Life and Death Decision Making in Cancer Cells

Signaling through receptors that contain cytoplasmic death domains can induce cancers to regress or in some instances may paradoxically promote the growth and spread of malignancies. The decision-making that underlies whether cancer cells can be induced to self-destruct in response to cytokines such as tumor necrosis factor has been studied, and yet not well understood, for decades. The Surgical Oncology Research Team has shown that the type 1 TNF receptor (TNFR1), a prototype for understanding how cytokines act in cells, acts not only through its death domain but also through a signaling complex that contains non-receptor protein tyrosine kinases. Activation of this novel complex activates of PI 3-kinase/Akt/mTOR signaling and transcription factors, including NF-kB, that promote inflammation and cell survival.

The identification of this novel TNFR1 signaling complex goes some considerable way towards explaining why the response of cancers to immune-based therapies is so complex. Ongoing research is now being directed towards understanding how the TNFR1/tyrosine kinase-signaling complex engages and activates transcription factors that render cancers unresponsive to tumor necrosis factor. Achieving this goal may make it possible to more effectively activate immune responses through which the body may more effectively fight and clear cancers.