Tumor Promotion via Injury- and Death-Induced Inflammation

Abstract

Summary Inhibition of programmed cell death is considered to be a major aspect of tumorigenesis. Indeed, several key oncogenic transcription factors, such as NF-κB and STAT3, exert their tumor promoting activity at least in part through upregulation of survival genes. However, many cancers develop in response to chronic tissue injury, where the resulting cell death increases the tumorigenic potential of the neighboring cells. In this review, we discuss a resolution to this paradox based on cell death-mediated induction of tumor promoting inflammatory cytokines, which enhance cell survival and trigger compensatory proliferation in response to tissue injury.

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

“…Xbp1 has been considered protumorigenic sustained, augments tumor formation in both an inflammatory (i.e., CAC after DSS/AOM) and noninflammatory (i.e., CRC in Apc min mice) context. Cytokines and other factors originating from the more prominent inflammatory infiltrate in Xbp1 /(IEC) mice exposed to DSS (Kaser et al, 2008) will likely contribute to increased tumorigenesis in the AOM/ DSS CAC model (Kuraishy et al, 2011) through effects on the Ire1-dependent and -independent pathways described here. However, it is clear that the hyperregenerative response observed in the setting of hypomorphic epithelial Xbp1 function is not only a consequence of increased inflammation as increases in colonic tumor formation were observed in Apc min ;Xbp1 /(IEC) mice, which is not associated with appreciable inflammation in this locale when Xbp1 is deficient (Kaser et al, 2008).…”

“…This is clinically evident by the common occurrence of tumors at sites of chronic injury (e.g., colitis-associated cancer [CAC] in inflammatory bowel disease [IBD] or gastric cancer upon Helicobacter pylori infection). Hence, the remarkable paradox emerges that cell death caused by tissue injury augments the tumorigenic potential of adjoining cells (Kuraishy et al, 2011). Inflammatory signals from the chronically inflamed intestinal microenvironment, such as IL-6 and IL-11 among others, have been identified to contribute to such tumorpromoting activities in the injured intestine (Becker et al, 2004;Bollrath et al, 2009;Grivennikov et al, 2009).…”

“…The mediators involved in regeneration of the ER-stressed, Xbp1-deficient intestinal epithelium, such as Stat3, IL-6/IL-11, and NF-B, also cooperate to drive CAC (Becker et al, 2004;Greten et al, 2004;Bollrath et al, 2009;Grivennikov et al, 2009;Kuraishy et al, 2011). We therefore induced CAC by azoxymethane (AOM), followed by three cycles of dextran sodium sulfate (DSS ; Fig.…”

Key cell signaling pathways modulated by zerumbone: Role in the prevention and treatment of cancer

“…Numerous cellular molecules serve as biomarkers of inflammation. These include pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin (IL)-1a, IL-1b, chemokine CXC chemokine receptor 4 (CXCR4) and its ligand CXCL12, interferon-g (IFN-g), inducible nitric oxide synthase (iNOS), adhesion molecules such as intracellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and endothelial leukocyte adhesion molecule (ELAM) and angiogenic factors such as vascular endothelial growth factor (VEGF) [31][32][33]. As the functional and causal relationship of inflammation with several carcinomas becomes more evident in recent years, agents that are found to modulate inflammationrelated molecular targets are receiving substantial interest in anticancer drug development programs.…”

Definition and semantics: “Peritoneal Carcinomatosis” should be abandoned and replaced by “Peritoneal Metastasis”

“…For more than one century, it is known that surgical scars may provide favorable conditions for tumor recurrence [7]. Tissue damage is implicated as a possible trigger in development of various cancers [8][9][10] as well as facilitating the growth of preexisting micro-metastases [11], suggesting that surgery may have clinical consequences beyond simply removing the primary cancer [12,13]. Exacerbation of growth of preneoplastic cells and progression to cancer by the wound inflammatory response has been recently nicely demonstrated in a functional model [14].…”