Necroptosis, tumor necrosis and tumorigenesis

Abstract

Necroptosis, known as programmed necrosis, is a form of caspase-independent, finely regulated cell death with necrotic morphology. Tumor necrosis, foci of necrotic cell death, occurs in advanced solid tumors and is often associated with poor prognosis of cancer patients. While it is well documented that apoptosis plays a key role in tumor regression and the inactivation of apoptosis is pivotal to tumor development, the role of necroptosis in tumorigenesis is still not fully understood as recent studies have reported both tumor-promoting and tumor-suppressing effects of necroptosis. In this short review, we will discuss some recent studies about the role of necroptosis in tumorigenesis and speculate the implications of these findings in future research and potential novel cancer therapy targeting necroptosis.

Keywords: immunosuppression; inflammation; necroptosis; tumor metastasis; tumor necroptosis; tumorigenesis.

Figure 1. FIGURE 1: A simplified scheme of the molecular mechanism of necroptosis.

In certain types of cells/tissues, necroptosis can be induced through different pathways under certain conditions including the engagement of death receptors and the infection of DNA or RNA viruses (MCMV: mouse cytomegalovirus). While RIPK3 and MLKL proteins are the core components of the necroptotic machinery, RIPK1, ZBP1/DAI, and TRIF are the key effectors that orchestrate the necroptotic process by recruiting RIPK3 in response to different stimuli. The aggregation of RIPK3 results in the autophosphorylation of the protein and the activated RIPK3 will phosphorylate MLKL and induce the oligomerization of MLKL, which then initiates the execution of necroptosis. DAI: DNA-dependent activator of interferon; MLKL: mixed lineage kinase domain-like; RIPK: receptor interacting protein kinase; TRIF: Toll-interleukin receptor-domain-containing adapter-inducing interferon-β; ZBP: Z-DNA-binding protein.

Figure 2. FIGURE 2: Necroptosis of tumor cells can have immunogenetic or immunosuppressive effect on tumor immunity.

While acute necroptosis is more immunogenetic and favors anti-tumor immunoactivity, chronic necroptosis promotes pro-tumor immunity through releasing immunosuppressive factors such as CXCL1 and K⁺.