Cellular Basis of Cancer

1. Cellular Basis of Cancer Dr Rosemary Bass rosemary.bass@northumbria.ac.uk

2. Cancer: Characteristics of cancer cells Malignant & benign tumours Oncogenes & tumour suppressor genes (TSG) Invasion, Metastases, Angiogenesis.

3. Contents • Introduction • Causes • History • Terminology • Incidence Rates • Cancer Types • Progressive Nature of Cancer

4. Introduction to Cancer • "cancer" from latin for "crab" • disease of higher, multicellular organisms • cell growth is dysregulated (abnormally controlled)

5. www.cancerresearchuk.org www.mariecurie.org.uk www.macmillan.org.uk What is cancer? Cancer is a disease where cells grow out of control and invade, erode and destroy normal tissue. The driving forces behind the development of cancer are damaged genes. Cancer develops when cells start to divide at the wrong time and in the wrong place, then continue to divide and invade nearby tissues and organs. It is this uncontrolled growth of cells that causes a swelling or tumour. Cancer is not one disease but many, all with some similar features but all with a distinctive character, which varies according to the cancer's type and location.

6. info.cancerresearchuk.org • Bone cancers found in Egyptian mummies • But rare in comparison to modern incidence Cancer - Background • Is cancer a modern disease? • (David & Zimmerman (2010) Nat Rev Can10,728). • Increased incidence of cancer due to humans living longer - fewer deaths from infectious diseases • Cancer occurs in all higher animals • Evidence from ancient pictures & writings

7. Percival Pott (1775) - first scientific investigation of cancer • Scrotal cancer in men who had been boy-sweeps iaphomepage.org/ int302/potts iaphomepage.org/ int302/potts Cancer - History • Pott suggested soot as causative agent - carcinogen • Advised frequent washing and changes of clothes • First epidemiological study on cancer

8. Introduction to Cancer • Terms "cancer", "neoplasm" and "tumour" often used interchangeably • Cancer usually means carcinoma (malignant tumour of epithelial origin) • Neoplasm usually means the newly-formed tumour • Tumour refers to any benign or malignant growth

9. Introduction to Cancer (2) • Cancer is "new growth resulting from abnormal proliferation of transformed cells" • Growth may be rapid, moderate or slowvs normal cells • The clinical study of cancer is "oncology" • Cancer is now the second most common cause of death in developed countries (after cardiovascular disease)

10. Cancer Incidence One in three people will be diagnosed with cancer One in four people will die from cancer Every two minutes someone is diagnosed with cancer in the UK (<300,000 new cases p.a.) Cancer affects mainly older people. Deaths from cancers of the lung, bowel, breast and prostate together account for 54% of all cancer deaths. http://info.cancerresearchuk.org/cancerstats/keyfacts/?a=5441 http://info.cancerresearchuk.org/cancerstats/incidence/

11. Cancer is a large collection of many diseases, with many causes • Cancer kills because the uncontrolled replication of cells within the tumour disrupts the structural integrity of the patient – leading to the spread of the disease – metastasis

12. Cancer rare in young, increased incidence with age • With demographic shifts in the population, such that the population in Western countries is increasingly aged, this will lead to increased prevalence of cancer. Report from Foresight Ageing Population Panel ,The Age shift - priorities for action, http://www.education.edean.org/pdf/Intro013.pdf

13. Cancer More Common in Some Tissues • most common types in men: • - lung • - prostate • - colon rectum • most common types in women: • - breast • - cervix • - colon rectum • - lung

14. The 20 Most Commonly Diagnosed Cancers, UK 2008 (Excluding Non-Melanoma Skin Cancer) Non-melanoma skin cancer (NMSC) = very common condition, BUT it is curable in the vast majority of cases. NMSC routinely omitted from the overall total for new cases of cancer

15. 10 Most Commonly Diagnosed Cancers in Males, UK 2008 (Excluding Non-Melanoma Skin Cancer)

16. 10 Most Commonly Diagnosed Cancers in Females, UK 2008 (Excluding Non-Melanoma Skin Cancer)

17. Cancer Survival Cancer survival figures are usually written as a % or number of patients alive five years after diagnosis. This does not necessarily mean that the patient is cured: No recurrence of cancer Recurrence of cancer but alive Recurrence after the five years. The figures quoted are true for the population but not for an individual. http://www.ncsdf.org/

18. Causes of cancer • Hereditary (though probably <5%) • Environmental: radiation • chemical • hazards in workplace • Lifestyle diet • smoking • alcoholsex • Viruses http://info.cancerresearchuk.org/cancerstats/causes/lifestyle/tobacco/

19. Most cancers are “avoidable” – being due to environmental and lifestyle factors • 1/3 of ALL cancers are attributable to SMOKING http://info.cancerresearchuk.org/cancerstats/causes/lifestyle/tobacco/

20. http://info.cancerresearchuk.org/cancerstats/causes/lifestyle/tobacco/http://info.cancerresearchuk.org/cancerstats/causes/lifestyle/tobacco/ Cancer Research-UK data on risk of lung cancer in relation to intensity of smoking and age at which smoking ceased.

