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A luminal epithelial stem cell that is a cell of origin for prostate cancer

Abstract

In epithelial tissues, the lineage relationship between normal progenitor cells and cell type(s) of origin for cancer has been poorly understood. Here we show that a known regulator of prostate epithelial differentiation, the homeobox gene Nkx3-1, marks a stem cell population that functions during prostate regeneration. Genetic lineage-marking demonstrates that rare luminal cells that express Nkx3-1 in the absence of testicular androgens (castration-resistant Nkx3-1-expressing cells, CARNs) are bipotential and can self-renew in vivo, and single-cell transplantation assays show that CARNs can reconstitute prostate ducts in renal grafts. Functional assays of Nkx3-1 mutant mice in serial prostate regeneration suggest that Nkx3-1 is required for stem cell maintenance. Furthermore, targeted deletion of the Pten tumour suppressor gene in CARNs results in rapid carcinoma formation after androgen-mediated regeneration. These observations indicate that CARNs represent a new luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer.

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Figure 1: Expression of Nkx3-1 in epithelial cells of the intact, regressed and regenerated anterior prostate.
Figure 2: Bipotentiality and self-renewal of CARNs in vivo.
Figure 3: Generation of prostatic ducts in renal grafts by single lineage-marked CARNs.
Figure 4: Nkx3-1 mutants display prostate epithelial defects in a serial regeneration assay.
Figure 5: The CARN population contains a cell type of origin for prostate cancer.
Figure 6: Possible lineage relationships in the prostate epithelium.

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Acknowledgements

We thank M. Kim for her initial observations on Nkx3-1 expression in the regressed prostate, and C. Cordon-Cardo, E. Gelmann, C. Mendelsohn and B. Reizis for comments on the manuscript. We are also grateful to C. Bieberich, M. Capecchi, P. Chambon and F. Costantini for providing mice and reagents. This work was supported by grants from the NIH (C.A.-S. and M.M.S.), DOD Prostate Cancer Research Program (K.D.E., C.A.-S. and M.M.S.), and the NCI Mouse Models of Human Cancer Consortium.

Author Contributions X.W., M.K.-D., K.D.E., C.A.-S. and M.M.S. designed experiments, Y.P.-H. and S.M.P. generated mouse reagents, X.W., M.K.-D., K.D.E., D.W., H.Y. and M.V.H. performed experiments, and X.W., M.K.-D., C.A.-S. and M.M.S. wrote the manuscript.

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Correspondence to Michael M. Shen.

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Wang, X., Julio, Md., Economides, K. et al. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 461, 495–500 (2009). https://doi.org/10.1038/nature08361

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