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.

Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling

“…Abnormal expression patterns of β-catenin have been observed in 20-71% of prostate cancer samples (51)(52)(53), and high levels of β-catenin are concomitantly associated with increasing Gleason score and castration resistance (53,54). Although recent studies showed that mutations in allophycocyanin and β-catenin can be detected in approximately 10% and 12% of castrationresistant prostate cancer, respectively (55)(56)(57), it seems that Wnt/ β-catenin signaling could play a more common role in prostate cancer than would be predicted by the point mutation rates of these downstream effectors (53,58,59). Alterations in Wnt ligands and their modulators that are secreted from prostate epithelia and the surrounding stroma may serve as the alternative mechanism for activation of Wnt signaling in a subset of human prostate cancer.…”

Contradictory Relationships between Cancer and Normal Cells and Implications for Anti-cancer Therapy

“…These injured normal cells may secrete WNT16B protein into the tumor microenvironment. Once WNT16B is absorbed into the cancer cells, it induces survival by promoting tumor cell growth and invasion and fostering resistance to chemotherapy (Campisi et al, 2012). These results indicate that normal cells in the tumor microenvironment are also involved in inducing tumor cell metastasis and resistance to chemotherapy.…”

Une nouvelle cause de la résistance des tumeurs à la chimiothérapie

“…Une toute récente publication dans Nature Medicine [1] jette un pavé dans la mare, en décrivant un mécanisme paradoxal de résistance : l'altération de l'ADN de cellules bénignes non tumorales, les fibroblastes produisant le collagène et situés dans le micro-environnement de la tumeur. Ces fibroblastes dont l'ADN a été modifié, stimulent la résistance des cellules tumorales au traitement ainsi que la progression de la tumeur.…”

“…2) L'effet stimulant de la protéine WNT16B sur la prolifération des cellules épithéliales néoplasiques a déjà été signalé [3]. Dans l'étude analysée ici [1], les auteurs le confirment en comparant une souche de fibroblastes prostatiques avec expression bloquée de WNT16B et une souche exprimant WNT16B. Seule cette dernière stimule la croissance tumorale et la migration des cellules malignes.…”