21. Diet is also a major factor in cancer incidence • Data above show breast cancer incidence relation to dietary fat. • Similar relationships hold for prostate & other cancers. • The importance of diet &lifestyle in cancer incidence is shown by “epidemiological” studies. • Early epidemiological studies of Japanese people who moved to N. America showed that after 1 generation this population had the same breast cancer risk as the general N. American population.

22. Origins of Cancer • There are many connections between embryogenesis &cancer • Most tumours arise in the cells that come in contact with the outside world &these are epithelial cells – i.e. the epidermal keratinocytes of the skin, epithelial cells lining digestive tract, respiratory system etc. • Cancers are classified differently based on their cell of origin: • Epithelial cancers = carcinomas • Mesenchymal (ie connective tissue cell types such as fibroblasts) cancers = sarcomas • Blood/lymphoid tissue = leukaemias/lymphomas

23. Terminology (2) - Examples 2. Solid Tumours • suffix "-oma" defines solid tumour • prefix defines tissue type eg: - adenoma = benign tumour of glandular tissue - fibroma = benign tumour of connective tissue - fibroadenoma = mixed tumour of glandular + connective tissue

24. Terminology (3) - Examples - carcinoma - malignant tumour of epithelial cells - sarcoma = malignant tumour of connective tissue cells - adenocarcinoma = malignant tumour of glandular epithelium others - lymphoma = tumours of lymph tissue - teratoma = primitive germ cell tumour of gonads

25. Tissue Proliferation Rates • Rapid Proliferation – bone marrow, gastrointestinal mucosa, ovary, testis, hair follicles • Slow Proliferation – lung, liver, kidney, endocrine glands, vascular endothelium • Almost no Proliferation – muscle, bone, cartilage, nerve

26. The molecular genetic basis of cancer • Cancer is a genetic disease • Cancer arises from mutations in critical genes • Proto-oncogenes- the “accelerators” • Tumour suppressor genes (TSGs) – the “brakes” • Cancer is a multistep process involving a series of genetic 'hits‘ • Cancer is clonal - one cell 'goes wrong‘ • Many factors working both inside and outside the cell can determine a cell’s likelihood of sustaining genetic damage

27. Causes of Cancer - Genetic Factors Oncogenes • retroviral cancer-causing genes • cellular equivalents = proto-oncogenes • encode growth factors (GFs), GF receptors or nuclear proteins

28. First identified Oncogene: Rous isolated virus from spontaneous chicken sarcomas = Rous Sarcoma Virus (RSV) (retrovirus)

29. WHAT ARE ONCOGENES? "A gene that causes the transformation of normal cells into cancerous tumour cells." "Mutated and/or over-expressed version of normal gene, that in a dominant fashion releases the cell from normal growth restraints."

30. GAIN OF FUNCTION A proto-oncogene is the wild-type allele (normal gene) of an oncogene. Activating mutation of proto-oncogene creates the oncogene One allele usually only affected = DOMINANT

31. WHAT SORTS OF GENES HAVE THE POTENTIAL TO BE ONCOGENES? growth factors growth factor receptors G proteins cytoplasmic tyrosine kinases serine-threoninekinases other cytoplasmic proteins nuclear proteins

32. Oncogene Function Growth Factors int-1 matrix protein sis Platelet derived growth factor Growth-Factor Receptor (Tyrosine Kinase type) erb-B Epidermal growth factor receptor kit Stem cell growth factor receptor met Hepatic growth factor receptor ros Unknown ligand ret Glial-derived neurotrophic factor with GFR-a1-4 receptors G proteins H-ras GTPase K-ras GTPase N-ras GTPase

33. Oncogene Function Cytoplasmic Tyrosine Kinases bcr-abl Tyrosine kinase hck Tyrosine kinase lck Tyrosine kinase src Tyrosine kinase Serine-ThreonineKinases raf/mil Serine-Threonine Kinase Other cytoplasmic proteins bcl-2 Prolongs life-span of cell Nuclear proteins erb-A Thyroid hormone receptor fos Transcription factor Transcription factor L-myc myc Transcription factor

