Inflammation and cancer Flashcards
1
Q
What happens in acute inflammation?
A
defensive reaction against injury caused bu trauma, toxic chemicals... = protective response - vascular changes - neutrophil recruitment - cytokine production leads to resolution - clearance of stimuli - clearance of inflammatory cells and cytokines - repair and normal function
2
Q
What happens in chronic inflammation?
A
- angiogenesis
- mononuclear cell infiltration
- fibrosis
3
Q
What infiltrates the tumour microenvironment?
A
- CD8+ cytotoxic T cells
- greater infiltration = longer survival of the cancer
4
Q
How do CD8+ cytotoxic T cells act in cancer cells?
A
- cancer cells are recognised by dendritic cells which travel to lymph nodes and encounter tumour antigen specific CD8 t cells
- T cells activated and migrate to tumour
- tumour cells present antigen to t cell and CD8 t cell mounts and responds = induced production of perforin
- perforin makes holes in membrane of cancer cells = granzymes which induce apoptosis
5
Q
How do tumour cells escape killing?
A
- down-regulation of cancer antigens = t cells will not be able to recognise tumour
- mutations in MHC genes or genes needed for antigen processing = lack of T cells recognition
- secretion of immunosuppressive protein or expression of inhibitory cell surface proteins = inhibition of T cell activation
6
Q
What are the different types of inflammation in tumourigenesis?
A
- chronic inflammation infection autoimmunity - mutations, genomic instability
- tumour-associated inflammation - tumour growth, angiogenesis
- inflammation caused by environmental and dietary exposure
- therapy-induced inflammation - tumour re-emergence, resistance to therapy
7
Q
What are some examples of chronic inflammation?
A
- chronic infection before cancer - HSV, kaposi’s sarcoma - malignant transformation associated to the infection and the promotion of chronic inflammation caused by persistant infection
- chronic inflammation before cancer - none-infectious eg. chronic inflammatory bowl disease, COPD - prolonged damage and dysregulated inflammation
- chronic inflammation induced by environmental exposure - tobacco smoke induced conditions like COPD
- obesity increases cancer risk by 1.6 fold = chronic inflammation
8
Q
What is the effect and response to tumour-associated inflammation?
A
- solid malignancies trigger an intrinsic inflammatory response that builds up a pro-tumour microenvironment
- radiation and chemotherapy produce necrosis that induced inflammation similar to wound healing
9
Q
Describe the two pathways involved in cancer related inflammation (CRI)
A
- intrinsic pathway = induced by activation of oncogenes by mutation, rearrangement, inactivation of TSG that cause neoplasia. Transformed cells release inflammatory mediators
- extrinsic pathway = chronic inflammatory conditions or infectious diseases increase the risk of cancer
- pathways converge = smoldering inflammation in tumour microenvironment
10
Q
Why are inflammatory mediators produced in tumours with no links to inflammation?
A
- activation of protein kinase RET, RAS, MYC
- induced expression of CSF, IL-1b and TNF-a
- cyclooxigenase 2 (COX2) which promotes pro-inflammatory prostaglandin E2 - down regulated TSG and DNA repair mechanisms
- induces expression of leukocyte recruiting chemokines
11
Q
How is NF-KB involved in inflammation?
A
- key regulator of innate immunity but also a strong tumour promoter
- inflammatory cell detects signals (PAMPs) through TLRs
- signalling pathways associated with molecules and cell surface receptors combinate in the translocation into the nucleus of NK-Fb
- NF-Kb activates expression of pro-inflammatory cytokines (TNF-a, IL-1) - can impact tumour cell
- NK-Fb also induces expression of survival factors and angiogenic factors which promotes survival of tumour
- in tumour cells NF-KB can be activated by genetic alterations
- there are also interactions between NF-Kb and Hif1-alpha, linking innate immunity to the response to hypoxia
12
Q
What cells are found in the tumour microenvironment?
A
- CSC
- Cancer cells
- immune inflammatory cells
- invasive cancer cells
- cancer associated fibroblasts (CAF)
13
Q
How is inflammation during a tumour initiated?
A
- production of ROS or RNI = initiate mutations
- promote tumour initiation - inflammatory response which produces cytokines = promotes more ROS and RNI
- viscous cycle
14
Q
How does inflammation during a tumour progress?
A
- macrophages, DC, t-cells
- produce cytokines and chemokines which activate TF in the NK-Kb pathway, Stat-3
- results in growth, proliferation, invasion, angiogenesis
15
Q
What are TAMs?
A
- tumour associated macrophages - major component of the leukocyte infiltrate of tumour
- highly diverse both phenotypically and functionally
- diversity is dynamic = plasticity
- polarisation towards an M2/wound healing phenotype and away from an M1 or pro-inflammatory phenotype = hallmark of tumour progression
