GEN Exclusives

More »

GEN News Highlights

More »
Aug 6, 2012

Exposing the Roots of Chemotherapy Resistance

  • Scientists claim that increased production and secretion of WNT16B by fibroblasts into the tumor microenvironment plays a key role in promoting both cancer growth and acquired resistance to chemotherapy. A Fred Hutchinson Cancer Research Center-led team has shown that when stromal fibroblasts are subjected to genotoxic stress resulting from chemotherapy they upregulate by up to 64-fold the transcription of WNT16B, and this secreted factor directly impacts on tumor cell growth and chemotherapy resistance. 

    Published studies by Peter S. Nelson, M.D., and colleagues demonstrated that elevation of WNT16B transcription is evident in the stroma of human prostate, breast, and ovarian cancers that have previously been treated using chemotherapy. And when the researchers looked specifically at prostate cancer patients given neoadjuvant chemotherapy, they found that higher post-therapy levels of WNT16B in the tumor microenvironment were associated with an increased likelihood of cancer recurrence.

    The tumor growth–promoting role of WNT16B produced by stromal fibroblasts subjected to genotoxic stress was demonstrated by incubating neoplastic epithelial cells in either conditioned medium from irradiated (i.e., DNA-damaged) fibroblasts that were capable of expressing and secreting WNT16B, or conditioned medium from irradiated fibroblasts that expressed a WNT16B-inhibiting shRNA. The results of this set of experiments showed that, dependent on the cell line used, cancer cells cultured in conditioned medium from the WNT16B-deficient irradiated fibroblasts were 15–35% less invasive and proliferative than those cultured in conditioned medium from unmodified irradiated fibroblasts.

    A relationship between cancer growth and WNT16B expression by stromal fibroblasts was separately demonstrated in vivo, in experimental mice implanted with prostate cancer cells and with either prostate fibroblast cells that were capable of producing WNT16B, or those that expressed a WNT16B-silencing shRNA. Tumors growing in the presence of WNT16B-expressing fibroblasts were much larger, and also more poorly differentiated and invasive than those developing in mice implanted with WNT16B-deficient fibroblasts.

    Having established that WNT16B can promote tumor growth through paracrine signaling, the researchers went on to determine that WNT16B-enriched conditioned medium from irradiated fibroblasts activated canonical Wnt signaling in different prostate cancer cell lines, resulting in the upregulation of known β-catenin target genes, and promotion of mesenchymal characteristics. β-catenin target genes were also expressed more highly in tumors with elevated stromal WNT16B expression than those with low WNT16B expression. The upregulation of WNT16B production by stromal fibroblasts exposed to genotoxic stress was induced through NF-κB binding to the WNT16B gene.

    In a final set of in vivo experiments, the Fred Hutchinson team separately demonstrated that stromal WNT16B significantly blocked the response of either breast or prostate tumors to chemotherapy.

    Dr. Nelson et al say their studies support the notion that factors released into the tumor environment by nonmalignant cells can influence cancer growth, invasiveness, and response to chemotherapy. “Our results provide strong support for previous studies that implicate constituents of the tumor microenvironment as important contributors to this resistance,” they write. And while the team says their reported data indicate that microenvironment proteins such as WNT16B represent attractive targets for boosting the effectiveness of anticancer therapies, strategies focused on inhibiting upstream master regulators, such as NF-κB, may be even more efficient and effective adjuncts to cytotoxic therapies.

    Dr. Nelson et al describe their findings in Nature Medicine, in a paper titled “Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B.”


Add a comment

  • You must be signed in to perform this action.
    Click here to Login or Register for free.
    You will be taken back to your selected item after Login/Registration.

Related content

Jobs

GEN Jobs powered by HireLifeScience.com connects you directly to employers in pharma, biotech, and the life sciences. View 40 to 50 fresh job postings daily or search for employment opportunities including those in R&D, clinical research, QA/QC, biomanufacturing, and regulatory affairs.
 Searching...
More »

GEN Poll

More » Poll Results »

Alzheimer's Therapies

Do you think an effective treatment for Alzheimer’s will be found within the next 10–15 years?