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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 prostate cancer cells show decreased metastatic growth in vivo.a Representative images of mice inoculated intra-cardiac with either 100,000 ALDH7A1-kd-Pro4luc knockdown or NT-Pro4luc control cells at day 21, 28, and 35 after inoculation (n = 10/group). b Total tumor burden of ALDH7A1-kd-Pro4luc cells (closed circles) compared with NT-Pro4luc cells (open circles). c Total number of metastases per mouse in the mice injected with either ALDH7A1-kd-Pro4luc cells (closed circles) or NT-Pro4luc control cells (open circles). d Total number of bone metastases per mouse in the mice injected with either ALDH7A1-kd-Pro4luc (closed circles) NT-Pro4luc control (open circles) cells
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Fig4: ALDH7A1 knockdown prostate cancer cells show decreased metastatic growth in vivo.a Representative images of mice inoculated intra-cardiac with either 100,000 ALDH7A1-kd-Pro4luc knockdown or NT-Pro4luc control cells at day 21, 28, and 35 after inoculation (n = 10/group). b Total tumor burden of ALDH7A1-kd-Pro4luc cells (closed circles) compared with NT-Pro4luc cells (open circles). c Total number of metastases per mouse in the mice injected with either ALDH7A1-kd-Pro4luc cells (closed circles) or NT-Pro4luc control cells (open circles). d Total number of bone metastases per mouse in the mice injected with either ALDH7A1-kd-Pro4luc (closed circles) NT-Pro4luc control (open circles) cells

Mentions: Inoculation of cancer cells into the left cardiac ventricle of immunodeficient mice is a widely used animal model of bone metastasis [4, 32, 36]. Significant differences in tumor growth and metastasis formation were observed (Fig. 4). In line with our intra-bone model, the ALDH7A1-kd-Pro4luc cells failed to reproducibly generate bone metastases, although limited growth was observed occasionally (Fig. 4a). Furthermore, metastatic tumor burden was significantly lower in the ALDH7A1-kd-Pro4luc group compared with the NT-Pro4luc control cells (Fig. 4b). Moreover, the total number of (bone) metastases was significantly decreased in the mice injected with the ALDH7A1 knockdown cells (Fig. 4c, d).Fig. 4


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 prostate cancer cells show decreased metastatic growth in vivo.a Representative images of mice inoculated intra-cardiac with either 100,000 ALDH7A1-kd-Pro4luc knockdown or NT-Pro4luc control cells at day 21, 28, and 35 after inoculation (n = 10/group). b Total tumor burden of ALDH7A1-kd-Pro4luc cells (closed circles) compared with NT-Pro4luc cells (open circles). c Total number of metastases per mouse in the mice injected with either ALDH7A1-kd-Pro4luc cells (closed circles) or NT-Pro4luc control cells (open circles). d Total number of bone metastases per mouse in the mice injected with either ALDH7A1-kd-Pro4luc (closed circles) NT-Pro4luc control (open circles) cells
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Related In: Results  -  Collection

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Fig4: ALDH7A1 knockdown prostate cancer cells show decreased metastatic growth in vivo.a Representative images of mice inoculated intra-cardiac with either 100,000 ALDH7A1-kd-Pro4luc knockdown or NT-Pro4luc control cells at day 21, 28, and 35 after inoculation (n = 10/group). b Total tumor burden of ALDH7A1-kd-Pro4luc cells (closed circles) compared with NT-Pro4luc cells (open circles). c Total number of metastases per mouse in the mice injected with either ALDH7A1-kd-Pro4luc cells (closed circles) or NT-Pro4luc control cells (open circles). d Total number of bone metastases per mouse in the mice injected with either ALDH7A1-kd-Pro4luc (closed circles) NT-Pro4luc control (open circles) cells
Mentions: Inoculation of cancer cells into the left cardiac ventricle of immunodeficient mice is a widely used animal model of bone metastasis [4, 32, 36]. Significant differences in tumor growth and metastasis formation were observed (Fig. 4). In line with our intra-bone model, the ALDH7A1-kd-Pro4luc cells failed to reproducibly generate bone metastases, although limited growth was observed occasionally (Fig. 4a). Furthermore, metastatic tumor burden was significantly lower in the ALDH7A1-kd-Pro4luc group compared with the NT-Pro4luc control cells (Fig. 4b). Moreover, the total number of (bone) metastases was significantly decreased in the mice injected with the ALDH7A1 knockdown cells (Fig. 4c, d).Fig. 4

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