Role of Interleukin-22 in Tumor Angiogenesis
- Author(s): Protopsaltis, Nicholas James
- Advisor(s): Ferrara, Napoleone
- et al.
There is increasing recognition that the immune system plays a crucial role in either the promotion or inhibition of tumor development and growth. Current models of tumorigenesis rely on cells’ ability to evade the immune system. Escaping immune-mediated destruction, however, is only one step in the beginning of tumor growth. While many types of immune cells have been implicated in cancer progression or suppression, the TH17 subset of CD4+ helper T cells is of particular interest due to their clinical implication as being a negative prognostic indicator in some types of cancer, and a positive indicator in others. TH17 cells produce two main cytokines: their hallmark cytokine interleukin-17, and interleukin-22. Interleukin-22 is known for exhibiting a multitude of effects in different types of epithelium, but its role in angiogenesis is only beginning to be elucidated.
This study begins by examining the effects of interleukin-22 on endothelial cells in-vitro. It was found that IL-22 stimulates endothelial cell proliferation, survival, and chemotaxis. It also induces activation of the STAT3, MAPK, and AKT pathways in endothelial cells, consistent with its known signaling effects in cells of epithelial origin.
The mouse T cell lymphoma EL4 was used as a tumor model for a number of in-vivo studies. It was found that these tumors produce interleukin-22 both in-vitro and in-vivo, and that blockade of IL-22 in-vivo results in a statistically significant decrease in tumor growth in C57BL/6, athymic nude, and Rag 1-/- mice. Additionally, it was observed that anti-IL22 antibody therapy decreased blood vessel density within EL4 tumors.
A mouse glioblastoma cell line, GL261, was also investigated to determine the role of interleukin-22 in tumor growth and angiogenesis. IL-22 blockade resulted in decreased tumor growth in both C57BL/6 and athymic nude tumor bearing mice.
In summation, the data observed indicates that interleukin-22 can directly act on endothelial cells to induce angiogenesis. Furthemore, blocking IL-22 in-vivo results in a statistically significant reduction in tumor growth using multiple tumor models.