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Chronic inflammation is implicated in

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the pathogenesis of carcinoma

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Inflammatory diseases increase the risk of developing

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cancer (including cervical, gastric, intestinal, oesophageal, ovarian, prostate and thyroid cancer)

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Non-steroidal anti-inflammatory drugs reduce the risk of

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developing cancers (such as colon and breast cancer) and reduce the mortality caused by these cancers.

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Signalling pathways involved in inflammation operate

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downstream of oncogenic mutations (such as mutations in the genes encoding RAS, MYC and RET)

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Inflammatory cells, chemokines and cytokines are present in

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the microenvironment of all tumours in experimental animal models and humans from the earliest stages of development

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The targeting of inflammatory mediators (chemokines and cytokines, such as TNF-α and IL-1β), key transcription factors involved in inflammation (such as NF-κB and STAT3) or inflammatory cells decreases

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the incidence and spread of cancer

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Adoptive transfer of inflammatory cells or overexpression of inflammatory cytokines

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promotes the development of tumours

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An inflammatory infiltrate promotes tumourigenesis at multiple steps: local invasion

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An inflammatory infiltrate promotes angiogenesis and control ECM remodelling. Operating in paracrine loops, cytokines and growth factors produced by inflammatory cells and neoplastic cells induce the expression of genes associated with survival, invasion and migration.

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An inflammatory infiltrate promotes tumourigenesis at multiple steps: distant metastasis

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The autocrine and paracrine chemokine- and cytokine-mediated signalling promotes the survival of malignant cells in distant organs, again attracting a tumour-promoting infiltrate and stimulating angiogenesis. ROS produced by inflammtory cells is genotoxic.

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Cytokines and growth factors are also involved in

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the intravasation of tumour cells into blood vessels and in lymphatic spread.

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Cancer and inflammation are connected by two pathways

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the intrinsic pathway and the extrinsic pathway

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The intrinsic pathway is activated by

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genetic events that cause neoplasia. These events include the activation of various types of oncogene by mutation, chromosomal rearrangement or amplification, and the inactivation of tumour-suppressor genes. Cells that are transformed in this manner produce inflammatory mediators, thereby generating an inflammatory microenvironment in tumours for which there is no underlying inflammatory condition (for example, breast tumours)

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In the extrinsic pathway, inflammatory or infectious conditions augment the risk of

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developing cancer at certain anatomical sites (for example, the colon, prostate and pancreas)

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The intrinsic pathway and the extrinsic pathway

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converge, resulting in the activation of transcription factors, mainly nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (STAT3) and hypoxia-inducible factor 1α (HIF1α), in tumour cells. These transcription factors coordinate the production of inflammatory mediators, including cytokines and chemokines, as well as the production of cyclooxygenase 2 (COX2) (which, in turn, results in the production of prostaglandins).

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Smouldering cancer-related inflammation has many

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tumour-promoting effects.

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These transcription factors recruit and activate

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various leukocytes, most notably cells of the myelomonocytic lineage. The cytokines activate the same key transcription factors in inflammatory cells, stromal cells and tumour cells, resulting in more inflammatory mediators being produced and a cancer-related inflammatory microenvironment being generated

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Regulation of the NF-κB family of transcription factors

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function as heterodimers is critical to inflammatory signalling. NF-κB is sequestered in the cytoplasm by IκB. A variety of receptors activate IKK, which phosphorylates IκB, tagging it for degradation by the ubiquitin-proteasome pathway.

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Chronic liver inflammation acts via NF-κB to induce liver cancer

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Chronic liver inflammation can be induced in mice by interfering with bile production through knockout of the mdr gene. These mice develop metastatic liver cancer. This model allows various nodes in the inflammatory pathway to be investigated as therapeutic targets

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NSAIDs, anti-TNFα antibody and interference with NF-κB degradation

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greatly reduce the incidence of liver cancer in this model

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Velcade/Bortezomib

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a proteasome potent inhibitor effective against multiple myeloma which inhibits degradation of IκB

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By interfering with degradation of IκB, Velcade

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can target the activity of NF-κB in multiple myeloma cells, triggering apoptosis.

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Inhibition of COX-2 suppresses

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the synthesis of prostaglandin inflammatory mediators

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Cyclo-oxygenase 2 is a target of

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NF-κB. It's expression is induced in the reactive stroma of tumours as well as in neoplastic epithelial cells. It is involved at two steps in the production of prostaglandin H2.

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Prostaglandin E2 induces many affects in cells including

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including proliferation, migration and invasion.

