@article{f3c90657888f4d4da816bb068c304fdb,
title = "Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B",
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.",
author = "Yu Sun and Judith Campisi and Celestia Higano and Beer, {Tomasz M.} and Peggy Porter and Ilsa Coleman and Lawrence True and Nelson, {Peter S.}",
note = "Funding Information: 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.",
year = "2012",
month = sep,
doi = "10.1038/nm.2890",
language = "English (US)",
volume = "18",
pages = "1359--1368",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "9",
}