Tumour-Promoting Inflammation PDF

Cancer Promoting Inflammation Prof. Joanne Lysaght [email protected] Learning outcomes: Define the differences between acute and chronic inflammation. Discuss the key targets linking inflammation and cancer. Identify different physiological states which are associated with...

Cancer Promoting Inflammation Prof. Joanne Lysaght [email protected] Learning outcomes: Define the differences between acute and chronic inflammation. Discuss the key targets linking inflammation and cancer. Identify different physiological states which are associated with inflammation and cancer.  Cardinal features of Inflammation  Inflammation is usually associated with tissue injury.  Heat  Redness from dilatation, increased blood flow, vascular permeability  Swelling  Pain from migration of leucocytes and their local actions  Loss of function INFLAMMATION GOOD COP/BAD COP? ACUTE CHRONIC Normal Wound Inflammation Anti-microbial peptides  Chronic inflammation Failure to resolve acute inflammation results in chronic inflammation. The persistence of initiating factors are needed to maintain inflammation. Same cells and mediators are involved in both acute and chronic inflammation  Chronic inflammation and Cancer ▪Acute inflammation is not regarded as a risk factor for the development of neoplasia but chronic inflammation is. ▪The longer the inflammation persists, the higher the risk of cancer. ▪The fact that individuals on NSAIDs have a decreased incidence of cancer. Aspirin >7.5yrs 20yr risk of cancer death was reduced by 30% for all solid cancer and 60% for GI cancers.  Add-Aspirin Trial The trial will have over 11,000 participants globally Each patient will have undergone or begun treatment for early stage breast, stomach, oesophagus or prostate cancer. The trial will test whether taking aspirin daily for five years after traditional cancer treatments can stop it from returning and also examine any possible side-effects. Patients will then be followed up for a decade after they finish taking the drug. The trial is being led by University College London.  The Hallmarks of Cancer Inflammation is a powerful early tumour promoter, facilitating genomic instability and promoting angiogenesis. Chemokines and cytokines influence all cell types within the tumour microenvironment -regulating growth, -migration and differentiation -cell activation -cell recruitment Inflammation now considered the 7th hallmark of cancer  Historical link between Inflammation and Cancer Aelius Galenus (AD 129–c. 200), Greek physician, almost 2000 years ago first described the similarity between inflammation and cancer, “but cancers were not hot but the veins were fuller”. The term cancer was originally used by Galenus. Rudolph Carl Virchow (1821 – 1902) In 1863, Virchow hypothesizes that immune infiltrate reflects the origins of cancer at sites of chronic inflammation, thus formally proposing the connection between inflammation and cancer. Harold F. Dvorak, MD In 1986, Dvorak noted that inflammation and tumours share some basic developmental mechanisms (angiogenesis), cell infiltrates (lymphocytes, macrophages, mast cells), and that tumours are like wounds that do not heal. Cancer; the wound that does not heal  Tumour Initiation-Intrinsic Inflammation Tumours can arise due to one or, more frequently, several mutations. – Dysregulated signalling – Oncogene activation or down regulation of tumour suppressor genes DNA damaging agents produced during acute and chronic inflammation have the ability to induce somatic mutations, resulting in sub-threshold neo-plastic states. Known as ‘initiation’ events these mutations exist in a benign state indefinitely – Until the occurrence of a secondary stimulatory event = progression – Hereditary mutations can also act as initiators. Under normal physiological conditions, cellular ROS induce ~10,000 oxidative DNA lesions per day, with any number of these being potentially mutagenic!  Tumour Promotion & Progression -Extrinsic Inflammation Exact mechanisms unclear and likely differ between factors. Promotion can result from exposure of initiated cells to damage via: – Inflammation – Chemical irritants – Factors released at the site of damage – Hormones – Partial organ resection – Chronic irritation Many ‘promoters’ induce cell proliferation, recruit inflammatory cells, increase ROS production or reduce DNA repair. Alberto Mantovani Nature 2008 Local inflammatory cells and molecules in the Tumour Microenvironment Wang M et al., J. Hematology and Oncology 2024  Inflammation, infection and cancer It’s estimated that 15-20% of all cancers are attributable to, or are associated with chronic inflammation induced by either infectious agents, chemical or physical agents and autoimmune reactions. – Examples of infection driven cancers: gastric cancer, hepatocellular carcinoma Persistent infection within the host can induce chronic inflammation. Infectious Agents associated with Cancer Of all cancer: H. Pylori 5.5% HPV 5.2% Hepatitis B and C 4.9% Schistosomes 0.1% Jin-Kyoung Oh et al., Annals of Global Health Inflammation occurring before Cancer Liu X et al, Genes and Diseases, 2023 Key