Ahmed Group Lecture 26 Radiation-induced carcinogenesis Lecture 26

Ahmed GroupAhmed GroupLecture 26Lecture 26

Radiation-induced carcinogenesis

Lecture 26


• Initiation, promotion, progression• Dose response for radiation-induced cancers• Importance of age at exposure and time since

exposure• Malignancies in pre-natally exposed children• Second tumors in radiation therapy patients• Effects of chemotherapy on incidence• Risk estimates in humans• Calculations based on risk estimates


Effect of Ionizing radiation

• Electromagnetic radiation (such as X- and gamma rays) are indirect ionizing radiation which deposits energy in the tissues through secondary electrons. These electrons can damage the DNA directly or can interact with water, leading to the formation of hydroxyl radicals that can interact with DNA and the enzymes. These processes will disrupt biochemical pathways and produce changes that will lead to cell death, neoplasia (in the somatic tissue), or heritable genetic damage (in the reproductive tissue).


Mechanism of carcinogenesis

• 3-multi step hypothesis• Oncogene/anti-oncogene hypothesis

• Four stage hypothesis


Radiation-Induced Carcinogenesis

• Experiments in vivo and in vitro utilizing chemicals and radiation identified three distinct steps in carcinogenesis.


3- Steps• InitiationInitiating events in chromosomes (such as aberrations) or in DNA. Initiators are radiation, chemical carcinogens, UV etc

• PromotionLow doses of tumor initiators are necessary to convert the initiated cells to cancer cells. Examples are TPA, phorbol esters, estrogen and excessive fat.

• ProgressionIncreased genetic instability resulting in aggressive growth phenotype


Other hypothesis (Oncogene/anti-oncogene

based)• Activation of proto-oncogenes• Loss of anti-oncogenes• Infection with certain viruses• Substitution of normal promoters of proto-oncogenes with strong promoters of viruses

• Chromosomal aberrations


Concept of oncogene model


Chromosomal changes leading to oncogene activation in

human malignancies


Loss of tumor suppressor gene


Rb : Familial vs Sporadic


Most common tumor suppressor genes


Process of Somatic homozygosity


Cooperating genes


Four-stage hypothesis

• Chromosomal damage in normal dividing cells

• Defect in differentiation genes• Gene defect in hyperplastic cells

• Gene defect in cancer cells


Chromosomal damage in normal cells

• Low or high dose radiation exposure can lead to chromosomal damage in normal cells. These cells may die, divide or differentiate.


Defect in differentiation genes

• One or two normal damaged cells develop a defect in differentiation genes, which prevent them from a normal pattern of differentiation and death. Continuing division of these cells leads to hyperplasia and develop in adenoma.


Gene defect in hyperplastic cells

• One or two hyperplastic cells in any adenoma can accumulate additional gene defects due to mutations or chromosomal damage, which can make them cancerous.


Colon tumor model





Dose-response relationship of

radiation-induced cancer


Radiation as a carcinogen

Evidence comes from:

• Tissue culture model• Animal model• Human model


Tissue culture model


Tissue culture model• Above 100 rads: the transformation frequency may exhibit a quadratic dependence on doses.

• Between 30 and 100 rads: the transformation frequency may not vary with dose

• Below 30 rads: the transformation frequency may be directly proportional to dose.


Transformation per irradiated cell


Enhancers


Protectors


Transformation incidence of

irradiated cells


Radiation + promoter

IR

C3H 10T1/2cells

IR+TPA


Supression of radiation-induced transformation


Animal Model


Radiation-induced leukemia


Radiation-induced tumors in mice

• Lung cancer• Bone tumor• Breast tumor• Ovarian tumor• Uterine carcinomas

•Skin cancer•Alimentary tract tumors•Thyroid cancer•Pituitary tumors•Adrenal tumors


Alterations in oncogenes in

radiation-induced cancer


Human Model


Marie Curie and Irene


Hand of dentist





Importance of age at exposure and time since exposure

Children and young adults are much more susceptible to radiation-induced cancer than the middle- and old-aged.


Leukemia

• Survivors of the A-bomb attacks on Hiroshima and Nagasaki

• Patients treated with ankylosing spondylitis


Thyroid Cancer• Survivors of the A-bomb attacks on Hiroshima and Nagasaki

• Residents of the Marshall islands exposed to iodine-131

• Children treated with x-rays for an enlarged thymus

• Children treated for diseases of the tonsils and nasopharynx

• Children epilated with x-rays for the treatment of tinea capitis


Thyroid cancer incidence





Basal cell carcinoma


Basal cell carcinoma


Risk of cancer following iodine-131 therapy





Quantitative risk estimates for radiation-induced cancer


Quantitativerisk estimatesfor radiation-induced cancer


Breast cancer incidence


Breast Cancer• Japanese female survivors of the A-bomb attacks on Hiroshima and Nagasaki

• Female patients in a Nova Scotia sanatorium subjected to multiple flouroscopies during artificial pneumothorax for pulmonary tuberculosis

• Females treated for postpartum mastitis and other benign conditions


Bone Cancer

• Young persons, mostly women, employed as dial painters, who ingested radium as a result of licking their brushes into a sharp point while applying luminous paint to watches and clocks

• Patients given injections of radium-224 for the treatment of tuberculosis or ankylosing spondylitis


Lung cancer

• Persons exposed to external sources of radiation, including the Japanese survivors and those with the ankylosing spondylysis

• Underground miners exposed to radon in the mine atmosphere


Bone sarcoma incidence


Skin cancer

• Radiologist• Dentist• X-ray technician

Squamous cell and basal cell carcinoma have been most frequently observed


Oncogenes in human radiation-induced

tumors

• Ras point mutations were also reported in human

radiogenic tumors

• Other oncogenes which are of prime importance in

the transformation / progression of radiogenic

tumors is RET oncogene in radiation-induced thyroid

tumors and c-myc gene amplification in other types

of radiogenic tumors


• In humans, it has been reported that mutations in the p53

gene is a potential marker of radon-associated lung

cancers from uranium miners

• Higher incidence of p53 mutations were reported in

thyroid carcinomas in children exposed to Chernobyl

accident when compared to studies on patients who had no

history of radiation exposure

• On the contrary, a lower incidence of mutation (2/33) and

overexpression (4/33) of p53 was reported in PTC from

children exposed to radiation after Chernobyl accident

p53 in human radiation-induced

tumors


Calculations based on risk estimates


Dose andDose-Rate EffectivenessFactor(DDREF)


Quantitative risk estimates for a number of specific cancer sites


Summary of risk estimates

For the populationcomposed of bothsexes the ICRPrecommendsthe following figures


Summary

• More than one theory on the mechanism of carcinogenesis

• Evidence indicate that genes such as oncogenes and anti-oncogenes are implicated in radiogenic tumors.

• Experiments from tissue culture model and also observations from humans exposed to radiation (unintentionally and accidently) strongly suggests that radiation is a potent carcinogen.

• Radiation can induced malignancy such as leukemia, breast cancer, lung cancer, bone cancer etc., depending on the latent period.

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Ahmed Group Lecture 26 Radiation-induced carcinogenesis Lecture 26