NEOPLASIA Lecture 4 Dr. Maha Arafah. Objectives List the various causes of neoplasm List the various causes of neoplasm

NEOPLASIANEOPLASIALecture 4Lecture 4

Dr. Maha ArafahDr. Maha Arafah

ObjectivesObjectives

List the various causes of neoplasmList the various causes of neoplasm

Carcinogenic AgentsCarcinogenic Agents

ChemicalsChemicals RadiationRadiation Microbial agentsMicrobial agents


Chemicals:Chemicals: Natural or syntheticNatural or synthetic Direct reacting or indirectDirect reacting or indirect Indirect Indirect need metabolic conversion need metabolic conversion

to be active and carcinogenicto be active and carcinogenic Indirect chemicals are called “ Indirect chemicals are called “

procarcinogens “ and their active end procarcinogens “ and their active end products are called “ ultimate products are called “ ultimate carcinogens”carcinogens”


All direct reacting and ultimate All direct reacting and ultimate chemical carcinogens are highly chemical carcinogens are highly reactive as they have electron-reactive as they have electron-deficient atomsdeficient atoms

They react with the electron rich They react with the electron rich atoms in RNA,DNA and other atoms in RNA,DNA and other cellular proteinscellular proteins


Examples:Examples: Alkylating agentsAlkylating agents Polycyclic hydrocarbons:Polycyclic hydrocarbons:

Cigarette smokingCigarette smoking Animal fats during broiling meatsAnimal fats during broiling meats Smoked meats and fishSmoked meats and fish


Aromatic amines and azo dyes:Aromatic amines and azo dyes: -naphthylamine cause bladder cancer in -naphthylamine cause bladder cancer in

rubber industries and aniline dyerubber industries and aniline dye Some azo dyes are used to color foodSome azo dyes are used to color food Nitrosamines and nitrosamides are used Nitrosamines and nitrosamides are used

as preservatives. They cause gastric as preservatives. They cause gastric cancer.cancer.

Aflatoxin B: produced by aspirigillus Aflatoxin B: produced by aspirigillus growing on improperly stored grains. It growing on improperly stored grains. It cause hepatocellular carcinomacause hepatocellular carcinoma


Mechanism of action of chemical Mechanism of action of chemical carcinogens:carcinogens: Most of them are mutagenic. i.e. cause Most of them are mutagenic. i.e. cause

mutationsmutations RAS and TP53 are common targetsRAS and TP53 are common targets


Radiation carcinogenesisRadiation carcinogenesis UV rays of sunlightUV rays of sunlight X-raysX-rays Nuclear radiationNuclear radiation Therapeutic irradiationsTherapeutic irradiations

Radiation has mutagenic effects: Radiation has mutagenic effects: chromosomes breakage, chromosomes breakage, translocations, and point mutationstranslocations, and point mutations


UV rays of sunlight :UV rays of sunlight : Can cause skin cancers: melanoma, Can cause skin cancers: melanoma,

squamous cell carcinoma, and basal cell squamous cell carcinoma, and basal cell carcinomacarcinoma

It is capable to damage DNA It is capable to damage DNA With extensive exposure to sunlight, the With extensive exposure to sunlight, the

repair system is overwhelmedrepair system is overwhelmed skin skin cancer cancer

They cause mutations in TP53 geneThey cause mutations in TP53 gene


Viral and Microbial oncogenesisViral and Microbial oncogenesis

DNA virusesDNA viruses

RNA virusesRNA viruses

other organismsother organisms

Carcinogenic AgentsCarcinogenic Agents Viral oncogenes:Viral oncogenes:

carry genes that induce cell replication as part of the viral life cycle

host cell has endogenous genes that maintain the normal cell-cycle

Viral infection mimics or blocks these normal cellular signals necessary for growth regulation


RNA Oncogenic virusesRNA Oncogenic virusesHuman T-Cell Leukemia Virus type 1 Human T-Cell Leukemia Virus type 1

(HTLV-1)(HTLV-1)• RNA retrovirus targets / transforms T-cellsRNA retrovirus targets / transforms T-cells