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NSAIDs that inhibit COX-2 can dramatically reduce

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the incidence of cancer

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NSAIDS examples

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Aspirin Iibuprofen Sulindac Celecoxib

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Apart from curing hangovers, aspirin prevents cancer, heart disease, stroke

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low dose aspirin (75 - 150 mg/day) over 5-10 years greatly reduces cancer incidence.

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Cancer

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a perverting of the rules governing homeostasis allowing the growth of new tissue (neoplasm) which is chaotically assembled

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Oncogenes and tumour suppressor genes have opposite effects

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for homeostasis, the action of oncogenes and TSGs must be counterbalanced. In neoplasia, this balance is upset by the activation of oncogenes and loss of tumour suppressor genes.

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TSGs comprise part of the bodies natural defences to

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neoplasia

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Malignant lesions have accumulated more mutations in oncogenes and TSGs than

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precursor premalignant lesions. Certain mutations occur at high frequency and are detected even early in the progression sequence

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Aneuploidy is a common trait in cancer cells

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defects in DNA damage repair and genomic instability generate a 'mutator' phenotype that allow more rapid acquisition of mutations.

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Proliferation is regulated by

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the mitogenic signalling pathway comprises a receptor in the plasma membrane which receives an extracellular signal in the form of a growth factor (mitogen). The signal is then propagated across the plasma membrane and amplified by a cascade of second messengers. Finally the signal reaches the nucleus where it is transformed into a program of gene expression.

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Frequently positive feed forward allows a small signal to

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exceed a threshold, while negative feedback switches the signal off

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Oncogenic activation of p21 RAS allows cells to proliferate in the absence of

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mitogens and matrix attachment

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When Ras binds guanine nucleotide triphosphate (GTP)

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it is active

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hen it binds guanine nucleotide diphosphate (GDP)

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it is inactive

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p53 plays an essential role in mediating growth arrest following

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DNA damage

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BH3 proteins regulate

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the multidomain Bcl-2 proteins and respond to a number of 'abnormality' inputs.Various physiological as well as exogenous stresses (including genotoxic chemotherapy and radiotherapy) operate through different BH3 proteins to antagonize different anti-apoptotic Bcl-2 family members.

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Loss of p53 greatly increases a cells chance to become

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neoplastically transformed by rendering it resistant to a number of insults such as loss of survival signalling or hypoxia that ordinarily would hamper tumour progression were p53 present to induce apoptosis

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p53 mutant cells are blinded to the

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activation of oncogenes

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loss of p53 allows cells to forego

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DNA damage repair and this enables the accumulation of the multiple mutations which drive tumour progression

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p53 loss also confers

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resistance to chemotherapy and radiotherapy

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Telomeres

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specialized structures that cap the ends of chromosomes synthesized by telomerase

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Telomeres function

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prevent the ends of chromosomes being joined together by double-strand break repair mechanisms

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The DNA component of each telomere is composed of

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the hexanucleotide repeat TTAGGG tandemly repeated thousands of times. Together with associated proteins they form the functional telomere

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The hexanucleotide repeats are added by

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a specialized reverse transcriptase, telomerase, which also contains an RNA template.

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The erosion of telomeres triggers

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breakage-fusion-bridge cycles of chromosomes and structural re-arrangment

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The effect of repeated cycles of fusion-bridges-double strand breaks

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scramble the genome and may drive progression toward malignancy

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Activation of telomerase before senescence allows

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cells to divide indefinitely and maintain a stable genome

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Primary cells divide exponentially, and telomeres

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shorten from 15 kilobases (kb) until they reach a critical length, 4-6 kb. Irreversible cell-cycle arrest then occurs

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If telomerase is activated before erosion is complete

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this rescues the genome from instability by re-establishing telomere maintenance

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If the p53 and RB1 pathways are suppressed in telomeres

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cells continue dividing until end protection is completely lost, resulting in telomeric crisis, cell death and massive genomic instability

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Activation of telomerase after the accumulation of mutations results in

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an unstable genome, allowing clones that carry multiple mutations to escape cell death (that is, to become immortal). Such cells are predisposed to oncogenic transformation

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The extracellular matrix can be

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a source of angiogenesis factors

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Cancer cell metabolism involves a shift in nutrient metabolism towards biosynthesis

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most of the increased nutrient uptake in proliferating cells is used to support biosynthetic reactions

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Stromal cells are a major source

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of invasive signals and extracellular proteases

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Both cancer associated fibroblasts (CAFs) and tumour associated macrophages (TAMs) are involved

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in a cross-talk with carcinoma cells that involves production of paracrine signalling molecules

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Both cancer associated fibroblasts (CAFs) and tumour associated macrophages (TAMs) are

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a major source of proteases in the tumour stroma

Cancer: Chronic Inflammation and tumour promotion – Flashcards

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