Chemotherapy May Trigger Tumor Resistance: Unexpected Findings

Megan Brooks

August 09, 2012

August 9, 2012 — A new study sheds light on why tumors become resistant to chemotherapy.

Researchers have found that commonly used anticancer treatments that damage DNA generate a response in normal (noncancerous) fibroblasts surrounding tumor cells that promotes tumor growth and resistance to subsequent rounds of treatment.

Blocking this response — namely, upregulating a protein called WNT16B in fibroblasts — might help reduce resistance and improve the effectiveness of chemotherapy, the researchers report.

Although the study was conducted in prostate tumors, the researchers say their findings could be relevant to other tumors as well. Their study was published online August 5 in Nature Medicine.

Acquired resistance to chemotherapy is extremely common and is a substantial barrier to effective treatment, Peter S. Nelson, MD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington, and colleagues write.

Cancer cells live in a "very complex and dynamic microenvironment, akin to a "neighborhood," with many normal cell types surrounding the cancer cell, Dr. Nelson explained in an email to Medscape Medical News.

"There is prior evidence that the tumor microenvironment influences the way cancers/cancer cells respond to or resist treatment. The major advance here is [the understanding] that treatment itself can alter the environment in a negative way and that WNT16B can influence the treatment response; this is entirely new," Dr. Nelson said.

"Completely Unexpected"

The researchers examined tissue collected from men with prostate cancer before and after exposure to genotoxic chemotherapy (mitoxantrone and docetaxel). After chemotherapy, they found evidence of DNA damage in fibroblasts and smooth muscle cells comprising the prostate stroma. This DNA damage in fibroblasts was associated with a massive "30-fold" overproduction of WNT16B in fibroblasts in the tumor microenvironment, Dr. Nelson explained.

"The increase in WNT16B was completely unexpected," he told Medscape Medical News. "We also showed that WNT16B, when secreted, interacts with nearby tumor cells and causes them to grow, invade, and, importantly, resist subsequent therapy."

The researchers also identified a "spectrum" of other proteins that are secreted after genotoxic chemotherapy and are capable of stimulating tumor cells. "Some microenvironment factors may be relevant to many types of cancer (e.g., prostate, breast, ovary), whereas other microenvironment factors may be more relevant to a particular type of cancer," Dr. Nelson noted.

"Microenvironment components can be considered good targets for therapy, either individually (e.g., WNT16B, because it alone has substantial effects) or collectively," Dr. Nelson concluded.

The work was funded by the National Institutes of Health, the Department of Defense, and the Prostate Cancer Foundation. The authors have disclosed no relevant financial relationships.

Nat Med. Published online August 5, 2012. Abstract

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