Cellular basis of cancerCellular basis of cancer

Dr Tim BraceyDr Tim Bracey

Consultant PathologistConsultant Pathologist

OutlineOutline

• You will each be allocated a You will each be allocated a questionquestion

• Work in pairs to “brainstorm” each Work in pairs to “brainstorm” each question for 10 minutes before we question for 10 minutes before we go through each in turngo through each in turn

• I will give some clinical examples!I will give some clinical examples!

1- What are the various factors that 1- What are the various factors that regulate the number of cells in a tissue?regulate the number of cells in a tissue?

• Balance between Balance between proliferation, proliferation, differentiation and cell differentiation and cell deathdeath

• Totipotent cells (zygote)Totipotent cells (zygote)

• Pluripotent “stem cells” Pluripotent “stem cells” can differentiate into can differentiate into many cell typesmany cell types

• Multipotent stem cells in Multipotent stem cells in adult organs/tissue adult organs/tissue replenish specialised cellsreplenish specialised cells

And gut!

Regulation of cell number in the Regulation of cell number in the intestinal cryptintestinal crypt

2- Can you define the following 2- Can you define the following terms?terms?

• HypertrophyHypertrophy• HyperplasiaHyperplasia• AtrophyAtrophy• MetaplasiaMetaplasia• DysplasiaDysplasia• NeoplasiaNeoplasia

HypertrophyHypertrophy

• Reversible increase in size of whole or Reversible increase in size of whole or part of an organ or tissue by increase in part of an organ or tissue by increase in cellular size but not numbercellular size but not number

HyperplasiaHyperplasia

• Increase in size due to increased Increase in size due to increased number of cells eg. BPH, number of cells eg. BPH, endometrial hyperplasiaendometrial hyperplasia

AtrophyAtrophy

• Decrease in size due to reduction in cell size Decrease in size due to reduction in cell size and or numberand or number

• Multifactorial (growth factors, hormones, Multifactorial (growth factors, hormones, inflammation etc)inflammation etc)

MetaplasiaMetaplasia

• Reversible change of one differentiated cell type to Reversible change of one differentiated cell type to another e.g. smoker’s respiratory epithelium, cervix another e.g. smoker’s respiratory epithelium, cervix “transformation zone”, Barrett’s oesophagus“transformation zone”, Barrett’s oesophagus

DysplasiaDysplasia

• ““bad form” in Greekbad form” in Greek

• Common term for pre-cancerous lesionsCommon term for pre-cancerous lesions

• Abnormal cells with architectural and cytological Abnormal cells with architectural and cytological abnormality but no invasion. Severe dysplasia also abnormality but no invasion. Severe dysplasia also called “carcinoma in situ”called “carcinoma in situ”

NeoplasiaNeoplasia

• Literally “new growth”Literally “new growth”• Abnormal disorganised growth in a Abnormal disorganised growth in a

tissue or organ usually forming a tissue or organ usually forming a distinct massdistinct mass

• Refers to both benign and Refers to both benign and malignant tumoursmalignant tumours

3- What is the value of having knowledge 3- What is the value of having knowledge of epidemiology of neoplasia?of epidemiology of neoplasia?

• Epidemiology can point to aetiology Epidemiology can point to aetiology and risk factorsand risk factors

• Common and rare cancersCommon and rare cancers– Planning of health care provisionPlanning of health care provision– Screening and preventionScreening and prevention– Identify genetic factors and “at risk Identify genetic factors and “at risk

groups”groups”

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Name 5 types of cancer Name 5 types of cancer with a known cause for with a known cause for eacheach

4- How can we broadly classify 4- How can we broadly classify different neoplasms?different neoplasms?

• Anatomical classificationAnatomical classification– Lung tumours, breast tumoursLung tumours, breast tumours

• HistogeneticHistogenetic– Based on presumed cell of originBased on presumed cell of origin– Carcinoma, sarcoma, lymphomaCarcinoma, sarcoma, lymphoma

• Behavioural Behavioural classificationclassification– Based on likely behaviour / aggressiveness Based on likely behaviour / aggressiveness

(malignant potential)(malignant potential)– What are the main differences between What are the main differences between

benign and malignant tumours?benign and malignant tumours?

5- What do the terms “grade” and “stage” 5- What do the terms “grade” and “stage” mean and what is their clinical mean and what is their clinical significance?significance?

• GradeGrade– How well does the cancer resemble normal How well does the cancer resemble normal

tissue?tissue?

– Low grade = well differentiatedLow grade = well differentiated

– High grade = poorly differentiatedHigh grade = poorly differentiated

• StageStage– Extent of spread (TNM most common)Extent of spread (TNM most common)

• Both influence prognosis and treatment Both influence prognosis and treatment (MDT meeting)(MDT meeting)

6- What are the key events in 6- What are the key events in process of metastasis?process of metastasis?

