biokimia-carcinogenesis

Carcinogenesis Overview
Neoplasia DefinitionsHypotheses of the Origin of NeoplasiaAgents Causing Neoplasia
*

Carcinogenesis - Overview
Neoplasia is an abnormality of cell growth and multiplication characterised byAt cellular level Excessive cellular proliferationUncoordinated growthTissue infiltrationAt molecular level Disorder of growth regulatory genesDevelops in a multistep fashion
*

Hypotheses of the Origin of Neoplasia
Oncogenes and Tumor Suppresor Genes

Viral Oncogene Hypothesis

Epigenetic Hypothesis

Failure of Immune Surveillance
Agents Causing Neoplasia
*

Carcinogenesis
Origin of Neoplasia two general typesMonoclonalInitial neoplastic change affects a single cellField originCarcinogen acts on large number of cells producing field of potentially neoplastic cells
*

Monoclonal

Initial neoplastic change affects a single cell

Subclones may evolve from initial clone due to further genetic changes

Eg. B-cell lymphoma, plasma-cell myeloma

Field origin

Carcinogen acts on large number of cells producing field of potentially neoplastic cells

Neoplasm arises from one or more of these cells, each from a separate clonal precursor

Polyclonal, multiple discrete, or multifocal neoplasms

Eg. Breast, urothelial, liver, colon

Carcinogenesis
Multiple Hits and Multiple FactorsKnudson proposed that carcinogenesis requires 2 hits1st event initiationCarcinogen = initiator2nd event promotionAgent = promoterMultiple hits occur 5 or moreEach hit produces a change in the genome which is transmitted to its progeny (ie. clone)Lag periodTime between exposure (first hit) and development of clinically apparent cancerAltered cell shows no abnormality during lag period
*

Carcinogenesis
1 Oncogenes and Tumor Suppresor GenesTwo categories of cell regulatory genesProto-oncogenes (cellular oncogene, c-onc)Tumor suppressor geneProto-oncogenes code for Growth factorsReceptorsSignal-relay or transduction factorsTumor suppressor genes code for factors that down-regulate the cell cycleP53Rb
*

Increase in promoter factors or decrease in suppressor factors result in uncontrolled cell growth

See figure on relationships of cellular oncogenes and suppressor genes to normal growth and neoplasia

NORMAL CELL

Growth factor

Growth factor receptor

Signal transduction

Activation of transcription

cytoplasm

nucleus

Carcinogenesis
1 Oncogenes and Tumor Suppresor GenesGene Activation and InactivationProto-oncogene is activated or tumor suppressor gene is inactivatednormal growth regulation is diverted into oncogenesisActivated proto-oncogene = activated oncogene, mutant oncogene, cellular oncogene
*

Mechanisms of activation & inactivation

Mutation

Translocation

Insertion of oncogenic virus to adjacent site

Amplification

Introduction of viral oncogene

Derepression

point mutationtranslocationgene amplification
How does proto-oncogene get activated?

Relationship between gene products of proto oncogene

Growth factors eg IGF

Growth factor receptors

Eg erb-2, ret

Signal transducing factors

Eg cytoplasmic kinases

DNA binding proteins concerned with transcription

cell cycle proteins eg cyclin D

NEOPLASTIC CELLS

Increased

In growth factor

Increased

In growth factor

receptors

Increased in signal transduction

Increase in activation of transcription

Carcinogenesis
2 Viral Oncogene HypothesisRNA Retrovirus produces DNA provirusDNA provirus containing viral oncogene (v-onc) is introduced, orDNA provirus without v-onc is inserted adjacent to c-onc in host cell DNARNA viruses is thought to have acquired v-onc sequence by recombinant mechanism from animal cellsDNA virusDo not contain viral oncogenesAct by blocking suppressor gene productsExamples HPV, EBV,HBV
*

See figure on RNA Virus oncogenesis

Carcinogenesis
3 Epigenetic HypothesisChanges in the regulation of gene expression rather than in the genetic apparatusPattern of gene expressions responsible for tissue differentiation (ie. epigenetic mechanism) are thought to be heritable
*

Carcinogenesis
4 Failure of Immune SurveillanceConceptsNeoplastic changes frequently occur in cellsAltered DNA result in production of neoantigens & tumor-associated antigensImmune response (cytotoxic) to neoantigens as foreign antigensNeoplastic cells escaping recognition and destruction become clinical cancers
*

