Oxygen deficiency in the colon cancer microenvironment can promote tumor growth

To effectively battle cancer, scientists must study the battlefield. Now, in a recent study published in Nature Communications, a multi-institutional research team including The University of Osaka has discovered some crucial intel: localized oxygen deficiency in the colon cancer microenvironment can promote tumor growth.

Until recently, oxygen deprivation, i.e., hypoxia, was thought to suppress tumor progression. Consequently, drugs that block the supply of oxygen to tumors were being used to treat cancers. However, these treatments achieved mixed results; sometimes, these drugs even accelerated tumor growth. Understanding why this happens has become an urgent question in cancer research.

We uncovered a surprising mechanism by which hypoxia may promote tumor growth, and it involves the formation of cells called inflammatory fibroblasts."

Akikazu Harada, lead author of the study

The research team found that when oxygen becomes scarce in certain areas of a colon tumor, the surrounding fibroblasts (normally 'good' cells that support tissue structure) transform into harmful inflammatory fibroblasts. The altered cells release factors that help tumors grow, such as epiregulin. In addition, they release Wnt5a protein, which helps maintain a low-oxygen state by inhibiting new blood-vessel formation at the site of its release, thereby maintaining hypoxia.

To validate the findings from the mouse model in human samples, the researchers pooled data from human samples obtained from patients with a healthy colon, colon cancer, and those with inflammatory bowel disease. Later, they analyzed the data and compared their findings with data from mice.

"We found that the malignant transformation of fibroblasts and the induction of Wnt5a-secreting fibroblasts are commonly observed in both mouse models and human samples," says Akira Kikuchi, senior author of the study.

This insight into the potential pathology of colon cancer and inflammation can provide the blueprints for a new cancer battle strategy: drug therapies that target Wnt5a-producing fibroblasts. As a result, fibroblasts are now being recognized as a key 'third' therapeutic target, complementing traditional treatments targeting cancer cells and immune cells.

This finding holds special importance for colon cancer, which is the leading type of cancer in Japan. Additionally, the observed pathological changes of fibroblasts could also apply to chronic inflammatory disorders like inflammatory bowel disease, offering fresh insights into their mechanisms and potential new treatment strategies for these challenging conditions.