players and targets linking inflammation and cancer 1. Chemokines and Cytokines 2. Reactive Oxygen Species 3. Inflammatory Oncogenes and TS 4. NF-B 1. Inflammatory Chemokines and Cytokines enhancing tumour progression  Targeting the molecular mechanisms that mediate the effects of inflammation in cancer Bintrafusp alfa: Fusion protein trapping TGF-β and blocking PD-L1 Pegilodecakin: Pegylated rhIL-10 Wang M et al., J. Hematology and Oncology 2024  2. Reactive Oxygen Species Chronic inflammation is accompanied by increased production of free radicals (oxygen and nitrogen) which cause DNA damage and mutagenesis. It is estimated that ROS derived from chronic inflammation is responsible for up to one third of all cancers. ROS induces changes in transcription factors and gene expression that mediate cellular stress responses. Macrophages and neutrophils are the major source of oxidants. Agents that scavenge ROS inhibit induction of DNA damage and mutagenesis, therefore dietary antioxidant supplements can inhibit the development of cancer.  Anti-oxidant Controversy Nobel laureate James D. Watson, Ph.D. claims that antioxidants in late-stage cancers can promote cancer progression, a theory he counts “among my most important work since the double helix”. Free-radical-destroying anti-oxidative nutritional supplements may have caused more cancers than they have prevented.  Reactive oxygen species may directly induce most apoptosis Some compounds like paclitaxel kill cancer cells through generation of ROS or interfering with ROS metabolism. Lower reactive oxygen species levels in stem cells reflect higher levels of antioxidants  3. Oncogenes and Inflammation Inflammation can originate from epithelial cells: Produce inflammatory cytokines and chemokines, growth and angiogenic factors. The Oncogene-driven association between cancer and inflammation- Ras expression induces IL-1 and IL-1, IL-6 and IL-8, promotes angiogenesis. Myc activation triggers release of CXCL1 and 2, recruiting mast cells-> angiogenesis. Src activation can lead to NF-B activation, upregulation of IL-6 and STAT3 phosphorylation.  3. Tumour Suppressor Genes and Inflammation p53 mutations have been documented in over 50% of human cancers. Loss of p53 function is associated with susceptibility to inflammasome-driven cancers eg UC driven CRC. Yang and Karin, Cell Death and Differentiation (2014) Could anti-inflammatory therapies partially compensate for loss of TS function? 4. NF-B  NF-B as a molecular target? NFκB Everything However certain natural products are thought to dampen NF-B including: curcumin, ginseng, resveratrol and green tea extract!...role for diet in cancer prevention? Obesity, Inflammation & Cancer  Obesity: National and International Statistics More than 1.9 billion adults were overweight and over 650 million were obese. Over 340 million children and adolescents aged 5-19yrs were overweight or obese in 2016. 41 million children under the age of 5 were overweight or obese in 2016. Obesity Policy and Action Plan Obesity Rates Mechanisms underlying the association between excess visceral adiposity and cancer remain largely unknown: What we do know: 1. Obesity induces a state of chronic systemic low grade inflammation. 2. Obesity may prevent the early detection of cancer due to co-morbidities. 3. Obesity may decrease the efficacy of radiotherapy, immunotherapy and chemotherapy.  Underlying principal Obesity is a state of systemic chronic inflammation Infiltration of expanding adipose tissue by macrophages and other immune cells Secreted factors from obese visceral fat induces significant tumour cell proliferation Lysaght J et al., Cancer Letters VEGF IL-6 Leptin Adiponectin VEGF IL-6 Leptin Adiponectin Lysaght J et al., Cancer Letters OE33 and HCT-15 show a dose dependent increase in proliferation in response to recombinant IL-6 and VEGF Immune cells are recruited to the VAT and liver in obesity-associated cancer where they contribute to inflammation or undergo apoptosis Obesity-associated cancer of the oesophagus Elevated chemokines in fat and liver Immune cell recruitment to fat and liver Tumour-fuelling NK cell Cold Tumours Inflammation by death T cells Tumour Progression Conroy, Lysaght et al., J Leuk Biol Cold Tumour Hot Tumour Conroy, Lysaght et al.,. Inflamm CX3CR1 Conroy, Lysaght et al. Cancer Letters Antagonism Inflammation after Cancer Development Liu X et al, Genes and Diseases, 2023 Additional Reading: NF-κB, inflammation, immunity and cancer: coming of age. Koji Taniguchi & Michael Karin Nature Reviews Immunology volume18, pages309–324 (2018) A guiding map for inflammation,Mihai G Netea, Frances Balkwill, Charles A Dinarello. Nature Immunology volume18, pages826–831 (2017) Targeting cancer-promoting inflammation — have anti-inflammatory therapies come of age? Jiajie Hou, Michael Karin & Beicheng Sun. Nature Reviews Clinical Oncology volume 18, pages261–279 (2021) Cancer-associated inflammation: pathophysiology and clinical. Piotr Pęczek, Monika Gajda, Kacper Rutkowski, Marta Fudalej, Andrzej Deptała & Anna M. Badowska-Kozakiewicz. Journal of Cancer Research and Clinical Oncology Volume 149, pages 2657–2672, (2023)