Mechanism for chemotherapy resistance identified

By Ingrid Grasmo, MedWire Reporter

Researchers have identified that chemotherapy induces subsequent treatment resistance through damaging healthy tissue, which in turn secretes novel factors that sustain the growth of residual tumor cells.

The findings are of importance as acquired resistance to anticancer treatments is a substantial barrier to reducing the morbidity and mortality associated with malignant tumors, they report.

"Cancer therapies are increasingly evolving to be very specific, targeting key molecular engines that drive the cancer rather than more generic vulnerabilities, such as damaging DNA. Our findings indicate that the tumor microenvironment also can influence the success or failure of these more precise therapies," said lead study author Peter Nelson (Fred Hutchinson Cancer Research Center, Seattle, Washington, USA) in a press statement.

Nelson noted that chemotherapy primarily fails for advanced cancer because the doses necessary to treat the cancer successfully are often lethal to the patient. Regimens using smaller doses and cycles may not eradicate all tumor cells resulting in resistance to subsequent rounds of treatment.

For the study, the researchers studied the effects of chemotherapy exposure in men with prostate cancer who were enrolled in a clinical trial of a neoadjuvant combination therapy comprising a genotoxic drug, mitoxantrone, and the microtubule poison docetaxel.

Following chemotherapy, evidence of DNA damage was present in fibroblasts and smooth muscle cells comprising the prostate stroma. Genome-wide analysis of transcriptional responses to genotoxic stress induced by chemotherapy revealed that the tumor microenvironment secreted a number of proteins.

One of these proteins was Wnt family member wingless-type MMTV integration site family member (WNT)16B secreted by fibroblasts, which was shown to be excreted in concentrations up to 30-fold higher than that in normal cells.

The WNT family of genes and proteins plays an important role in normal development and also in the development of some cancers, but this is the first time a role in chemotherapy resistance has been suggested.

The authors believe that WNT16B triggers oncogenic signaling pathways supporting cancer cell survival and in turn reducing the cell response to chemotherapy, thereby promoting cancer cell growth.

It was also found that expression of WNT16B is regulated by nuclear factor of κ light polypeptide gene enhance in B cells (NF-κB) after DNA damage, and that WNT16B was elevated in normal tissue surrounding breast, ovarian, and prostate tumors from cancer patients following chemotherapy treatment. This finding further supports the importance of tumor microenvironment signaling pathways in chemotherapy response.

The findings are published in Nature Medicine.

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