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Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B

Nature Medicine volume 18, pages 13591368 (2012) | Download Citation

Abstract

Acquired resistance to anticancer treatments is a substantial barrier to reducing the morbidity and mortality that is attributable to malignant tumors. Components of tissue microenvironments are recognized to profoundly influence cellular phenotypes, including susceptibilities to toxic insults. Using a genome-wide analysis of transcriptional responses to genotoxic stress induced by cancer therapeutics, we identified a spectrum of secreted proteins derived from the tumor microenvironment that includes the Wnt family member wingless-type MMTV integration site family member 16B (WNT16B). We determined that WNT16B expression is regulated by nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB) after DNA damage and subsequently signals in a paracrine manner to activate the canonical Wnt program in tumor cells. The expression of WNT16B in the prostate tumor microenvironment attenuated the effects of cytotoxic chemotherapy in vivo, promoting tumor cell survival and disease progression. These results delineate a mechanism by which genotoxic therapies given in a cyclical manner can enhance subsequent treatment resistance through cell nonautonomous effects that are contributed by the tumor microenvironment.

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Acknowledgements

We thank J. Dean and D. Bianchi-Frias for helpful comments, A. Moreno for administrative assistance and N. Clegg for bioinformatics support. S. Hayward, Vanderbilt University, and J. Ware, Medical College of Virginia, provided BPH1 and M12 cells, respectively. Primary human prostate (PSC27), ovarian (OVF28901) and breast (HBF1203) fibroblasts were provided by B. Knudsen, Cedars Sinai Medical Center, E. Swisher, University of Washington, and P. Porter through the Seattle Breast SPORE (P50 CA138293), Fred Hutchinson Cancer Research Center, respectively. B. Torok-Strorb, Fred Hutchinson Cancer Research Center, provided HS5 and HS27A HPV E6/E7 immortalized human bone marrow stromal cells. We thank the clinicians who participated in the trials of neoadjuvant chemotherapy: M. Garzotto, T. Takayama, P. Lange, W. Ellis, S. Lieberman and B.A. Lowe. We are also grateful for the participation of the patients and their families in these studies. Breast cancer specimens were obtained from the Fred Hutchinson Cancer Research Center/University of Washington Medical Center Breast Specimen Repository. We thank N. Urban, Fred Hutchinson Cancer Research Center, for providing ovarian cancer biospecimens funded through the POCRC SPORE grant P50CA83636. This work was supported by a fellowship from the Department of Defense (PC073217), R01CA119125, the National Cancer Institute Tumor Microenvironment Network U54126540, the Pacific Northwest Prostate Cancer SPORE P50CA097186 and the Prostate Cancer Foundation.

Author information

Affiliations

  1. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Yu Sun
    • , Peggy Porter
    • , Ilsa Coleman
    •  & Peter S Nelson
  2. Buck Institute for Research on Aging, Novato, California, USA.

    • Judith Campisi
  3. Lawrence Berkeley National Laboratory, Berkeley, California, USA.

    • Judith Campisi
  4. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Celestia Higano
    •  & Peter S Nelson
  5. Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Celestia Higano
    •  & Peter S Nelson
  6. Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon, USA.

    • Tomasz M Beer
  7. Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.

    • Tomasz M Beer
  8. Department of Pathology, University of Washington, Seattle, Washington, USA.

    • Lawrence True
    •  & Peter S Nelson

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Contributions

Y.S. designed and conducted experiments, and wrote the manuscript. J.C. provided reagents and technical advice. C.H., T.M.B. and P.P. provided clinical materials for the assessments of treatment responses. I.C. analyzed data. L.T. analyzed tissue histology and immunohistochemical assays. P.S.N. designed experiments, analyzed data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Peter S Nelson.

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DOI

https://doi.org/10.1038/nm.2890

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