Signaling by Damaged Normal Tissues Promotes Cancer Growth and Resistance to Chemotherapy

Chemotherapy can damage normal tissues and induce cells such as fibroblasts to secrete signaling molecules that promote tumor growth and development of resistance to further drug treatment.

One of the signaling molecules that is being studied extensively in this regard is the protein Wnt-16, as evidence has suggested that stimulation of WNT16 expression in nearby normal cells is responsible for the development of chemotherapy-resistance in cancer cells.

The WNT gene family consists of structurally related genes that encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. WNT16B expression is regulated by nuclear factor of kappa light polypeptide gene enhancer in B cells 1 (NF-kappaB) after DNA damage, as can occur to normal cells during radiation or chemotherapy. Subsequently WNT16B signals in a paracrine manner to activate the Wnt expression program in tumor cells. The expression of WNT16B in the tumor microenvironment has been found to weaken the effects of cytotoxic chemotherapy in vivo, promoting tumor cell survival and disease progression.

Investigators at the Fred Hutchinson Cancer Research Center (Seattle, WA, USA) studied the tumor growth-promoting role of WNT16B produced by DNA-damaged stromal fibroblasts by incubating neoplastic epithelial cells in either conditioned medium from irradiated 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, which were published in the August 5, 2012, online edition of the journal Nature Medicine, 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.

“Cancer cells inside the body live in a very complex environment or neighborhood. Where the tumor cell resides and who its neighbors are influence its response and resistance to therapy,” said senior author Dr. Peter S. Nelson, professor of medical oncology at the Fred Hutchinson Cancer Research Center. “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.”

“This study is an example of collaborative, translational research that capitalizes on years of federally funded investments into the development of tissue banks and clinical trials in which we were able to track long-term patient outcomes. Investing in this type of infrastructure is critical but may take many years to see payoff,” said Dr. Nelson.

Related Links:
Fred Hutchinson Cancer Research Center