Question ID: WS-110
Submitted by: Michael Tainsky
August 3, 2011
Why do many cancer cells and preneoplastic immortal cells abrogate their innate immunity pathway, which is generally considered to be a cytoprotective mechanism? Background: Mammalian cells possess mechanisms to protect themselves from bacteria and viral infections that involve toll-like receptors and signaling leading to induction of DNA-activated protein kinase, RNA-L, and various interferons. However, tumor cells and immortal preneoplastic cells frequently lose a functional innate immunity pathway. It is surprising that cancer cell would lose a defensive pathway. Some intracellular mechanism triggers the innate immunity response pathway. This trigger is upregulated as part of the mechanism of cellular transformation and only cells that abrogate the innate immunity response can tolerate this molecular trigger. Feasibility: The pathways of innate immunity are well characterized involving cell surface and intracellular toll-like receptors. Activation of these molecules results in a series of phosphorylation events on proteins leading changes in programs of gene expression. What is the nature of this intracellular trigger that is a necessary step in the mechanism of cellular transformation resulting in activation innate immunity? Loss of this pathway, a necessary step in cancer cell evolution, can be exploited for the development of cytotoxic treatments to specifically kill innate immunity deficient tumor cells yet spare the normal cells that have retained their innate immunity pathways. Implications of success: The functional differences in innate immunity pathways between normal and tumor cells can be exploited for the development of tumor-specific cytotoxic therapies. The first step in exploiting this difference between normal and tumor cells is a full understanding of mechanisms by which innate immunity is abrogated in tumors. Secondly, we need to identify the intracellular triggers that activate innate immunity as a step in cellular carcinogenesis. Elucidating these mechanisms can lead to the development of therapeutic small molecules or infectious agents that should have minimal side effects against normal cells.
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