Journal Article

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

Campisi, Judith, Sun, Yu, Higano, Celestia, Porter, Peggy, Nelson, Peter S, Beer, Tomasz M, Coleman, Ilsa, True, Lawrence

2012

Overview

Responses to anticancer therapy are hampered by several factors, and Peter S. Nelson and colleagues here identify a protective effect of the tumor microenvironment. After cytotoxic chemotherapy, inflammatory NF-κB signaling activates the secretion of WNT16B, which acts on epithelial cells, promoting their survival and fostering tumor growth in vivo . This pathway is also active in human tumors treated with chemotherapy and illustrates the potential caveats of cyclical therapy and the need to overcome environmental protection to successfully eliminate tumors. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 692/699/67/1059/2326 / 692/699/67/327 / 692/699/67/589/466 / Analysis of Variance / Animals / B-Lymphocytes - metabolism / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cancer therapies / Cell Line / Chemotherapy / Cytotoxicity / Deoxyribonucleic acid / DNA / DNA Damage / Drug resistance / Drug Resistance, Neoplasm - physiology / Gene Expression Profiling / Humans / Immunohistochemistry / Infectious Diseases / Male / Metabolic Diseases / Mice / Mice, SCID / Microenvironments / Molecular Medicine / Morbidity / Mortality / Neurosciences / NF-kappa B - metabolism / Prostate cancer / Prostatic Neoplasms - drug therapy / Prostatic Neoplasms - physiopathology / Tumor Microenvironment - physiology / Tumors / Wnt Proteins - metabolism / Wnt Signaling Pathway - physiology