General Pathology

Carcinogenesis

Carcinogenesis
(the origin, development & production of cancer)

Gender
Geographic variation Age

Hereditary (genetic predisposition)

Autosomal dominant inherited Ca syndromes Familial Ca Autosomal recessive syndromes of defective DNA repair Radiation Chemicals Viral carcinogens

Environmental

Inherited Predisposition to Cancer

Inherited Ca Syndromes (Autosomal Dominant) Inherited predisposition indicated by strong family history of uncommon cancer and/or associated marker phenotype

Examples

Familial retinoblastoma Familial Adenomatous Polyposis (FAP) of the Colon Multiple Endocrine Neoplasia (MEN) syndromes Neurofibromatosis types 1 & 2

Familial Ca
Evident familial clustering of cancer but role of inherited predisposition may not be clear in an individual case Examples
Breast Ca Ovarian Ca Colon Ca (other than FAP)

Autosomal Recessive Syndromes of Defective DNA Repair Examples

Xeroderma pigmentosum Ataxia telangiectasia

Cell Growth
Parenchymal cells
Stem cell Cell Growth

4 phases of proliferating cells

G1 cell prepares to undertake DNA synthesis S DNA synthesis occurs G2 cell prepares mechanisms for the distribution of the newly synthesised chromosomes to the daughter cells M mitosis

Growth factors

The Molecular Basis of Cancer

Non-lethal genetic damage (mutations)
Environmental agents (chemicals; radiation; viruses) Inherited (monoclonal expansion of a single progenitor cell that has occurred genetic damage)
Growth-promoting proto-oncogenes Growth inhibiting cancer suppression genes (anti-oncogenes) Genes that regulate apoptosis

3-classes of normal regulatory genes (principle targets for genetic damage)

Genes that regulate DNA repair

Predisposition to mutations in genome (neoplastic transformation) Malignant neoplasms have several phenotypic attributes (e.g. excessive growth; local invasiveness; metastatic tendencies) Progression at the molecular level results from accumulation of genetic lesions

Tumour progression (Mutistep process phenotypic & genetic levels)

Simplified Scheme of Molecular Basis of Cancer Formation

Normal cell
successful DNA repair

acquired/environmental DNA damaging agents (chemicals; radiation; viruses)

DNA damage
Failure in DNA repair inherited mutations in genes affecting DNA repair, or genes affecting cell growth or apoptosis

mutations in genome of somatic cells

activations of growthpromoting oncogenes

alterations in genes that regulate apoptosis

inactivation of cancer suppressor genes

malignant neoplasm

clonal expansion additional mutations (progression) heterogeneity

expression of altered gene products and loss of regulatory gene products

6 fundamental changes in cell physiology that dictate malignant phenotype

Self-sufficiency in growth signals oncogenes Insensitivity to growth tumour suppressor genes Evasion of apoptosis Limitless replication potential

Sustained angiogenesis
Ability to invade & metastasize

Mutations in genes that regulate these traits are seen in every cancer
Single mutation does not cause cancer several mutations & genetic alterations required Sub-clonal colonies may form due to further genetic alterations in daughter cells

Cancer Genes
Oncogenes: Genes (in viral & mammalian cells) that promote autonomous cell growth in cancer cells Derived by mutations in proto-oncogenes Characterized by ability to promote cell growth in absence of normal growth promoting signals (capable of initiation & proliferation of malignant cells) Produce oncoproteins (growth factors) devoid of any regulatory elements A gene in normal cells that is of identical structure to certain viral genes Some are important regulators of cell division, & damage may change them into oncogenes Products apply brakes to cell proliferation Examples:
RB gene Transforming Growth Factor (TGF) Adenomatous Polyposis Coli- TP53

Proto-Oncogenes

Tumour-Suppressor Genes (anti-oncogenes):

Oncogenes
V-oncs (viral oncogenes)
Acute transforming retroviruses Contain DNA sequences not found in non-tumour forming retroviruses Non-identical sequences found in normal human cells (proto-oncogenes) and concerned with normal growth
DNA inserted into target cells and integrated into cell nucleus Actively transform DNA sequences Change in gene structure synthesis of abnormal products Changed gene expression increased production of normal products that stimulate growth Point mutations Translocations Amplification

C-oncs (cellular oncogenes)

Activation of proto-oncogene

Changes in genes due to

Viral-Oncogenes
RNA viruses
HTLV-1

DNA viruses
HPV (type 16 & 18) EBV HBV/HCV

Tumour Suppressor Genes

(prevent entry of cells into growth cycle) (genes lost, mutated or inactivated by binding protein products of DNA viruses)

RB genes

Chromosome 13q14 E.g. retrinoblastoma; osteosarcoma; breast cancer; small cell ca;
Chromosome 17q13 E.g. lung; colon; breast; ovary E.g. adenomatous polyposis coli (APC); neurofibromatosis type 1 (NF-1) Heterozygous loss benign tumours Homozyous loss malignant tumours DCC deleted in colon Ca WT-1 Wilms tumour

p53

APC & NF-1 genes

Other

Stroma of Tumours
Suppoting CT framework Framework induced by tumour cells

Contains blood vessels, lymphatics & nerves

FBF; TGF; EGF

Tumour Progression
Number of genetic events hyperplasia-adenoma-dysplasia-carcinoma progression Accumulation of mutations & chromosomal abnormalities

Development of sub-populations of cells which have different properties in terms of invasiveness, metastatic tendency & susceptibility to therapeutic measures
Tumours become more malignant with time