Collectively, our data emphasize a role for the kinase activity of RIP1 in certain inflammatory disease models, but question its relevance to tumor progression and metastases.
In particular, anti-VEGF/R therapies produce hypoxia-induced invasion and metastasis in a spontaneous mouse model of pancreatic neuroendocrine cancer (PanNET), RIP1-Tag2.
Non-invasive MRI imaging showed that combination of GA and 3-BrPA inhibited pancreatic tumor and metastasis by more than 90% and significantly prolonged life span of RIP1-Tag2 transgenic pancreatic cancer mice.
Finally, RIS1 seemed to be functionally involved in tumor development, as low-frequency MSI tumors (MSI-L) with RIS1 mutated usually were associated with a worse prognosis: 83% of them developed metastasis, and no patient with MSI-L tumor and RIS1 mutated (35.3% of MSI-L) survived >25 months after surgery (log rank P < 0.001).