CARCINOGENESIS

Dr. Rashmi Gautam

Competency –
 PA 7.3 Enumerate carcinogens and describe the process of
carcinogenesis
CARCINOGEN
A substance or agent that can induce cancer

 Chemical Carcinogens
 Physical Carcinogens
 Microbial Carcinogens
Chemical Carcinogenesis

Carcinogenesis is a multistep process

Initiation  Results from exposure of cells to a sufficient dose

of a carcinogenic agent.
 Causes permanent DNA damage (mutations).

 Promoters- not tumorigenic by themselves

Promotion  induce tumors to arise from initiated cells
 many factors contributing to oncogenesis act by
stimulating proliferation. Eg.
1. unopposed estrogenic stimulation of the endometrium and
breast
2. chronic inflammatory processes associated with tissue repair
(e.g., inflammatory bowel disease, chronic hepatitis, and
Barrett esophagus)
Initiator carcinogens

 Highly reactive electrophiles (have electron-deficient

Mutated cell
atoms) that can react with nucleophilic (electron-
rich) atoms in the cell. DNA lesions
 Their targets are DNA, RNA, and proteins passed on to its
 Non-lethal damage to the DNA that is repaired in daughter cells.
some error-prone fashion.

Two categories:
• Direct acting- do not require metabolic conversion to become carcinogenic.
• Indirect acting - require metabolic conversion to become active carcinogens
Direct-Acting Carcinogens -
 do not require metabolic conversion
 Most are weak carcinogens
 some are important because they are cancer chemotherapeutic drugs (e.g.,
alkylating agents)

Indirect-Acting Carcinogens -
 require metabolic conversion to become active carcinogens
 Most chemical carcinogens act indirectly
 Polycyclic hydrocarbons—are present in fossil fuels, animal fats during the process of
broiling or grilling meats
 benzo[a]pyrene - formed during the high-temperature combustion of tobacco in
cigarettes
 aromatic amines and azo dyes - in the aniline dye and rubber industries
Direct acting carcinogens Indirect acting carcinogens- ( Procarcinogens)
Alkylating Agents - Require Metabolic Activation
β-Propiolactone Polycyclic and Natural Plant and
Anticancer drugs Heterocyclic Aromatic Microbial Products
(cyclophosphamide, Benz[a]anthracene
Hydrocarbons
Aflatoxin B1
chlorambucil, 7,12Dimethylbenz[a]anthr
Griseofulvin
nitrosoureas acene
Safrole Betel nuts
Aromatic Amines, Others
Acylating Agents
Amides, Azo Dyes
Nitrosamine
1-Acetyl-imidazole 2-Naphthylamine Vinyl chloride
Dimethylcarbamyl Benzidine nickel, chromium
chloride Dimethylaminoazobenzen Insecticides, fungicides
e (butter yellow)
Indirect acting carcinogens- ( Procarcinogens)
- Require Metabolic Activation

 metabolized by cytochrome P-450–dependent monooxygenases

 The genes that encode these enzymes are polymorphic
 activity and inducibility of these enzymes vary significantly among
individuals
 Eg Light smokers with the susceptible CYP1A1 genotype have a
sevenfold higher risk of developing lung cancer compared with
smokers without the permissive genotype.
Radiation Carcinogenesis
Radiant energy, in the form of the UV rays of sunlight or as ionizing
electromagnetic and particulate radiation, is mutagenic and
carcinogenic.
 UV light exposure - skin cancers
 Ionizing radiation - variety of cancers.
may arise decades later
 Radiation may have additive or synergistic effects with other potentially
carcinogenic factors.
Ultraviolet Rays
 The UV portion of the solar spectrum is divided into three wavelength ranges:
UVA (320–400 nm)
UVB (280–320 nm): responsible for the induction of cutaneous cancers.
UVC (200–280 nm): potent mutagen, not considered significant because it is filtered out by
the ozone layer
 Increased incidence of squamous cell carcinoma, basal cell carcinoma, and
melanoma of the skin
 The degree of risk depends on the type of UV rays, the intensity of exposure, and
skin pigmentation (reflecting the quantity of light-absorbing melanin in the skin).
 Persons of European origin with fair skin - highest incidence of skin cancers
globally.
 Ultraviolet Rays

UV rays

 Pyrimidine dimers are repaired by the nucleotide

pyrimidine dimers to form in
excision repair (NER) pathway
DNA
covalent cross-linking of Excessive sun exposure overwhelms the capacity of
pyrimidine bases NER pathway

Error-prone DNA repair mechanisms become

distorts the DNA helix operative

Cells survive but mutations are introduced

prevents
proper pairing of the dimer with Cancer
bases in the opposite DNA strand  As seen in hereditary disorder xeroderma
pigmentosum
Ionizing Radiation

• Electromagnetic (x-rays, γ rays)

Carcinogenic
• Particulate (α particles, β particles, protons, neutrons)
• Computed tomography (CT) scans - children who get two or three
CT scans have a threefold higher risk of leukemia,
• Hierarchy of tissue vulnerability to radiation-induced cancers
Myeloid leukemias
Cancer of the thyroid
Cancers of the breast, lungs, and salivary glands.
• skin, bone, and the gastrointestinal tract are relatively resistant to
radiation-induced neoplasia, e
Microbial Carcinogenesis

Oncogenic RNA Viruses

• Human T-Cell Leukemia Virus Type 1 (HTLV)

