A type of white blood cell is responsible for growth and branching of blood vessels which supports tumor growth in colon cancer, according to a Northwestern Medicine study published in the Journal of Clinical Investigation.
Neutrophils, a type of white blood cell, are the first responders to infections and injury to the body. They are equipped with an arsenal of toxic molecules to fight infections. Following an injury or disease, neutrophils migrate from the blood vessels into surrounding tissues, sometimes exacerbating inflammation and causing tissue damage.
In cancer, neutrophils can be recruited by the tumor to work against the body’s immune system while also driving inflammation, which has been linked to tumor progression, said Ronen Sumagin, PhD, associate professor of Pathology and senior author of the study.
“Many colon cancers feature robust neutrophil presence and this has been associated with poor prognosis,” said Sumagin, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “In a previous study, we have provided a direct link between neutrophil-mediated inflammation and tumor progression, but we did not know how tumors impact neutrophil activity.”
In the current study, Sumagin and his collaborators used genetic sequencing to examine how neutrophil functions are changed during the transition from acute gut inflammation to early- and late-stage colon cancer. They found that, once recruited by a tumor, neutrophils acquire new functionalities to promote the development of blood vessels inside the tumor, effectively diverting blood flow from the body to instead feed the cancer.
Additionally, investigators found that once inside the tumors, neutrophils expressed higher levels of MMP14, an enzyme known to modulate tissue composition and promote blood vessel branching and growth. This was true both in human colon cancer and in mouse models of colon cancer.
Next, the scientists used a targeted drug to inhibit MMP14 in mice and found that tumor-promoting blood vessel density was reduced and tumor growth was decreased, according to the study.
The findings represent a new potential therapeutic target for colon cancer, Sumagin said.
“What we discovered on initial observation was the reprogramming of neutrophils by the tumor microenvironment and acquisition of angiogenic signatures,” Sumagin said. “We then found that tumor-infiltrating neutrophils, among others, upregulate MMP14, which has already been implicated in angiogenesis, meaning it can help create vessels. But for the first time, we are showing that neutrophils are the major source of MMP14 in the tumor microenvironment and that MMP14 is an important driver of tumor vascularization.”
Sumagin and his collaborators will now investigate exactly how MMP14 works to promote blood vessel growth in tumors, he said.
“Now we want to address this further and ask: ‘What is MPP14 doing in a tumor to promote growth of blood vessels? Is it only blood vessels or does it impact other cell types like stromal cells or the tumor cells themselves by changing the extracellular matrix?’” Sumagin said. “Those are the two main areas that we are pursuing at the moment.”
Triet Bui, PhD, a former student in the Sumagin laboratory, was first author of the study.
The study was supported by grants from the Digestive Health Foundation, the American Cancer Society Research Scholar Award, the Crohn’s & Colitis Foundation Senior Research Award, as well as National Institutes of Health grants DK124199 and AI153568, and the Department of Defense’s Congressionally Directed Medical Research Program Horizon Award.