Mutations in blood stem cells can worsen colon cancer

Researchers at the University of Florida College of Medicine have uncovered how typical ageing-related blood system alterations can cause some colon tumours to spread more quickly.

The findings of the study published in the Journal of Experimental Medicine (JEM), also suggested how these effects might be therapeutically targeted to reduce tumor growth and improve patient survival.

The hematopoietic stem cells, which dwell in the bone marrow and give rise to every type of blood cell in the body, gradually develop DNA mutations as we age. The majority of these mutations have no noticeable effects, but a few of them can increase a specific stem cell's capacity for survival and proliferation, leading to a high number of blood cells with the same mutation. Clonal hematopoiesis, a syndrome that affects 10 to 20 per cent of elderly persons, has been linked to a higher risk of blood cancer development. Clonal hematopoiesis, however, is more frequently observed in patients with a variety of different cancers that do not involve the blood system and is linked to a quicker rate of tumour development and a shorter overall survival period.

 “However, whether the presence of clonal hematopoiesis causes the aggressive phenotype of unrelated solid tumors has not been vigorously addressed,” says Olga A. Guryanova, now an associate professor at the University of Florida College of Medicine and a member of the University of Florida Health Cancer Center, who led the new JEM study.

Guryanova and colleagues decided to investigate the role of clonal hematopoiesis in colitis-associated colon cancer (CAC). Inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, is a well-known risk factor for colon cancer, and clonal hematopoiesis is prevalent in both IBD and colon cancer patients.

The researchers generated mice with clonal hematopoiesis by transplanting them with blood stem cells lacking one copy of Dnmt3a, the most frequently mutated gene in clonal hematopoiesis patients. The mice were then treated with drugs that induce the development of CAC. Guryanova’s team found that CAC occurred more frequently, and developed more rapidly, in mice with clonal hematopoiesis, resulting in larger tumors with a worse histopathology.

Guryanova and colleagues determined that one way clonal hematopoiesis promotes the development of CAC is by increasing the number of blood vessels that supply the intestinal tumors with the nutrients and oxygen they need to grow. Blocking the formation of these extra blood vessels with axitinib, a drug approved by the FDA to treat advanced kidney cancer, inhibited the growth of CAC tumors in mice with clonal hematopoiesis. In contrast, axitinib had little effect on the growth of CAC tumors in mice without clonal hematopoiesis.

“Our results show that alterations in Dnmt3a in bone marrow stem cells can have profound impact on the development of CAC through multiple mechanisms, some of which may be therapeutically targetable,” Guryanova said. “Our findings, for the first time, solidify the causal relationship between clonal hematopoiesis and the severity of solid tumors and identify potential therapeutic strategies.”