Inflammasomes and Cancer

Abstract

Inflammation affects all stages of tumorigenesis. A key signaling pathway leading to acute and chronic inflammation is through activation of the caspase-1 inflammasome. Inflammasome complexes are assembled on activation of certain nucleotide-binding domain, leucine-rich repeat-containing proteins (NLR), AIM2-like receptors, or pyrin. Of these, NLRP1, NLRP3, NLRC4, NLRP6, and AIM2 influence the pathogenesis of cancer by modulating innate and adaptive immune responses, cell death, proliferation, and/or the gut microbiota. Activation of the inflammasome and IL18 signaling pathways is largely protective in colitis-associated colorectal cancer, whereas excessive inflammation driven by the inflammasome or the IL1 signaling pathways promotes breast cancer, fibrosarcoma, gastric carcinoma, and lung metastasis in a context-dependent manner. The clinical relevance of inflammasomes in multiple forms of cancer highlights their therapeutic promise as molecular targets. In this review, we explore the crossroads between inflammasomes and the development of various tumors and discuss possible therapeutic values in targeting the inflammasome for the prevention and treatment of cancer. Cancer Immunol Res; 5(2); 94-99. ©2017 AACR.

Figure 1. Diverse roles of inflammasome sensors in tumorigenesis

A, NLRP1b, NLRP3 and NLRP6 mediate the production of IL-18, contributing to the protection against colitis-associated colorectal cancer (–,,,–29). The IL-18 axis can also induce tumoricidal activity of NK cells against metastasized colonic tumor cells (19), downregulation IL-22 binding protein (IL-22BP) (20), and inhibiting the colonization of colitogenic microbiota (27) possibly through its role in MUC2 secretion by goblet cells (29,31). The NLRP3 inflammasome and the IL-1β–IL-1 receptor (IL-1R) signaling axis drives a T-cell response towards transplantable tumor cells (24). Mouse NAIP1–6 proteins control phosphorylation of STAT3 and the expression of genes encoding anti-apoptotic and proliferation-related molecules (32). NLRC4 controls the suppression of melanoma growth by amplifying inflammation in macrophages and potentiates production of IFN-γ in T cells (34). AIM2 inhibits phosphorylation of AKT and cMyc activities and stem cell proliferation, while preventing colonization of colitogenic microbiota (35,36). B, The NLRP3–IL-1β–IL-1R signaling axis suppresses the tumoricidal activity of NK cells and T cells and promotes methylcholanthrene (MCA)-induced fibrosarcomas (23). It also induces secretion of IL-17 by CD4⁺ T cells and dampens the anti-tumor efficacy of chemotherapeutic agents in thymoma (42). Overexpression of IL-1β mobilizes myeloid-derived suppressor cells (MDSCs) to the stomach and induces gastric cancer (40). IL-1 signaling drives accumulation of MDSCs and promotes primary and metastatic mammary tumors (41). Inflammasome-independent activity of NLRP3 suppresses NK cells and increases lung metastasis in certain models of melanoma (23,37). The NLRC4 inflammasome mediates expression of adipocyte-mediated vascular endothelial growth factor A (VEGFA) and accelerates the progression of breast cancer (43). In some cases, ASC increases the viability and growth of melanoma cells (38) and promotes inflammation in infiltrating myeloid cells and the development of skin cancer (39). Mutations in the gene encoding NLRP1 is linked to melanoma and epidermal hyperplasia in humans (5,6).

Figure 2. Therapeutic targets of the inflammasome pathway

Recognition of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) by inflammasome-initiating sensors leads to the activation of the inflammasome and initiation of pyroptosis and release of the bioactive form of IL-1β and IL-18 (3). IL-1β and IL-18 engage in autocrine and paracrine signaling pathways via the IL-1 receptor (IL-1R) and IL-18 receptor (IL-18R), respectively. The inflammasome signaling pathway can be inhibited by pharmacological inhibition of activation of the inflammasome (Parthenolide, MCC950, Glyburide, and BAY-11–7082) (–48), ASC oligomerization (CRID3) (49), caspase-1 (Thalidomide and Belnacasan or VX-765) (45,50), and IL-1R (Anakinra or Kineret, and Rilonacept or Arcalyst) (44,51), or neutralizing IL-1β (Canakinumab or Ilaris) (52) or IL-18 (IL-18 binding proteins or IL-18BP) (53).