Flashcards in Graeme Finlay-3 Deck (18):
What is the importance of inflammation/chronic infection in cancers?
15-25% of cancer arise from chronic infection and its associated inflammation
Chemically induced cancers may also involve oxyradical overload
What did Virchow hypothesize about cancer and chronic inflammation?
That cancer originates at sites of chronic inflammation because irritants and injury and inflammation induces proliferation, however its enhanced proliferation does not cause cancer but promotes it when environment is rich in inflammatory cells, growth factors, activated stroma which supports (lymph)angiogenesis and DNA-damaging agents
What is unique about the inflammation in cancer?
Inflammation is normally self-limiting tumours behave as wonds that fail to heal and occurs when pro-inflammatory cytokines dominate at the cost of anti-inflammatory cytokines
What role may inflammatory mechanisms play in late cancer progression/metastasis?
MMP production, remodelling ECM to facilitate invasion
EC selectin-tumour ligand interactions
What can link inflammation to the process of carcinogenesis?
Activation of the transcription factors nuclear factor-kappaB and STAT3 are integral to inflammatory responses are frequently found in tumours and link inflammation to carcinogenesis
How does colorectal cancers occurring at an increased frequency in inflammatory bowel disease generate chronic inflammation?
The chronic inflammation arises through abnormal responses to gut bacteria with cells sense the presence of microbial products through TLRs which signal through MYD88 which leads to activation of kinase (inhibitor of NF-KappaB kinase beta) which turns of an inhibitor of NF-kappaB inducing NF-kapaB transactivation function
What are the two routes through which inflammatory bowel diseases may cause cancer?
Indirect pathways where damage to the mucosa allows bacteria into the submucosa where they stimulate inflammatory cells to generate inflammatory conditions which are rich in cytokines and prostaglandins
Direct pathways where interaction with bacterial products with epithelial cell receptors or mutant oncoproteins induce inflammatory signalling in the epithelial cells themselves, activation of NF-kappaB induces anti-apoptotic proteins such as BCL-Xl and cell survival
What occurs if there is genetic deletion of MyD88 or IKKbeta?
Cells are senesitized to damage during colitis andreduces tumour formation indicatingthat the activation of NFkappaB leads to inappropriate cell survival and transformation
What proinflammatory conditions are linked with colo-rectal cancers?
Inflammatory bowel disease
Lack of exercise
Lack of dietary fibre
Obesity fir which every increase of 2.4 units BMI is associated with an increase of 7% CRC risk
How can lean fat be protective for CRC?
This can maintain an anti-inflammatory environment with high insulin-sensitivity
This adipose tissue contains anti-inflammatoyr M2 macrophages and anti-inflammatory T reg cells and Th2 lymphocytes and eosinophils
How does obesity result in the production of an inflammatory environment?
Hypertrophic and hyperplastic adipocytes can induce an inflammatory environment and insulin resistance as
Altered lipid metabolism generates ER stress and ROS
Chemokine secretion leads to abundant pro-inflammatory M1 macrophages, CD8 and Th1 T cells, neutrophils and mast cells
Adipocyte necrosis and elevated levels of free fatty acids activate macrophage TLRs, NFkappa B activity and inflammatory cytokines
Leptin concentrations increase
What inflammatory signals from tissues such as fat leads to activation of colon epithelial cells?
Insulin-resistance results in elevated levels of insulin and IGFs which signal via insulin receptor substrate-1, RAS and PI3K to activate proliferation and suppress cell death
TNF and IL-1beta inhibit GSK3beta (this activates beta-catenin, proliferation and survival_ this activates inhibitors of NF-kappaB kinase
IL-6 and leptin signal via JAK-STAT to promote survival and invasion
What is produced by TAMs which have been manipulated by cancer to be part of the trophic, scavenger phenotype?
Growth factors such as HGF, EGFR ligands that stimulate tumour cell growth and mobility
VEGF as a result of HIF-alpha activation by hypoxia and soluble CSF-1 in avascular areas of tumours
TNFalpha that upregulates thymidine phosphorylase which is an angiogenic mediator
Macrophage migration inhibitory factor which suppresses the transcriptional activity of p53 and activates DNA replication
TGFbeta which is immunosuppressive
Proteases that degrade basement membranes and promte invasion
What occurs as a result of inflammatory cytokines activating NF-kappaB?
Upregulation of macrophage’s inducible nitric oxide synthase which leads to NO which causes vascular dilatation, damage to DNA, inhibition of DNA repair and inhibition caspases and p53 function
Upregualtion of cyclooxygenase II and prostaglandin synthesis
These effects suppresses apoptosis and leads to the propagation of DNA damage
Inhibitors of inflammation and specifically cyclooxygenase II have been tested for anti-cancer activity
What is the role that IL-6 can play in cancer?
This promotes tumour development and maintains the neoplastic phenotype of established tumours with experiments showing that brief exposure to monocyte chemotactic protein 1 induces a self-sustaining IL-6 autocrine loop
What occurs in the induction phase when cancer cells are exposed to monocyte derived MCP-1?
The cancer cells rapidly activate MEK/ERK and IKK/NFkappaB signalling to induce IL-6 and become transformed
They form colonies in agar and grow in rag-1 deficient mice
What occurs in the maintenance phase of cancer cells exposed to monocyte derived MCP-1?
Cells from agar colonies retain a highly transformed phenotype indefinitely, they produce IL-6 in a self sustaining autocrine loop by:
Activating signal transducer and activator of transcription (STAT)-3
STAT-3 suppresses transcription of the estrogen receptor-alpha gene
This is required for transcription of the micro-RNA miR200c
Loos of miR200c leads to activation of the stress kinase JNK2 which activates HSF-1 leading to the demethylation of a critical cytosine at base 1099 in the IL6 promoter and activation of c-Jun which binds to the IL-6 promoter
Loss of miR200c also activates p65/Re1A subunit of NFkaapaB in the IL-6 promoter
c-Jun and p65/Re1A drive expression of IL-6