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Molecular Mechanisms of Malignancy

Molecular Mechanisms of Malignancy. Prof Orla Sheils. Carcinogenesis. What Causes Cancer?. Carcinogens  Age  genetic make up  immune system  diet  day-to-day environment  Viruses. Age. Age. Diet. In addition to chemicals and radiation,

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Molecular Mechanisms of Malignancy

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  1. Molecular Mechanisms of Malignancy Prof Orla Sheils

  2. Carcinogenesis

  3. What Causes Cancer? • Carcinogens  • Age  • genetic make up  • immune system  • diet  • day-to-day environment  • Viruses

  4. Age

  5. Age

  6. Diet

  7. In addition to chemicals and radiation, • viruses also can trigger the development of cancer. • HPV • HBC • HCV • EBV • HHV8

  8. Factors in Carcinogenesis

  9. Trends in Cancer Incidence

  10. Which of the following is FALSE? • Cancer is a genetic disease. • Few Cancers can be linked with the environment. • Some genes are protective against cancer. • Several factors may combine to cause cancer. • Rates of incidence remain static for different cancer types

  11. Environmental triggers

  12. Chernobyl • Pripyat, Ukraine • 26th April 1986 • Reactor 4 steam and hydrogen explosions • Resultant graphite fire burned for 10 days • >400 times more fallout than Hiroshima

  13. Chernobyl • An official exclusion zone around the plant remains in place, extending for 30 kilometres (18 miles). • It is one of the most radioactive spots on Earth.

  14. Chernobyl

  15. Chernobyl today…

  16. Radioisotopes in immediate area

  17. Fallout

  18. Consequences • Acute radiation deaths • Reproductive disorders • Increases in various cancers • Breast • Leukaemia • Lung • Stomach • Skin • Prostate • Uterus • Large increase in thyroid cancer in children & adolescents

  19. Thyroid Cancer and exposure to ionising radiation

  20. Background • Thyroid Cancer • most frequently occurring endocrine malignancy • sub-divided into a number of diagnostic /morphological categories. • 5 year survival rate >96% depending on subtype • Papillary thyroid carcinoma (PTC) • Most common thyroid malignancy • Ireland~100 cases/yr, U.S.~37,500 cases/yr • Incidence on the rise - global estimate 0.5 million new cases this year

  21. Papillary Thyroid Carcinoma Follicular Carcinoma Pathological Pathways ret/BRAF Follicular Epithelial Cell RAS

  22. Melanoma 80% PTC 30-69% Colorectal 10% MAPK/ERK pathway (BRAF V600E)

  23. Both BRAF and RET/PTC changes cause cells to grow and divide. • They impact on the MapK pathway

  24. MAPK/ERK signalling Proliferation

  25. ret/PTC oncogene • The DNA mutations that cause some forms of papillary thyroid cancer are known to involve over-activation or specific parts of the RET gene. • The altered form of this gene, known as the PTC oncogene is found in 10%-30% of papillary thyroid cancers overall, and in a larger percentage of papillary thyroid cancers occurring in children and/or associated with radiation exposure. • These RET mutations usually are acquired during a person's lifetime rather than being inherited.

  26. Markers of PTC • ret/PTC • To date 15 chimeric mRNAs involving 10 different genes have been described • Ret/PTC-1 and ret/PTC-3 are the most common types, accounting for 90%.

  27. RET proto-oncogene • Located on 10q11.2. • Transmembrane growth factor receptor with an intracellular tyrosine kinase domain. • Ligands include members of the GDNF family. • Activates a variety of signal transduction pathways incl.: MAPK/ERK, PI3K/AKT and JNK • Normally expressed in cells of neural crest origin • Important in embryogenesis • Not expressed in mature thyroid tissues

  28. Ret activation and morphology • In the setting of radiation induced PTC it is apparent that specific ret/PTC rearrangements are associated with specific tumour morphology • ret/PTC-1 associated with classic morphology • ?low dose/long latency • ret/PTC-3 associated with solid/follicular morphology and adverse prognosis. • ?higher dose/short latency

  29. BRAF

  30. BRAF • Member of the Raf kinase family • Serine/threonine kinases • Function in Ras/Raf/MEK/ERK pathway • 3 isoforms: A-Braf, B-Raf, C-Raf/Raf-1 • BRAF implicated in several cancers • Most common mutation: T1799A  V600E • Mutation mimics phosphorylation leading to Ras-independent kinase activity

  31. ret/PTC and BRAF in an Irish PTC cohort

  32. ret/PTC and BRAF in an Irish PTC cohort

  33. Sorafenib (Nexavar) • Inhibits tumour cell proliferation and angiogenesis by targeting RAF KINASES and VEGF RECEPTORS; • Multi-kinase inhibitor that targets serine/threonine and receptor tyrosine kinases to decrease tumour growth and angiogenesis; • FDA approved orphan drug indication for hepatocellular carcinoma in 2006. 

  34. Sunitinib • Description: Inhibits VEGF-R2 and PDGF-Rbeta tyrosine kinase; • has antineoplastic activity.  • Sunitinib is in a class of medications called multikinase inhibitors. • It works by blocking the action of the abnormal protein that signals cancer cells to multiply. • This helps stop or slow the spread of cancer cells and may help shrink tumours.

  35. Melanoma 80% AZD6244 PTC 30-69% PD0325901 Colorectal 10% MEKi

  36. The Nobel Prize in Physiology or Medicine 2006for their discovery of RNA interference - gene silencing by double-stranded RNA" Andrew Z. Fire Craig C. Mello Stanford University School of Medicine University of Massachusetts Stanford, CA, USA Medical School Worcester, MA, USA The discovery that gene expression can be altered through RNA interference has stimulated research on the role of RNA interference in the development of cancer.

  37. The discovery that gene expression can be altered through RNA interference has stimulated research on the role of RNA interference in the development of cancer.

  38. The number of peer-reviewed publications on miRNA and cancer in the period from 2001-2007 (Adapted from www.mirnatherapeutics.com)

  39. miRNAs • emerged as major players in the complex networks of gene regulation • implicated in various aspects of human disease. • have already significantly improved our understanding of carcinogenesis.

  40. As active players in important human oncogenic signalling pathways, miRNAs should affect cancer diagnosis and prognosis

  41. The main function of miRNAs appears to be in gene regulation. N Engl J Med 2008;359:2641-50

  42. miRNA production • Base pairing between the miRNA and its target directs RISC to either destroy the mRNA or impede its translation into protein. • [The initial stem–loop configuration of the primary transcript provides structural clues that have been used to guide searches of genomic sequence for candidate miRNA genes.]

  43. miRNA expression profiles are broadly altered in cancers

  44. miRNA and Carcinogenesis • A. pre-miRNAs are exported from nucleus to the cytoplasm where they are processed by the enzyme Dicer to yield mature miRNA. These miRNAs cleave mRNA’s or inhibit translation in association with RISC. • B. Overexpression of miRNAs may inhibit expression of target genes such as tumour suppressors. • C. Reduced expression of miRNAs may increase expression of particular oncogenes.

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