Ask any cell biologist how cancer arises and the answer will be: by a mutation in a stem cell. In a new publication in Nature Genetics, scientists from Erasmus MC break through this dogma. They show that an intestinal tumor can also arise from a specialized cell type, such as an intestinal cell that produces mucus or antibacterial molecules.
Contradictory
The researchers came upon their discovery because of a contradiction, explains research leader Riccardo Fodde. ‘The main risk factors for colon cancer, namely chronic inflammation and Western eating habits, cause stem cells to be suppressed. If stem cells disappear under these conditions, they cannot be the origin of the cancer, can they? Moreover, we know from previous research that specialized intestinal cells revert to a stem cell-like cell type in response to tissue damage caused by inflammation, to repair the intestinal wall.’ Could the specialized intestinal cell then be the origin of intestinal tumors that arise in the context of inflammation?
That hypothesis turned out to be correct. In mice with a genetic predisposition to cancer in specialized intestinal cells, tumors developed from the moment the intestine became inflamed. The origin of these intestinal tumors was not a stem cell, but the specialized intestinal cell, Fodde and colleagues showed.
Goosebumps
Then the researchers noticed something else. The mice’s intestinal tumors resemble not only the tumors found in people with chronic inflammatory bowel disease, such as Crohn’s disease and ulcerative colitis, but also the intestinal tumors of people who do not have such a condition. PhD candidate Mathijs Verhagen used machine learning to predict that about 40 percent of human intestinal tumors have their origin in a specialized intestinal cell.
‘That result gave me goose bumps’, says Fodde. ‘That number is much higher than we expected. We think it can be explained by the chronic inflammation that Western dietary habits induce in the gut. This leads to the loss of stem cells and the activation of specialized cells, which can then grow into a tumor. So this happens not only in the relatively small group of intestine cancer patients with intestinal inflammation, but in many more people.
More young patients
The researchers link their findings to a worrisome development: colon cancer, by definition disease related to ageing, is increasingly being diagnosed in young people. ‘Our results confirm the suspicion that there is a relationship between Western lifestyle, chronic inflammation and the development of colon cancer at a young age, possibly from specialized cell types.’
Their results are also important because they may lead to a new classification of colon cancer, the researchers argue. Fodde: “Intestinal tumors arising from specialized cells have a worse prognosis than tumors arising from intestinal stem cells. The researchers’ hope is that the updated classification will lead to improved predictions of disease progression and personalized treatments.
