A gut reaction: Tackling colorectal cancer using ‘mini-guts’

Fall 2018

In Dr. Samuel Asfaha’s laboratory you will find the hallmarks of medical research from petri dishes to microscopes. More unusually, you will find ‘mini-guts’ – gastrointestinal (GI) structures developed from stem cells. While the mini-guts are only one cell thick their structure is similar to a normal GI tract in humans.

Dr. Asfaha, a scientist at Lawson Health Research Institute and gastroenterologist at London Health Sciences Centre, is studying these mini-guts to understand the role of stem cells in colorectal cancer.

Colorectal cancer, cancer of the colon or rectum, develops over several years. “For a cell in the gut to be mutated over several years, it is reasonable to think it’s a stem cell since they have a long lifespan and regenerate other cells,” says Dr. Asfaha.

In one project Dr. Asfaha is studying how inflammation can mutate stem cells and lead to colorectal cancer. During his time at Columbia University, Dr. Asfaha’s team discovered a unique cell that has a long lifespan but is resistant to genetic mutation. As soon as they added inflammation to the cell’s environment, the cell led to the development of tumours. The team termed it a facultative stem cell; it only takes on the characteristics of a stem cell in the condition of inflammation.

Dr. Asfaha’s team at Lawson is now growing mini-guts to understand how inflammation changes this cell and transforms it into a cancer. This includes studying two proteins expressed by the cell called COX-1 and COX-2 which are targets of aspirin, a drug previously shown to reduce patients’ risk of colorectal cancer.

Dr. Asfaha is examining whether taking aspirin or other anti-inflammatory drugs can prevent the transformation of this cell. “Unfortunately, aspirin can be toxic to the gut,” he explains. “But if we better understand how aspirin might inhibit the transformation of this cell, we can develop a new class of drugs with less toxicity.”

While stem cells of the gut were first identified in 2007, Dr. Asfaha identified a second stem cell population in 2015 and proved its importance to the growth of colon cancer. When mutated, these particular stem cells lead to tumours that are resistant to radiation therapy.

“Radiation therapy is very important for treatment of rectal cancer, but not all patients respond to it,” says Dr. Asfaha. “In another of our projects, we’re trying to determine if radiation-resistant tumours form from mutation of this particular stem cell.”

Dr. Asfaha’s team is currently studying both stem cell populations in the GI tract using their mini-gut system. They want to further understand each stem cell and the tumours that develop. They hope to understand the mechanisms that make some tumours resistant to radiation and identify a drug that can make these tumours more sensitive.

One day, Dr. Asfaha hopes to use the mini-gut system to study patient-specific tumours. “No two cancers are the same,” explains Dr. Asfaha. “We hope to eventually take individual patient samples, grow a mini-gut from their tumour and see what therapies work best against it.”

Through continued innovation, the team hopes mini-guts will help drive colorectal cancer research forward.

This article is adapted from Lawson Link magazine. To read the full article, visit www.lawsonresearch.ca/lawsonlink.

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From left: Dr. Asfaha, Lawson scientist; Hayley Good, PhD candidate; and Elena Fazio, postdoctoral fellow, working in Dr. Asfaha’s lab.