BB5506: The biology, genetics and treatment of human cancer

Key Issues
• Defining cancer. • What causes cancer? • Cellular changes and cancer development. • What types of cells become cancerous? • The genetics of cancer

Key Issues
• Tumour Progression
– Changes continue to occur after a cancer has formed.

– Invasion – Metastasis – Escaping Apoptosis

• Are all cancers lethal?
– Why does cancer kill?

• Cancer diagnosis and treatment.

• Can cancer be prevented?

Cancer on a Global Scale

CRUK Website

What is Cancer?
• Cancer is not a single disease but a collection of different diseases with one key feature in common. – Uncontrolled growth

• Other common properties – Life threatening if untreated – Generalisations about cancer are invalid - always an exception to disprove any generalisation.
• Difficult to define cancer in one statement.

A definition!
• “ a set of diseases characterised by unregulated cell growth leading to invasion of surrounding tissues and spread (metastasis) to other parts of the body.” • Problem – Invasion and metastasis may not be valid in defining cancer. – E.g. some cancers do not metastasise

Some Terminology
• Neoplasm: – “New growth” but no other qualification as to type of growth. • Tumour: – A growth resulting from the abnormal proliferation of cells

• Benign tumour: – Self limiting or non-invasive.
• Malignant: – proliferating indefinitely and invading underlying tissues. • Cancer: – specifically refers to malignant tumours

Classifying cancers
• Epithelial - Carcinoma – Most common cancer type • Mesenchymal – Sarcoma – Smooth muscle: leiomyosarcoma – Bone: Osteosarcoma – Fat cells: Liposarcoma • Nervous System – Eye retinoblastoma – Astrocytes: Astrocytoma • White blood cells: Leukaemnia – Myeloid cells: Myelocytic leukaemia – Lymphocytes: Lymphocytic leukaemia – Lymphoma: solid tumour from B or T cells

What Causes Cancer?
• Discuss causes please!

What causes cancer?
• Underlying theme: alterations to regulatory pathways
– Permanent?

• Changes must occur at the DNA level • Many agents can cause changes to the DNA in experimental models may not have the same effect in humans • Major causes - those factors to which we are exposed to all the time. – Sunlight (environmental) – Diet • Lifestyle is the major cause of cancer.

Cancer and Age

Normal cells

Transformed Cells

Life History of a Cancer
• Several pathways must be affected. Much research has been devoted to finding out what these stages are.

• Animal experiments have defined the basic steps – Initiation - Promotion - Progression

INITIATION Initiated Normal cells cells

PROMOTION PROGRESSION cancer Cancer dedifferentiated differentiated cells cells

• Several changes may occur at each stage and continue after cell has become cancerous

Other Models of Cancer
Cell Biology Normal cells Immortal cell Cancer cell

Molecular Biology
A

DNA Changes
B C

Normal

Precancer

Cancer

Metastasis

Clinical Model

Normal

Hyperplasia excess ‘normal cells’

Carcinoma in situ localised

Invasive cancer surrounding tissue

Metastatic remote tissue

Clonal origin of Cancer
• Cancers are clones descended from a single ancestral cell. – There may be subsequent heterogeneity in the tumour as a result of genetic instability. • Cancer cells are usually less differentiated than the normal cells of the tissue they arose from. – De-differentiation? – Cancer arising from a precursor or stem cell?

Regulation of cell growth
• Multiple pathways of cell growth regulation – Major mechanisms will be examined during the module
• To get cancer several regulatory pathways must be altered – activated/inactivated. • There are intermediate stages between normal and cancerous cells. • Majority of cancer research is involved in studying little individual steps. • Many changes need to accumulate – Live longer - greater chance of getting cancer

Inherited vs Somatic cancers
• Majority of genetic alterations (mutations) occur after birth – Changes occur to somatic cells
• A few inherited cancers in which the mutation(s) is passed via the germ cells – The phenomenon is rare • Inherited cancer account for about 5-10% of all cancers. • Inherited cancers do provide useful information about the multi-step process of cancer development

Cancer Associated Genes
• Oncogenes: Accelerators or positive regulators of cell growth. – Mutation of an oncogene has a dominant effect. – Stimulate more proliferation, less cell death, less cell quiescence.
• Tumour suppressor genes: Brakes - negative regulators of cell growth. – Stop cell proliferation, stimulate cell death or quiescence.

Cancer Associated Genes
• DNA Repair genes
– Have many of the properties of classical tumour suppressor genes.

• Defects in nucleotide excision repair genes responsible for 2000x fold increase in skin cancer in xeroderma pigmentosum patients.
• Defects in mismatch repair responsible for certain type of colon cancer (HNPCC)

Actions of Tumour Suppressors
• “Caretakers”
– Maintain genomic integrity/stability by DNA repair.

• “Gatekeepers”
– Inhibit proliferation (e.g. P53, P16) – Promote cells death (Apoptosis) (Bcl, Bax, Caspases).

• “Landscapers”
– Genes involved in defining aspects of tumour morphology and differentiation (Integrins, MMPs – matrix metalloproteinases).

Importance of Cancer Genetics
• Understanding the molecular evens of cancer is important because:
– It will be important in defining causes of cancer. – It will assist in diagnosis. – It will help predict prognosis. – It will provide opportunities for novel therapeutic target sand new treatments.

Examples of tumour suppressor genes

Examples of Oncogenes

Tumour Progression

What is this process?

Who is this person and why is he so important? Think about the previous slide!

What are we looking at here?

Why do cancers metastasise?
Comment?