34. HOW ARE PROTO-ONCOGENES ACTIVATED? Mutation Amplification Translocation

35. Gene Amplification Chromosome rearrangement fusion to actively normal protein greatly nearby strong transcribed gene overproduced enhancer causes greatly overproduces normal protein to be overproduced fusion protein; or fusion protein is hyperactive ACTIVATION OF PROTO-ONCOGENES Deletion or point mutation in coding sequence DNA RNA hyperactive protein made in normal amounts

36. Tumour Suppressor Genes (TSGs) • 100s recessive genes that normally regulate or suppress cell growth • loss of function of TSG can lead to tumour formation or progression • first identified in rare, inherited childhood tumours (retinoblastoma) • TSG protein functions may be tissue-specific (RB - retina; BRCA1 - breast, ovary etc.)

37. HOW CAN TUMOUR SUPPRESSOR GENES BE LOST? Mutation Deletion Loss of heterozygosity (allelic deletion) Methylation Haploinsufficiency

38. LOSS OF HETEROZYGOSITY (LOH) Heterozygosity= individual is heterozygote for a genotype 1 normal gene, 1 mutated gene When second copy is mutated (doesn't have to be the same mutation) neither allele will have functioning gene - homozygous for mutated gene, hence LOH Evolving tumour cells can discard the second, still functional tumour suppressor gene copy Also occur via missegregation or mitotic recombination

39. PROMOTER METHYLATIONepigenetic • Methyl groups attached to cytosines at CpG • CpGmethylation causes repression of transcription (if present in promoter of gene) • Histonedeacetylases (HDACs) recognise and bind MeCpG • acetate groups removed from histones • resulting chromatin configuration disfavours transcription

40. HAPLOINSUFFICIENCY Heterozygous for a certain gene mutation or hemizygous (only one copy) at a particular locus (often due to a deletion of the corresponding allele) is clinically affected because a single copy of the normal gene is incapable of providing sufficient protein production as to assure normal function Human Rb+/- develop normally Mouse Smad4+/- predisposed to tumours in stomach Mouse p27Kip1+/- tumour prone Mouse PTEN+/- acceleration of prostate cancer and Human

41. WHAT SORTS OF GENES CAN BE TUMOUR SUPPRESSOR GENES? Signalling Smad4, DCC, APC Transcription WT-1, p53 Gene Expression VHL Cell Cycle ControlpRb, p53 Cell Adhesion E-cadherin Cytoskeletal Architecture NF-2 DNA Damage and Repair p53, ATM BRCA1, BRCA2

42. One single oncogene will not cause cancer – cooperativity Cooperating oncogenes in mice- Land H et al., (1983) Nature 304, 596-602; Ruley HE (1983) Nature 304, 602-606.

43. Causes of Cancer - Age • cumulative effect of carcinogens • cumulative effect of mutations • age-related metabolic / hormonal changes • reduced ability to repair DNA

44. Causes of Cancer - Environmental • viruses • - eg. human papilloma virus cervical cancer • ionising radiation • - eg.131I  thyroid cancer post-Chernobyl • - eg. UV radiation  skin cancer • chemicals in food / environment • - eg. arsenic in tobacco smoke  lung cancer

45. Cell Growth Cell Death Normal Cells Cell Death Cell Growth Tumour Cells Normal tissues balance cell growth with cell death. In cancer this balance is disrupted.

46. Acquired Characteristics of Cancer • Limitless replication capacity • Evasion of apoptosis • Self-sufficiency of growth signals • Insensitivity to growth inhibitory signals • Tissue invasion and metastasis • Sustained angiogenesis • From: • Hanahan D and Weinberg RA • (2000) The hallmarks of cancer. Cell 100:57-70

47. Is there hope for the future?Yes – definitely! Cancer Prevention Novel Therapeutics Molecular Diagnostics Cancer Genetics

49. Normal Growth chemicals, viruses, radiation Single transformed cell dysregulated growth Promotion (smoking, free radicals, radiation) Progressive Nature of Cancer Normal Cells Initiation (tumourigenesis) Persistent cell clone

50. dysregulated growth - progressive mutations, persistence of tumour cell subclones, enhanced blood supply Benign Tumour Carcinoma in situ further growth - mutations, production of tissue-modelling enzymes, enhanced blood supply Metastasis Progressive Nature of Cancer(2) Dysplasia Invasive Tumour