Supporting evidence

Higher incidence of neoplasia in the immunodeficient and immunosuppressed

Cancer is disease of elderly

Challenges to hypothesis

Immunodeficient and immunosuppressed individuals develop mainly lymphomas

Thymectomised patients show no increase in neoplasia

Immune response to tumors are ineffective at time of clinical expression

See diagram on immune response to cancer

Neoplasia DefinitionsHypotheses of the Origin of NeoplasiaAgents Causing NeoplasiaChemical OncogensisRadiation OncogenesisViral OncogenesisNutritional OncogenesisHormonal OncogenesisGenetic Oncogenesis
*

Carcinogenesis
Agents Causing Neoplasm
Carcinogens substances known to cause cancer or produces an increase in incidence of cancer in animals or humansCause of most cancers is unknownMost cancers are probably multifactorial in originKnown carcinogenic agents constitute a small percentage of casesUnidentified environmental agents probably play a role in 95% of cancers
*

Carcinogenesis
1 - Chemical CarcinogenesisTypesProximate or direct-acting : act locally without metabolic changeIndirect acting : carcinogenic only after being metabolised into active compounds (procarcinogen ultimate carcinogen)
*

Major chemical carcinogens

Polycyclic hydrocarbons

Aromatic amines

Aflatoxins

Nitrosamines

Cancer chemotherapeutic agents

Asbestos

Heavy metals

Vinyl chloride

See table on major chemical carcinogens and their cancers

Carcinogenesis
Mode of carcinogenesisInducing changes in DNA eg. Base alkylation, deletion, breakage, cross-linkageEpigenetic mechanismsSynergistic action with virusesPromoter for other carcinogensDifficulties in identifying carcinogenNumerous industrial, agricultural, household chemicals present in low levelsExposed to large number of chemicals in a lifetimeLong lag phase
*

Potency

Varies with carcinogen

Expressed in amount that must be given to induce cancer on a regular basis (Eg. Saccharin 10g/kg/d, aflatoxin 10-6 g/kg/d)

Carcinogenesis
2 Radiation OncogenesisTypes of oncogenic radiationUltravioletX-rayRadioisotopesNuclear FalloutMode of oncogenesisDirect effect on DNAActivation of cellular oncogenes
*

X-rays, radioisotopes and nuclear power plants account for

Carcinogenesis
UV RadiationSolar UV radiation associated with skin cancers squamous CA, basal cell CA, malignant melanomaFair-skinned and elderly are susceptibleUV light is believed to induce cross-linkages between DNA molecules and CA occurs when repair mechanisms are not efficient
*

Carcinogenesis
X-ray radiationEarlier use of X-rays caused skin cancer, leukemia and papillary thyroid CARadiotherapy causes raditation-induced malignancy 10-30 yrs later usually sarcomasDiagnostic X-rays are considered to have no increased risk except in abdominal x-rays which increase incidence of leukemia in the fetus
*

Carcinogenesis
RadioisotopesOsteosarcoma common among factory workers who use radium-containing paintsRadioactive mineral mining in Europe and USA associated with lung cancerThorium increases risk of liver cancer hepatocellular, angiosarcoma, cholangiocarcinomaRadioactive iodine increased risk of cancer 15-25 years later
*

Radium is metabolised and incorporated into bone like calcium

Thorium used in diagnostic radiology (1930-1955)

Carcinogenesis
Nuclear FalloutHiroshima, Nagasaki (atomic blasts)Marshall islands (atmospheric testing of nuclear divide containing radioactive iodine)Chernobyl, 1986
*

Hiroshima, Nagasaki (atomic blasts) population 0showed increased incidence of leukemia, CA breast, CA lung, CA thyroid

Marshall islands (atmospheric testing of nuclear devide containing radioactive iodine) increased thyroid CA

Chernobyl, 1986 radioactive iodine

Carcinogenesis
3 Viral OncogenesisTypes Oncogenic RNA VirusesOncogenic DNA VirusesMode of OncogenesisRNA Virus DNA Virus
*

RNA Virus

Introduction of DNA provirus containing oncogene (v-onc)

Insertion of DNA provirus adjacent to cellular oncogene (c-onc)

