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

WNT16B is activated in fibroblasts through NF-κB and promotes an epithelial to mesenchymal transition (EMT) in neoplastic prostate epithelium through paracrine signalingnHighlight:DNA damage secretory program (DDSP)nHighlight:expression of WNT16B increased between eightfold and 64-fold as a result of these treatmentsnHighlight:Wnt family members participate in well-described mesenchymal and epithelial signaling events that span developmental biology, stem cell functions and neoplasianHighlight:DNA damage increased WNT16B protein expressionnHighlight:Genotoxic treatments induced the expression of WNT16B protein in primary human fibroblasts isolated directly from breast and ovarian tissues and in the prostatesnHighlight:In patients with prostate cancer treated with neoadjuvant chemotherapy, higher WNT16B immunoreactivity in prostate stroma after treatment was associated with a significantly greater likelihood of cancer recurrencenHighlight:paracrine WNT16B activity can promote tumor growth in vivo and accounts for a substantial component of the full DDSP effect on neoplastic epitheliumnHighlight: were upregulated (approximately fivefold and over tenfold, respectively) after exposure to WNT16B-enriched conditioned medium (Fig. 4b). In human prostate cancers treated with chemotherapy, β-catenin localized in the nucleus of tumor cells (Supplementary Fig. 4a). We also found that β-catenin target genes were expressed more highly in tumors with elevated stromal WNT16B expression relative to those with low WNT16B expression (P < 0.05) (Fig. 4c). To confirm that β-catenin signaling contributed to the epithelial phenotypes resulting from exposure to PSC27-RAD–conditioned medium, we treated prostate cancer cells with the tankyrasenHighlight:Wnt signaling is known to promote the acquisition of mesenchymal cell characteristics that can influence the migratory and invasive behavior of epithelial cells through an EMTnHighlight:NF-κB is also pivotal in mediating the stress-associated induction of inflammatory networks, including the upregulation and secretion of interkeukin-6 (IL-6) and IL-8nHighlight:WNT16B as a new member of the cellular genomic program that is regulated by NF-κB signaling in response to DNA damagenHighlight:the outcomes of genotoxic exposures to any specific benign or neoplastic cell depend on the integration of innate damage response capabilities and the context that is dictated by the composition of the tumor microenvironmentnHighlight:although intrinsic drug resistance is clearly operative in some cancers, acquired resistance can also occur without alterations in intrinsic cellular chemosensitivity, and our results provide strong support for previous studies that implicate constituents of the tumor microenvironment as important contributors to this resistancenHighlight:specific microenvironment DDSP proteins that promote therapy resistance such as WNT16B are attractive targets for augmenting responses to more general genotoxic therapeuticsn]]>

About Dr. Nathan Goodyear
About Dr. Nathan Goodyear

Dr. Nathan Goodyear, a medical doctor with years of experience in the field of integrative cancer care, has announced the launch of an online training program. This program, available on his new website, will provide individuals with access to video trainings led by Dr. Goodyear himself, covering a range of topics related to integrative cancer care. These trainings will include information on the latest research and techniques in the field, as well as guidance on how to incorporate these approaches into a patient’s overall cancer treatment plan. With this online program, Dr. Goodyear hopes to make his expertise and knowledge more widely accessible, and help more people understand the benefits of integrative cancer care.

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