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 PROMOTION PROGRESSION

Normal Initiated Cancer cancer
cells cells differentiated dedifferentiated
cells cells

• Several changes may occur at each stage and continue

after cell has become cancerous
 Other Models of Cancer
Cell Biology

Normal Immortal Cancer

cells cell cell

Molecular Biology
DNA Changes
A B C

Normal Precancer Cancer Metastasis

 Clinical Model

Hyperplasia Carcinoma Invasive

Normal excess in situ cancer
‘normal localised surrounding
cells’ 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 -
M1 M2 Transformed
– Enhanced proliferative
capacity

• 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