1.1. Local growthLocal growth

2.2. AngiogenesisAngiogenesis

3.3. Altered cell motility and Altered cell motility and cell-cell interactionscell-cell interactions

4.4. Altered ECMAltered ECM

5.5. Invasion of lymph / blood Invasion of lymph / blood vesselsvessels

6.6. Survival in vesselsSurvival in vessels

7.7. Arrest at distant siteArrest at distant site

8.8. Survival at distant siteSurvival at distant site

9.9. More local growth and More local growth and repeat cyclerepeat cycle

7- In what ways do neoplastic 7- In what ways do neoplastic cells differ from normal cells?cells differ from normal cells?

• Appearance of cellsAppearance of cells– Increased nuclear to cytoplasmic ratio and nuclear Increased nuclear to cytoplasmic ratio and nuclear

pleomorphismpleomorphism

– Darker nuclear staining (hyperchromasia)Darker nuclear staining (hyperchromasia)

• Genetic / Biochemical changesGenetic / Biochemical changes– Altered chromosomal / DNA content (aneuploidy and Altered chromosomal / DNA content (aneuploidy and

mutation of key regulatory genes)mutation of key regulatory genes)

– Altered antigen expression (evade immunity)Altered antigen expression (evade immunity)

• Behaviour of cellsBehaviour of cells– Immortality in cell culture (no senescence)Immortality in cell culture (no senescence)

– Loss of contact inhibition and anchorage independenceLoss of contact inhibition and anchorage independence

– Form tumours in animalsForm tumours in animals

8- What lines of evidence suggest 8- What lines of evidence suggest cancer is a genetic disease?cancer is a genetic disease?

• Cancer increases according to the sixth power Cancer increases according to the sixth power of ageof age

• Some cancers run in familiesSome cancers run in families• Germline mutations lead to early and Germline mutations lead to early and

sometimes multiple cancerssometimes multiple cancers• Carcinogens alter DNA sequences (mutagens)Carcinogens alter DNA sequences (mutagens)• Tumour cells show mutations and chromosomal Tumour cells show mutations and chromosomal

changes, some of which are characteristic of changes, some of which are characteristic of certain cancers (9;22 in 95% CML cases)certain cancers (9;22 in 95% CML cases)

9- How do neoplasms 9- How do neoplasms present clinically?present clinically?

• LocalLocal– SOL, compression, ulceration, bleeding, invasion local SOL, compression, ulceration, bleeding, invasion local

structuresstructures

• SystemicSystemic– As aboveAs above

• ParaneoplasticParaneoplastic– Anaemia, electrolyte disturbance, inappropriate Anaemia, electrolyte disturbance, inappropriate

hormone production, skin changes, dermatomyositis hormone production, skin changes, dermatomyositis etc.etc.

• Incidental findingIncidental finding– Screening (“incidentalomas”)Screening (“incidentalomas”)

10a- What are oncogenes?10a- What are oncogenes?

OncogenesOncogenes

• A proto-oncogene is a gene involved in A proto-oncogene is a gene involved in growth regulation that can become an growth regulation that can become an oncogene after mutation or oncogene after mutation or overexpressionoverexpression

• Oncogenes are genes Oncogenes are genes thatthat increase the increase the malignant potential of a cellmalignant potential of a cell

• Oncogenes were first discovered in Oncogenes were first discovered in animal virusesanimal viruses

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What is the clinical What is the clinical importance of oncogenes?importance of oncogenes?

Do you know any Do you know any examples of “targeted examples of “targeted cancer drugs”?cancer drugs”?

10b- What are tumour 10b- What are tumour suppressor genes?suppressor genes?

Tumour suppressor genesTumour suppressor genes

• These are genes that normally act as “brakes” These are genes that normally act as “brakes” on cell proliferation or which normally promote on cell proliferation or which normally promote cell differentiation or apoptosiscell differentiation or apoptosis

• Deletion or inactivation of TSGs increases cell Deletion or inactivation of TSGs increases cell malignant potentialmalignant potential

• Inactivation of both Inactivation of both copiescopies of a TSG is normally of a TSG is normally required for this (“two hit hypothesis”)required for this (“two hit hypothesis”)

• Alteration of proto-oncogenes and TSGs are Alteration of proto-oncogenes and TSGs are needed for development of malignant tumoursneeded for development of malignant tumours

11- What are the stages of the cell 11- What are the stages of the cell cycle and what are checkpoints?cycle and what are checkpoints?

12- What is p53 and how 12- What is p53 and how does it work?does it work?

• TSG altered in at least 70% cancersTSG altered in at least 70% cancers

p53 “master controller”p53 “master controller”

13- What are the molecular events that occur in 13- What are the molecular events that occur in the genome of neoplastic cells to escape normal the genome of neoplastic cells to escape normal growth control?growth control?

Questions?Questions?