Cellular Basis of Cancer

Dr Rosemary Bassrosemary.bass@northumbria.ac.uk

Cancer:

Characteristics of cancer cells

Malignant & benign tumours

Oncogenes & tumour suppressor genes (TSG)

Invasion, Metastases, Angiogenesis.

•Causes

Contents• Introduction

•History

•Terminology• Incidence Rates

•Cancer Types

•Progressive Nature of Cancer

• "cancer" from latin for "crab"

•disease of higher, multicellular organisms

•cell growth is dysregulated (abnormally controlled)

Introduction to 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.

www.cancerresearchuk.org

www.mariecurie.org.uk

www.macmillan.org.uk

What is cancer?

• Is cancer a modern disease?(David & Zimmerman (2010) Nat Rev Can10,728).

•Cancer occurs in all higher animals

•Evidence from ancient pictures & writings

Cancer - Background

• Increased incidence of cancer due to humans living longer - fewer deaths from infectious diseases

•Bone cancers found in Egyptian mummies•But rare in comparison to modern incidence

info.cancerresearchuk.org

•Pott suggested soot as causative agent - carcinogen

Cancer - History•Percival Pott (1775) - first scientific investigation of cancer

iaphomepage.org/ int302/potts

•Scrotal cancer in men who had been boy-sweeps

iaphomepage.org/ int302/potts

•Advised frequent washing and changes of clothes

•First epidemiological study on cancer

•Terms "cancer", "neoplasm" and "tumour" often used interchangeably

•Cancer usually means carcinoma (malignant tumour of epithelial origin)

Introduction to Cancer

•Neoplasm usually means the newly-formed tumour

•Tumour refers to any benign or malignant growth

•Cancer is "new growth resulting from abnormal proliferation of transformed cells"

•Growth may be rapid, moderate or slow vs normal cells

•Cancer is now the second most common cause of death in developed countries (after cardiovascular disease)

•The clinical study of cancer is "oncology"

Introduction to Cancer (2)

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.

Cancer Incidence

http://info.cancerresearchuk.org/cancerstats/keyfacts/?a=5441http://info.cancerresearchuk.org/cancerstats/incidence/

• 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

• 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

• Cancer rare in young, increased incidence with age

- lung

Cancer More Common in Some Tissues•most common types in men:

- prostate- colon rectum

•most common types in women:

- breast- cervix- colon rectum - lung

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)

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 cancerRecurrence of cancer but alive Recurrence after the five years.

The figures quoted are true for the population but not for an individual.

Cancer Survival

http://www.ncsdf.org/

Causes of cancer

• Hereditary (though probably <5%)

• Environmental: radiationchemicalhazards in workplace

• Lifestyle dietsmokingalcohol

sex

• Viruseshttp://info.cancerresearchuk.org/cancerstats/causes/lifestyle/tobacco/

• 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/

Cancer Research-UK data on risk of lung cancer in relation to intensity of smoking and age at which smoking ceased.

http://info.cancerresearchuk.org/cancerstats/causes/lifestyle/tobacco/

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.

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 = carcinomasMesenchymal (ie connective tissue cell types such as fibroblasts) cancers = sarcomasBlood/lymphoid tissue = leukaemias/lymphomas

•suffix "-oma" defines solid tumour

Terminology (2) - Examples2. Solid Tumours

•prefix defines tissue type eg:

- adenoma = benign tumour of glandular tissue

- fibroma = benign tumour of connective tissue

- fibroadenoma = mixed tumour of glandular + connective tissue

- sarcoma = malignant tumour of connective tissue cells

Terminology (3) - Examples- carcinoma - malignant tumour of

epithelial cells

- adenocarcinoma = malignant tumour of glandular epithelium

others

- lymphoma = tumours of lymph tissue- teratoma = primitive germ cell tumour of gonads

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

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

Oncogenes

Causes of Cancer - Genetic Factors

• retroviral cancer-causing genes

• cellular equivalents = proto-oncogenes

•encode growth factors (GFs), GF receptors or nuclear proteins

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."