Cancer cells can escape apoptosis.

Apoptosis

Changes continue at the molecular and cellular level which promote progression.

Multistage Nature of Cancer
• Cancers most commonly occur in older people

• Time is needed to accumulate multiple changes
• More changes that are required the older the age at which that cancer is likely to occur. • Clinical data show a linear relationship between log age and log incidence. • Probability of getting cancer = agen • For colon cancer n = 5/6

Colon cancer development

Genes and Colon Cancer
• APC: Signal transduction protein – cell membrane molecule (cadherin) to cytoskeleton. Disruption of tight linkage between cells. • K-Ras: Signal tranduction from membrane to nucleus.

• SMAD4 loss: Signalling pathway for TGF. Growth inhibition and causes differentiation.
• P53: – Proliferation – DNA repair – Apoptosis • MLH1/MSH2: – Mismatch DNA repair genes.

Why does cancer kill people

Cancer and Death
• Cancer is responsible for 25% of UK deaths.
– 1 in 3 people will get cancer.

• Many cancers are curable – Skin cancer: non-melanoma (70%) – Testicular cancer (90% survival rate) – Breast cancer (80% survival rate) • Many are not – Ovarian (30% survival rate) – Liver (<5% survival rate)

Why does cancer kill?
• A vital organ(s) may be affected due to metastasis or local invasion – Why bone metastases are so lethal is not known.

• Wasting/cachexia: may be due to toxin release by tumours. • Subsequent opportunistic infections (pneumonia) causing death.

Cancer Treatment

Treatment
• Prevention: Best form of treatment
– stop smoking – stay out of direct sunlight

• Next best: Screening
– Identifying those at risk – Finding tumours at the early stage so easier to treat.

• Treatment: removal, killing (or both) of the tumour cells
– – – – – – Surgery Chemotherapy (cytotoxics, hormone,) Radiotherapy Gene therapy Photodynamic therapy Immunotherapy

• Systemic attack

Problems
• Inoperable tumours. • Drug/radio - resistance: genetic instability of cancer cells quickly results in – Development of non-responsive tumours. – Selection of resistant tumours by therapy. • Cellular heterogeneity: sub populations of cancer cells within a tumour respond differently.

• Therapeutic Index – Tumour cells are more sensitive to therapy than normal cells – Kill the tumour before you kill the patient • Drug metabolism effect – metabolic inactivation/activation

Problems
• Therapeutic Index – Tumour cells are more sensitive to therapy than normal cells. – Kill the tumour before you kill the patient. • Drug metabolism effect – metabolic inactivation/activation

Pathology of Cancer: Examination
• Intact tissue analysis – microscopic histopathology, section cutting cytological staining. Cancer cells having abnormal appearance. – Antibodies for a proliferation marker (PCNA)
• Individual cell analysis: cytology – non-invasive, non surgical, less precise than histopathology

• Biochemical or chemical analysis. Changes at the level of specific DNA mutations, RNA, protein (tumour markers)
– Tumour markers

Histological section
• Cancer Cells – High DNA content – Loss of normal ploidy level – Darkly staining – Loss of tissue architecture
Haematoxylin and eosin stained tissue section prostate cancer

• Pathology is aimed at trying to assist the clinician with DIAGNOSIS and PROGNOSIS • DIAGNOSIS – is this cancer? – what type of cancer? – has the surgeon removed it all? • PROGNOSIS – what is the clinical outlook? – what type of treatment (aggressive or not)? – is the cancer likely to have metastasised already?

Model Systems to studying cancer
• Animal studies – Surface painting – injection – xenograft (injecting tumour cells) • Through these studies concepts of initiation and promotion were developed. • Most cases required two separate carcinogens often in a specific order to produce a tumour. • Certain carcinogens produce specific tumours - reflection of their target – cells – genes

Cell Culture model of cell growth
• Hayflick model of cell growth • M1: Cells senesce and die – Acquire changes Transformed – Enhanced proliferative capacity

M1

M2

• M2: Fully immortal – Unlimited proliferative capacity

Transformation & Immortality
• Normal cells in culture will undergo about 40 population doublings. – Senesce and die. • Cells which have “changed” will have – enhanced proliferative capacity: transformed – unlimited proliferative capacity: immortal

• Many tumours may only be transformed and may not have acquired an immortal phenotype.
• The Transformation may be sufficient to threaten life.

Transformation & Immortality
• Normal cells in culture will undergo about 40 population doublings. – Senesce and die. • Cells which have “changed” will have – enhanced proliferative capacity (transformed) – unlimited proliferative capacity (immortal) • Many tumours may only be transformed and may not have acquired an immortal phenotype. • The enhanced growth characteristics, being enough to threaten life.

Cell Culture Models
• Normal or tumour derived cells can be studied.
• Cell types can be exposed to – drugs – carcinogens – transfected with genes – antisense therapy – antibodies – hormones etc • effects accurately quantitated

Animal Studies
• Transgenic mice
– Transfection of a transgene into into fertilised egg which is then transferred to uterus of female mouse – analysis of potential function of gene.

• Knockout mice
– Ablation of a specific gene function to determine effect on cancer development

• Immunodeficient mice
– Tumour transplantation studies

Summary
• Hard to define cancer – A collection of diseases (a huge clinical challenge). • Mainly a multistep phenomenon – Accumulation of genetic aberrations. – Disease associated with age. • Cancer Genes – Oncogenes – TSGs (also DNA repair genes) • Classifying cancer - tissue of origin. • Multistep models of cancer – Animal studies etc • Pathology and diagnosis

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