Inflammation and cancer – PMC

11^,27–29 (Table 1) — upwards of 15% of malignancies worldwide can be attributed to infections, a global total of 1.2 million cases per yearnHighlight:macrophage migration inhibitory factor (MIF) from macrophages and T lymphocytes. MIF is a potent cytokine that overcomes p53 function by suppressing its transcriptional activitynHighlight:Infectious viral agents, for example, DNA tumour viruses, may also directly transform cells by inserting active oncogenes into the host genomenHighlight:only a subset of individuals infected with human papilloma virus, hepatitis B virus (HBV) or Epstein-Barr virus develop virus-associated malignanciesnHighlight:HCV core protein interacts with the signal transducer and activator of transcription 3 (STAT3) protein³⁶, a transcription factor involved in mediating cytokine signalling³⁷. This interaction induces sustained phosphorylation of a critical tyrosine residue, resulting in enhanced proliferation and upregulation of Bcl-x_L and cyclin-DnHighlight:similar pathway involving inflammation, IL-6 and STAT3 is downstream of H. pylori in the generation of stomach cancernHighlight:Chemokines were initially defined functionally as soluble factors regulating directional migration of leukocytes during states of inflammationnHighlight:the chemokine-receptor system can be altered dramatically in neoplastic tissue, particularly at the invasive edgesnHighlight:chemokines induce direct effects on stromal and neoplastic cells in addition to their roles in regulating leukocyte recruitment nHighlight:Much debate exists as to whether malignant cells metastasize to environments favouring their specific growth or whether different organs are endowed with the ability to arrest or attract specific types of malignant cells through chemotactic factors (the so-called homing theory)nHighlight:chemokines may be involved in regulating the spectrum of metastases in diverse cancer types.nHighlight:long-term users of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Much data indicates that use of these drugs reduces colon cancer risk by 40–50%, and may be preventative for lung, oesophagus and stomach cancernHighlight:NSAIDs to inhibit cyclo-oxygenases (COX-1 and -2) underlies their mechanism(s) of chemopreventionnHighlight:Aspirin is non-selective in its inhibition of platelet function by acetylating and irreversibly inactivating both COX-1 and COX-2. Inactivation prevents platelet synthesis of prostaglandins, endoperoxides and thromboxane A2.nHighlight:Other mechanisms have been proposed¹⁵, including induction of apoptosis through release of cytochrome C from mitochondria and subsequent activation of caspase-9 and -3, and/or interference with cell-cycle progression, reduction of carcinogen activation and stimulation of immune surveillance.nHighlight:TNF-α is also a key downstream mediator in inflammation. Despite the name, TNF-α is important in early events in tumours, regulating a cascade of cytokines, chemokines, adhesions, MMPs and pro-angiogenic activitiesnHighlight:TNF-α may be one of the ways in which inflammation acts as a tumour promoter.nHighlight:MMPs are produced by inflammatory cells and by stromal cells responding to chemokines and cytokines produced by inflammatory cells in tumour microenvironmentsnHighlight:Like inflammatory cells, MMPs may both promote tumour progression and attenuate itnHighlight:Early in the neoplastic process, these cells are powerful tumour promoters, producing an attractive environment for tumour growth, facilitating genomic instability and promoting angiogenesisnHighlight:Later in the tumorigenic process, neoplastic cells also divert inflammatory mechanisms such as selectin–ligand interactions, MMP production and chemokine functions to favour neoplastic spread and metastasisnHighlight:The pro-tumour actions of inflammatory cells include releasing growth and survival factors, promoting angiogenesis and lymphangiogenesis, stimulating DNA damage, remodelling the ECM to facilitate invasion, coating tumour cells to make available receptors for disseminating cells via lymphatics and capillaries, and evading host defence mechanismsnHighlight:cancer patients are often defective in their inflammatory responsesnHighlight:This may arise by two distinct tumour-mediated mechanisms: a failure to upregulate the anti-inflammatory cytokines, or subversion of the host response resulting from desensitization of receptors owing to high chemokine and cytokine concentrations that then blunt systemic responsesnHighlight:In a fully developed malignancy, there are ‘excess’ inflammatory cells in the tumour microenvironmentnHighlight:We must think globally and act locallynSticky notes:I like this, but we must think locally and globally.nHighlight:in many cases the overall innate immunity of the host is bluntednHighlight:challenge for the future is to normalize the inflammatory network to regain a normal host response overall: decreasing the high levels of tumour-promoting properties of the infiltrating cells, such as pro-inflammatory cytokines, while increasing their tumour-suppressing properties, such as anti-inflammatory cytokinesn]]>