• causes T-Cell leukemia/Lymphoma causes T-Cell leukemia/Lymphoma

• Endemic in Japan and CaribbeanEndemic in Japan and Caribbean

• Transmitted like HIV but only 1% of infected Transmitted like HIV but only 1% of infected

develop T-Cell leukemia/Lymphoma develop T-Cell leukemia/Lymphoma

• 20-30 year latent period20-30 year latent period


No cure or vaccine No cure or vaccine Treatment : chemotherapy with Treatment : chemotherapy with

common relapsecommon relapse


DNA Oncogenic VirusesDNA Oncogenic Viruses virus DNA forms stable association with virus DNA forms stable association with

host’s DNAhost’s DNA transcribed viral DNA transforms host celltranscribed viral DNA transforms host cell

Examples: Examples: papilloma virusespapilloma viruses

Epstein-Barr (EBV)Epstein-Barr (EBV)

Hepatitis B (HBV)Hepatitis B (HBV)

Kaposi sarcoma herpes virusKaposi sarcoma herpes virus


Human Papillomavirus (HPV)Human Papillomavirus (HPV)• 70 types70 types• squamous cell carcinoma of squamous cell carcinoma of

cervixcervix anogenital regionanogenital region mouth mouth larynxlarynx


sexually transmittedsexually transmitted Cervical cancer Cervical cancer

85% have types 16 and 1885% have types 16 and 18

Genital wartsGenital warts types 6 and 11types 6 and 11


HPV causing benign tumors:HPV causing benign tumors:

types 6, 11types 6, 11

HPV causing malignant tumors :HPV causing malignant tumors : types 16, 18, 31types 16, 18, 31

vDNA integrates w/ hostvDNA integrates w/ host


HPV (types 16 and 18)HPV (types 16 and 18) over-expression of Exon 6 and 7over-expression of Exon 6 and 7

E6 protein binds to Rb tumor E6 protein binds to Rb tumor suppressor suppressor

replaces normal transcription replaces normal transcription factorsfactors

decreases Rb synthesisdecreases Rb synthesis E7 protein binds to TP53E7 protein binds to TP53

facilitates degradation of TP53facilitates degradation of TP53


HPV infection alone is not sufficient -HPV infection alone is not sufficient - other risk factors:other risk factors:

cigarette smokingcigarette smoking

coexisting infectionscoexisting infections

hormonal changeshormonal changes


Epstein-Barr VirusEpstein-Barr Virus• common virus worldwidecommon virus worldwide• Infects B lymphocytes and epithelial cells Infects B lymphocytes and epithelial cells

of oropharynxof oropharynx

• causes infectious mononucleosiscauses infectious mononucleosis• EBV infection may cause malignancy EBV infection may cause malignancy

Burkitt’s LymphomaBurkitt’s Lymphoma B cell lymphoma in immunosuppressedB cell lymphoma in immunosuppressed Nasopharyngeal carcinomaNasopharyngeal carcinoma

Carcinogenic AgentsCarcinogenic AgentsEpstein-Barr Virus Epstein-Barr Virus

relatedrelated Nasopharyngeal carcinoma Nasopharyngeal carcinoma

Cancer of nasopharygeal epitheliumCancer of nasopharygeal epithelium

Endemic in South China, parts of AfricaEndemic in South China, parts of Africa 100% of tumors contain EBV genome in 100% of tumors contain EBV genome in

endemic areasendemic areas

Carcinogenic AgentsCarcinogenic Agents Epstein-Barr Virus Epstein-Barr Virus

relatedrelated Burkitt LymphomaBurkitt Lymphoma

highly malignant

B cell tumor

sporadic rare

occurrence worldwide

most common

childhood tumor in

Africa

all cases have

t(8:14))

Carcinogenic AgentsCarcinogenic Agents Epstein-Barr Virus Epstein-Barr Virus

relatedrelated causes B lymphocyte cell proliferationcauses B lymphocyte cell proliferation loss of growth regulationloss of growth regulation predisposes to mutation, esp. t(8:14)predisposes to mutation, esp. t(8:14)


Hepatitis B virus (HBV) Strong association with Liver Cancer

world-wide, but HBV infection is most common in Far East and Africa

HBV infection incurs up to 200-fold risk


Helicobacter Pylori• bacteria infecting stomach• implicated in:

peptic ulcers gastric lymphoma

Mucosal Associated Lymphoid Tumor (MALT)

gastric carcinoma

Documents

NEOPLASIA Lecture 4 Dr. Maha Arafah. Objectives List the various causes of neoplasm List the various causes of neoplasm