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

WHAT SORTS OF GENES HAVE THE POTENTIAL TO BE ONCOGENES?

growth factors

growth factor receptors

G proteins

cytoplasmic tyrosine kinases

serine-threonine kinases

other cytoplasmic proteins

nuclear proteins

Oncogene FunctionGrowth Factors int-1 matrix proteinsis

Platelet derived growth factor

Growth-Factor Receptor (Tyrosine Kinase type) erb-B Epidermal growth factor receptorkit

Stem cell growth factor receptormet

Hepatic growth factor receptorros

Unknown ligand

G proteins H-ras

GTPase

K-ras

GTPase

N-ras GTPase

ret Glial-derived neurotrophic factor with GFR-a1-4 receptors

33

Cytoplasmic Tyrosine Kinasesbcr-abl Tyrosine kinasehck Tyrosine kinaselck Tyrosine kinase

src Tyrosine kinase

Serine-Threonine Kinases raf/mil Serine-Threonine Kinase

Other cytoplasmic proteins bcl-2 Prolongs life-span of cell

Nuclear proteins erb-A

Thyroid hormone receptorfos Transcription factorL-myc Transcription factormyc Transcription factor

Oncogene Function

HOW ARE PROTO-ONCOGENES ACTIVATED?

Mutation

Amplification

Translocation

Deletion or point mutation in coding sequence

DNA

RNA

hyperactive protein made in normal amounts

fusion to activelytranscribed genegreatly overproducesfusion protein; or fusionprotein is hyperactive

Chromosome rearrangement

nearby strong enhancer causes

normal protein to be overproduced

Gene Amplification

normal protein greatly overproduced

ACTIVATION OF PROTO-ONCOGENES

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.)

HOW CAN TUMOUR SUPPRESSOR GENES BE LOST?

Mutation

Deletion

Loss of heterozygosity (allelic deletion)

Methylation

Haploinsufficiency

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 METHYLATION epigenetic

Methyl groups attached to cytosines at CpG

CpG methylation causes repression of transcription (if present in promoter of gene)

Histone deacetylases (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 normallyMouse Smad4+/- predisposed to tumours in stomachMouse p27Kip1+/- tumour proneMouse PTEN+/- acceleration of prostate cancer and Human

WHAT SORTS OF GENES CAN BE TUMOUR SUPPRESSOR GENES?

Signalling Smad4, DCC, APC

Transcription WT-1, p53

Gene Expression VHL

Cell Cycle Control pRb, p53

Cell Adhesion E-cadherin

Cytoskeletal Architecture NF-2

DNA Damage and Repair p53, ATMBRCA1, BRCA2

One single oncogene will not cause cancer – cooperativity

Cooperating oncogenesin mice-

Land H et al., (1983) Nature 304, 596-602; Ruley HE (1983) Nature 304, 602-606.

•cumulative effect of carcinogens

•cumulative effect of mutations

Causes of Cancer - Age

•age-related metabolic / hormonal changes

• reduced ability to repair DNA

•viruses- eg. human papilloma virus cervical cancer

• ionising radiation

Causes of Cancer - Environmental

- eg. 131I thyroid cancer post-Chernobyl- eg. UV radiation skin cancer

- eg. arsenic in tobacco smoke lung cancer

•chemicals in food / environment

CellGrowth

CellDeath

Normal Cells

Normal tissues balance cell growth with cell death.

Cell

GrowthCell

Death

Tumour Cells

In cancer this balance is disrupted.

Acquired Characteristics of Cancer

1. Limitless replication capacity2. Evasion of apoptosis3. Self-sufficiency of growth signals4. Insensitivity to growth inhibitory signals5. Tissue invasion and metastasis6. Sustained angiogenesisFrom: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

Normal Cells

Initiation(tumourigenesis)

Normal Growth

Persistent cell clone

Single transformed

celldysregulated growth

Progressive Nature of Cancer

chemicals, viruses, radiation

Promotion(smoking, free

radicals, radiation)

Progressive Nature of Cancer (2)

dysregulated growth - progressive mutations, persistence of

tumour cell subclones, enhanced blood supply

Dysplasia

further growth - mutations, production of tissue-modelling enzymes, enhanced blood supply

Invasive Tumour Metastasis

Benign Tumour

Carcinoma in situ