Researchers from Baylor College of Medicine have unlocked new clues about how the colorectal cancer tumor microenvironment is formed and regulated.

The team, led by Dr. Jason Heaney, an assistant professor of molecular and human genetics, and a member of the NCI-designated Dan L Duncan Cancer Center and of the Texas Medical Center Digestive Disease Center at Baylor, published the work today in the journal of the Proceedings of the National Academy of Sciences.

“We know that colorectal cancer results from genetic lesions in intestinal epithelial cells,” said Heaney. “But non-epithelial or stromal cells, which surround tumor epithelial cells and form the microenvironment necessary for tumor cell growth, also play an important role in shaping disease progression.”

Stromal cells fertilize the ground in which tumor cells grow, he said.

A tumor’s microenvironment is regulated by a form of cell to cell communication (called paracrine signaling), in which tumor epithelial cells produces signals that change the behavior of nearby stromal cells.

In response to signals from the tumor cells, stromal cells release their own signals that promote tumor epithelial cell growth. This cross-talk between tumor cells and stromal cells appears to be an important driver of tumor progression.

In lab studies using human cell lines and mouse models of colorectal cancer, Heaney and his research team found that tumor epithelial cells produce interleukin 33 (IL-33), an important mediator of normal immune and wound healing responses during infection in several tissues, to alter the behavior and differentiation of stromal cells.

“IL-33 promoted tumor development in the intestine and activated stromal cells that fueled cancer growth,” said Heaney. “By borrowing the normal immune and tissue repair responses that IL-33 induces in stromal cells during infection, tumor epithelial cells have acquired a means of creating a microenvironment favorable to their own growth.”

Heaney said the next steps are to identify which of the several types of stromal cells that respond to IL-33 signaling contribute to tumor growth and to explore the role of IL-33 in tumor metastasis. “IL-33 signaling may be a useful target for colorectal cancer prevention or therapy.”

Rebecca Maywald, a research assistant in Heaney’s lab at Baylor, performed the majority of the experiments.

Additional collaborators include Susan M. Benton, Emily P. Dawson and Denise G. Lanza, all of Baylor; Stephanie K. Doerner, Luca Pastorelli, Carlo De Salvo, Nathan A. Berger, Sanford D. Markowitz and Theresa T. Pizarro, all of Case Western Reserve University School of Medicine, Cleveland, Ohio; Heinz-Josef Lenz of Keck School of Medicine at University of Southern California, Los Angeles, CA and Joseph H. Nadeau of Pacific Northwest Research Institute, Seattle.

Funding for this work was provided by the Caroline Wiess Law Fund for Research in Molecular Medicine, the De Gregorio Family Foundation and the National Institutes of Health (CA150964, RR12305, DK056762)