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Researchers find mechanism that promotes cancer treatment resistance
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Treatment-induced DNA damage to the tumor microenvironment stimulates cancer therapy resistance, according to study results.
Typically, fibroblasts maintain the structural integrity of connective tissue, and they also are important for wound healing and collagen production, according to background information in the study. However, when exposed to chemotherapy, noncancerous fibroblast cells sustain DNA damage that stimulates growth factor production, which in turn promotes cancer growth.
Peter S. Nelson, MD, a member of the human biology division at Fred Hutchinson Cancer Research Center, and colleagues examined tissues they collected before and after chemotherapy in men with prostate cancer who were enrolled in a neoadjuvant clinical trial. After chemotherapy, the researchers found evidence of DNA damage in the fibroblasts and smooth muscle cells that make up the prostate stroma.
Nelson and colleagues found that treatment-induced DNA damage causes fibroblasts to produce a protein called WNT16B within the tumor microenvironment. High WNT16B levels promote cancer cell growth and encourage the survival of cancer cells after cytotoxic therapy.
The researchers saw up to 30-fold increases in WNT production, a finding Nelson referred to in a press release as “completely unexpected.”
“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,” Nelson and colleagues wrote. “Our findings indicate that the tumor microenvironment also can influence the success or failure of these more precise therapies.”
The ability of tumors to acquire resistance to cytotoxic and cytostatic therapeutics is a major challenge for oncologists. This resistance contributes to treatment failure in more than 90% of patients with metastatic carcinomas.
“We conclude that approaches targeting constituents of the tumor microenvironment in conjunction with conventional cancer therapeutics may enhance treatment responses,” the authors wrote.
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