden of the mice injected with ALDH7A1-kd-Pro4luc (closed circles) or NT-Pro4luc cells (open circles) subpopulation (n = 8/group *P < 0.05)
Mentions: When implanted orthotopically in the mouse prostate, no significant differences were observed in tumor growth between both groups (Fig. 3a). Strikingly, we observed marked differences in tumorigenicity and metastatic ability in bone/bone marrow using our preclinical models of intra-bone growth [4, 32, 36]. Tumor take and intra-bone tumor growth were significantly decreased in the ALDH7A1-kd-Pro4luc group versus NT-Pro4luc control cells (Fig. 3b).Fig. 3

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