DNA Virus

Inactivation of tumor-suppressor gene proteins

Enhancement of oncogene action

Carcinogenesis
Detection of viral genomeIdentification of viral-specific nucleic acid sequences by hybridisation with DNA/RNA probesRecognition of virus-specific antigens on infected cellsDetection of virus-specific mRNA
*

Carcinogenesis
4 Nutritional OncogenesisScant evidence linking cancer to diet except for known chemical carcinogensSome associationsLow-fiber diet and colonic CAFatty diet with breast caBetel leaves with oral caProtective agents ?antioxidant effect, awaiting confirmationBeta-caroteneVitamin C, ESelenium
*

Carcinogenesis
5 Hormonal OncogenesisTypesInduction of Neoplasms by HormonesDependence of Neoplasms on HormonesHormones inducing NeoplasmsEstrogen breast caDiethylstilbestrol (DES) vaginal and uterine ca
*

Estrogen

Granulosa cell tumor and recurrent ovulatory failure result in increased risk of endometrial CA

endometrial hyperplasia dysplasia neoplasia

Minimal increase in risk of breast CA with high-dose estrogen OCP

Diethylstilbestrol (DES)

Female children exposed to DES in utero high risk of vaginal clear-cell CA

Steroid hormones

OCP and anabolic steroids associated with liver cell adenoma, carcnoma

Carcinogenesis
Hormonal Dependence of NeoplasmsNeoplasm not caused by hormones but depend on hormones for optimal growthNeoplastic cells possess receptors for binding hormoneLoss of hormonal stimulation slow but does not halt growthExamplesProstate CABreast CAThyroid CA
*

Carcinogenesis
6 - Genetic Oncogenesis (Role of Inheritance)TypesMendelian inheritancePolygenic inheritanceAssociation with inherited diseasesMendelian InheritanceDominantRecessive
*

Dominant gene codes for activation factor

Recessive absence of tumor suppresor genes lead to failure in production of tumor suppressing factor

See table on tumor suppressor genes.

Carcinogenesis
ExamplesRetinoblastoma Wilms tumor OthersNeurofibromatosis (type 1 von Recklinghausens disease)Multiple endocrine adenomatosis (MEN)Familial polyposis coliNevoid basal cell carcinoma syndrome
*

Retinoblastoma inherited abnormality of one Rb1 gene is followed by mutation of counterpart Rb1 gene. Therefore the inheritance appears to be dominant. However it is the loss of expression of both Rb1 tumor suppressor genes that result in neoplasia hence the expression of a recessive change.

Wilms tumor deletion of part of WT-1 tumor suppressor gene by a mechanism similar to retinoblastoma.

Carcinogenesis
Polygenic InheritanceNeoplasms occuring in related individuals more often than expected on the basis of chanceBreast CA Colon CA
*

Breast CA 1st degree female relatives of premenopausal women with breast CA have 5X higher risk. The risk is higher when the relative has bilateral breast CA.

Colon CA occurs in families both as a complication of inherited familial polyposis coli and independently.

1/4th colon cancer patients demonstrate abnormalities of MSH2 gene which encodes a DNA housekeeper protein

Carcinogenesis
Association with Inherited DiseasesMany inherited diseases are associated with higher risk of neoplasiaTypes :Syndromes characterised by increased chromosomal fragilitySyndromes of immunodeficiency
*

Syndromes characterised by increased chromosomal fragility and associated with higher risk of neoplasia are such as xeroderma pigmentosum, Blooms syndrome, Fanconis syndrome, and ataxia-telangiectasia. There are frequent DNA abnormalities.

Syndromes of immunodeficiency predispose to neoplasia due to a failure of immune surveillance. The neoplasia is not inherited, but susceptibility is.

conclusion
Pathogenesis of cancer is complexit is a genetic disease- either acquired genetic abnormality or inherited genetic abnormalityIt arises when several mutations accumulate within genome

conclusion
Added insults from the environmental exposures to carcinogens : chemicals, radiation, virusesGrowth autonomy from activation of growth factors or by suppression of tumour suppressor genes

Pathogenesis

Acquired environmental factors

chemicals ,radiation ,viruses

Changes in genome

of somatic cells

Activation of growth

promoting oncogenes

Inactivation of cancer

supressor genes

Expression all altered gene products

and loss of regular gene products

MALIGNANT NEOPLSM

Genetic factors

biokimia-carcinogenesis

Documents

Transcript of biokimia-carcinogenesis