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Research Traces Mechanisms Involving Cytokines, Inflammation, and Intestinal Microbiota that Impact Colorectal Tumor Growth

January 15, 2019

“Having just established a concept of TEI and described that IL-1R signaling controls key TEI cytokines IL-17A and IL-22, it was really puzzling to us why blanket IL-1R inhibition does not translate into reduction in tumorigenesis,” said Oxana Dmitrieva, a leading author of the paper and PhD student at Fox Chase.“Having just established a concept of TEI and described that IL-1R signaling controls key TEI cytokines IL-17A and IL-22, it was really puzzling to us why blanket IL-1R inhibition does not translate into reduction in tumorigenesis,” said Oxana Dmitrieva, a leading author of the paper and PhD student at Fox Chase.PHILADELPHIA (January 15, 2019) — In pursuing a deeper understanding of how colorectal cancer (CRC) develops and progresses on the molecular level, Fox Chase Cancer Center researchers have found important and unexpected relationships between cytokines, tumor-elicited inflammation and the role of intestinal microbiota.

Sergei Grivennikov, PhD, assistant professor in the Cancer Prevention and Control Program at Fox Chase Cancer Center, and his team investigated the role that signaling by cytokine interleukin-1 (IL-1) plays in tumor formation. They found that cytokine signals elicit distinct, cell type-specific responses, and that these responses influence the overall inflammatory tone of the tumor microenvironment and direct tumor promotion. These, in combination, regulate the propensity for disease progression.

The paper, entitled “Cell-Type-Specific Responses to Interleukin-1 Control Microbial Invasion and Tumor-Elicited Inflammation in Colorectal Cancer” appears in the journal Immunity.

Grivennikov and his team were among the first to show that cytokines can serve as direct mediators of inflammatory-to-cancer cell signaling. This new study investigates the role that cytokines play in chronic inflammation and development of this disease. The team’s previous data show that tumor-elicited inflammation (TEI) occurs when cancer cells recruit the body’s inflammatory immune cells into their local microenvironment to promote tumor growth and progression.

IL-1 is a key regulator of inflammation and of the IL-17 pathway. Increased amounts of IL-17A within tumors are associated with poor prognosis for CRC. Blocking IL-17A curbs tumor progression in preclinical models of the disease. The new study examined the effects that blocked or deleted IL-1 receptors (IL-1R) had on different cell types.

“Having just established a concept of TEI and described that IL-1R signaling controls key TEI cytokines IL-17A and IL-22, it was really puzzling to us why blanket IL-1R inhibition does not translate into reduction in tumorigenesis,” said Oxana Dmitrieva, a leading author of the paper and PhD student at Fox Chase.

Sergei Grivennikov, PhD, assistant professor in the Cancer Prevention and Control Program.Sergei Grivennikov, PhD, assistant professor in the Cancer Prevention and Control Program.

Dmitrieva, Grivennikov, and colleagues dove deeper to find that IL-1R signaling controls colorectal cancer progression and inflammation within the tumor microenvironment through at least three distinct mechanisms:

  • In epithelial and cancer cells, IL-1R signaling serves as a direct growth factor for cancer cells. Inactivation of IL-1R in epithelium resulted in significantly decreased CRC tumor multiplicity, indicating that epithelial IL-1R signaling controls survival and proliferation of early tumor seeds. Importantly, these effects of IL-1R were completely independent of inflammation, as intratumoral cytokine expression were not changed. These results were both important and unexpected.
  • In T cells, IL-1R signaling promotes tumor creation, acting through induction of IL-17A and IL-22 dependent TEI. Ablation of T cell specific IL-1R signaling results in both reduction of CRC and reduction in intratumoral inflammation/TEI.  These results are extremely important but expected.
  • In contrast, researchers found that the two pro-tumorigenic entities mediated by IL-1 were counteracted by anti-tumorigenic IL-1R signaling in myeloid cells. Ablation of IL-1R in myeloid cells called neutrophils resulted in increased CRC tumorigenicity, intratumoral inflammation, and TEI cytokine production. This increased inflammatory response was caused by increased association and deep penetration of distinct types of microbiota. These results are both important and extremely unexpected.

“As clinical trials for IL-1 blockers in cancer gain steam, our data argues against ‘blanket’ inhibition of IL-1 in cancer and suggest that its cell type-specific inhibition may spare protective, microbiota-related functions in cancer,” Grivennikov said. “Potentially different strategies of cytokine inhibition should be applied to patients with different microbiota composition and dietary habits.”

      

The Hospital of Fox Chase Cancer Center and its affiliates (collectively “Fox Chase Cancer Center”), a member of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.
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