A gut reaction

Tackling colorectal cancer using ‘mini-guts’

IN DR. SAMUEL ASFAHA’S LABORATORY YOU WILL FIND...

the hallmarks of medical research from petri dishes to high-powered microscopes. More unusually, you will find ‘mini-guts’ – gastrointestinal (GI) structures developed from stem cells. The mini-guts are only one cell thick but their structure is similar to a normal GI tract in humans. “The ability to grow a fully structured gut lining in a dish is unique,” explains Dr. Asfaha, a Lawson scientist and gastroenterologist at London Health Sciences Centre.

Dr. Samuel Asfaha is growing mini-guts to study the origin and treatment of colorectal cancer.

“The gut contains stem cells that regenerate normal, healthy cells every few days. This allows us to grow healthy gut cells indefinitely.” Dr. Asfaha and his team are studying these mini-guts to understand the role of stem cells in colorectal cancer. Colorectal cancer, cancer of the colon or rectum, is the second leading cause of cancer death in Canada.

Dr. Asfaha’s team is growing mini-guts from both healthy tissues and cancerous ones, and mutating genes to see how they affect the tissues and their response to injuries caused by inflammation and radiation. The team is also using new technology to test different drugs on the mini-guts. This allows them to see what drugs work in preventing and treating colorectal cancer without harming healthy tissue.

THE ROLE OF INFLAMMATION

Inflammation is often associated with the development of cancer. For example, research has shown that inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, can increase a patient’s risk of colon cancer. But we also know that colorectal cancer develops over several years.

“The gut is a fascinating system as its cells are regenerated every two to five days by stem cells. For a cell in the gut to be mutated over several years and turn into cancer, it is reasonable to think it is a stem cell being transformed because they are long-lived and have the ability to regenerate other cells,” says Dr. Asfaha.

Before relocating to London, Ontario, Dr. Asfaha was part of a team of researchers at Columbia University in New York City. The team discovered a unique cell in the gut that has a long lifespan but is resistant to genetic mutation. As soon as they added inflammation to the cell’s environment, like that associated with IBD, the cell led to the development of tumours. They termed the cell a facultative stem cell; it only takes on the characteristics of a stem cell in the condition of inflammation.

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

Dr. Asfaha is currently conducting research to examine whether taking aspirin or other anti-inflammatory drugs can inhibit the transformation of this particular cell. “Aspirin can be toxic to the gut, especially when taken regularly at high doses, and can lead to the development of ulcers,” he explains. “If we can better understand how aspirin might inhibit the transformation of this cell, we can develop a new class of drugs that work in similar way but with less toxicity.”

A NEW STEM CELL POPULATION

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

The team is also growing mini-guts to examine the role of a newly discovered stem cell and its role in radiation-resistant cancer. The stem cells of the gut were first identified in 2007. In 2015, Dr. Asfaha identified another stem cell population in the gut 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. “We’re trying to determine if some patients don’t respond to therapy because their cancers were formed from mutation of this newly discovered stem cell.” Dr. Asfaha’s team is studying both stem cell populations in the GI tract using their mini-gut system. They want to further characterize each stem cell and the tumours that develop. They hope to understand the mechanisms that make some tumours resistant to radiation therapy and identify a drug that can make these tumours more sensitive to radiation.

Dr. Asfaha also has a goal of one day using the mini-gut system to study patientspecific tumours. “No two cancers are the same as cancer genetics differ between patients,” 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 these mini-guts will help drive colorectal cancer research forward.

Dr. Samuel Asfaha is a part of the Cancer research program at Lawson. He is an assistant professor in the Departments of Medicine and Oncology, Schulich School of Medicine & Dentistry at Western University.