“According to the 2009 report of the American Institute for Cancer Research, lifestyle and diet are factors that account for almost half of colorectal cancer (CRC) cases. Thus, research on the connection between diet and cancer is essential,” said Michael Bordonaro, PhD, assistant professor of Molecular Biology in the College’s Basic Sciences Department.

 

Dr. Bordonaro and his colleague, Darina Lazarova, PhD, also an assistant professor of Molecular Biology in the Basic Sciences Department, explained that their research will explore the effects of a fiber-derived product, butyrate, on the Wnt signaling pathway. “Cell signaling pathways are the information highways via which signals are transmitted in, to, and between cells; these signals determine whether the cell will live or die,” said Dr. Bordonaro.

 

Wnt signaling, he said, is required for the normal formation and function of the intestines but when the pathway is aberrantly activated, it contributes to colorectal carcinogenesis. “Logically, some proposed therapeutic approaches for CRC involve the suppression of the Wnt pathway,” he said. “However, we have found that butyrate, a degradation product of fiber in the colon, hyper-activates Wnt activity, and that the hyperactivated pathway contributes to programmed death (apoptosis) of the cancer cells. Therefore, hyperactivation of Wnt signaling is an alternative approach to eliminate colorectal cancer cells.” 

 

The team’s findings on the effects of butyrate on Wnt signaling may in part explain the protective role of dietary fiber against colon cancer. It has been established that high fiber intake (more than 35 grams a day) decreases the risk for colon cancer by 40%; however, individuals with a high intake of dietary fiber may still develop CRC. “In addition,” said Dr. Bordonaro, “epidemiological studies evaluating the association of fiber intake and colorectal cancer have given inconsistent results. Therefore, it is likely that pre-cancerous colonic cells may develop resistance to butyrate and eventually give rise to cancer even in the presence of high levels of diet-derived butyrate.”

 

Dr. Lazarova said that she and her colleagues have developed colorectal cancer cell lines that are resistant to butyrate at levels that are normally found in the colon. “These resistant cells do not exhibit hyperactivation of Wnt signaling in the presence of butyrate,” she said. “Importantly, these cells are also cross-resistant to other clinically relevant anti-cancer agents that mimic the effects of butyrate in colorectal cancer cells.

 

“The objective of our project is to determine the mechanism by which butyrate resistance develops, and to test approaches for reversing this resistance,” she continued. “Ultimately, we would like to prevent the development of butyrate resistance and to establish methods to reverse this resistance if it occurs.”

 

The researchers will study butyrate, a breakdown product of dietary fiber in the colonic lumen. Specifically, they will be using the sodium salt of butyrate, which will be provided by the company Sigma-Aldrich. “By applying butyrate in the cell growth medium, we can achieve levels similar to those detected in the human colon after the consumption of high fiber foods,” said Dr. Lazarova.

 

The high fiber diet and its protective role against colorectal cancer drew initial attention in the early 1970s when an association between high intake of dietary fiber and reduced risk for colon cancer was observed in African tribes. The phenomenon touched off several epidemiological studies in Europe and the U.S. “Although there is still controversy on this topic, the predominating consensus is that fiber intake of at least 30-35 grams a day may be protective,” commented Dr. Bordonaro. “Our work on butyrate resistance may help explain why some of the studies have yielded inconsistent results on the relation between fiber and colon cancer. Thus, we propose that the development of butyrate resistance could weaken the association between fiber intake and cancer prevention.”

 

To date, The Commonwealth Medical College has submitted over 100 research applications to the NIH and other research agencies and has received a total of $3.7 million in state and federal grant funding. This grant is the College’s first from the AICR.

 

The College is presently pursuing additional research grants in the nutraceuticals area. “We are currently exploring the possibility that additional agents derived from food may synergize with the effects of diet-derived butyrate on Wnt signaling,” confirmed Dr. Bordonaro. “It is likely that particular combinations of food have a more potent CRC-preventive effect than fiber alone. The contrary is also plausible: some foods may cancel the beneficial effect of butyrate. The interactions between the metabolites are complex and we are just starting to unravel them.”