Oncogenic DNA Viruses -

• HPV – Human Papilloma Virus
• EBV – Epstein Barr virus
• HBV - Hepatitis B virus
• HHV8 - human herpesvirus 8

Oncogenic bacteria
• H. Pylori
Oncogenic RNA Viruses -

• Human T-Cell Leukemia Virus Type (HTLV)

 assoc. tumor - adult T-cell leukemia/lymphoma (ATLL)
 endemic in Japan, South America, and Africa
 has tropism for CD4+ T cells
 two imp genes tax and HBZ
 Leukemia develops in 3% to 5% of the infected individuals
 long latent period of 40 to 60 years.
 Oncogenic DNA Viruses -
Human Papillomavirus
70 genetically distinct types of HPV identified
• Types 1, 2, 4, 6, 7and 11- benign squamous papillomas (warts)
• Types 16 and 18 - High-risk
SCC of the cervix and anogenital region
What explains the variation in cancer risk among HPV strains?
• Benign lesions: HPV genome is in a non-integrated episomal form
• Cancers: HPV genome is integrated into the host genome

• Like HTLV-1, the site of viral integration in host chromosomes is random,

but the pattern of integration is clonal.
• Integration always occurs in a fashion that interrupts the viral DNA within
the E1/E2 open reading frame
 loss of the E2 viral repressor Oncogenic
 increased expression of the HPV E6 and E7 genes potential of HPV
E6 and E7 genes - responsible for the oncogenic potential of HPV

 0ncogenic activities of E6 -
 degradation of p53
 Over expression of telomerase
reverse transcriptase (TERT)

 Oncogenic activities of E7 -
 Inactivates RB protein
 inactivates the CDK inhibitors
p21 and p27
 activate cyclins A and E.
High-risk HPV - promotes many of the hallmarks of cancer.
• express oncogenic proteins
• inactivate tumor suppressors
• activate cyclins
• inhibit apoptosis
• combat cellular senescence

Infection with HPV itself is not sufficient for carcinogenesis.

Genetic cofactors: Cotransfection with a mutated RAS gene
Environmental factors: cigarette smoking, coexisting microbial infections,
dietary deficiencies, and hormonal changes
Acquired immune abnormalities
Oncogenic DNA Viruses….
Epstein-Barr Virus -
• Member of the herpesvirus family
• Tumours – B cell-derived lymphomas (Burkitt lymphoma) & nasopharyngeal
carcinoma
• Viral infection of B cells
• latent - no viral replication, and the cells are not killed.

EBV surface glycoproteins

occurs in tonsils

recognize and bind the complement

receptor CD21 (B cell)
Oncogenic DNA Viruses….
Latently infected B cells - grow indefinitely (immortalization).
• “hi jacking” of several normal signaling pathways by EBV proteins
 EBV protein – LMP1 latent membrane protein –
o JAK/STAT signaling pathways – B cell proliferation
o activates BCL 2 – prevents apoptosis
 Other EBV proteins - EBNA 1 and EBNA 2
o Activates several growth promoting genes

The EBV proteins required for B-cell immortalization and proliferation are highly
immunogenic
Normal individuals- EBV-driven polyclonal B-cell If T-cell immunity is defective- EBV
proliferation is controlled by a cytotoxic T-cell response. transformed B cells can produce a rapidly
Depending on the timing and intensity of this response, progressive, fatal lymphoma
the individual either remains asymptomatic or develops a
self-limited episode of infectious mononucleosis
Burkitt lymphoma
• B cell neoplasm
• Endemic in central Africa and New Guinea
• most common tumor of childhood.
• Burkitt lymphoma cells do not express LMP-1, EBNA2, and other EBV
proteins that drive B-cell growth and immortalization.
• Several additional factors are involved apart from EBV
 concomitant infections such as malaria impair immune competence, allowing sustained
B-cell proliferation.
 T-cell immunity directed against EBV antigens eliminates most of the EBV-infected B
cells, but a small number of cells downregulate expression of these immunogenic
antigens.
 These cells persist indefinitely, even in the face of normal immunity.
 Lymphoma cells may emerge from this population only with the acquisition of specific
mutations- translocations involving the MYC oncogene, t(8;14) or other translocations
that dysregulate MYC.
• In Burkitt lymphoma, EBV is not directly oncogenic
• but by acting as a polyclonal B-cell mitogen sets the stage for the
acquisition of the (8;14) translocation and other mutations that
ultimately produce a full-blown cancer.
• In most individuals, EBV infection is readily controlled by effective
immune responses, and lymphomagenesis is rare.
• By contrast, in regions where Burkitt lymphoma is endemic, cofactors
such as chronic malaria may favor the acquisition of additional genetic
events (e.g., t(8 1 )) that lead to malignant transformation.
Nasopharyngeal carcinoma
• LMP-1 is expressed in nasopharyngeal carcinoma cells
• It activates the NF-κB pathway, which upregulates the expression of VEGF, FGF-2,
MMP-9, and COX-2 - contribute to oncogenesis.
• Prominent infiltrates of T cells seen which respond to viral antigens such as LMP-1, but
this response is ineffective, suggesting immune evasion mechanisms
• Express the immune checkpoint molecule PD-L1 and are responsive to PD-L1 inhibitors.
Oncogenic DNA Viruses….
Hepatitis B and C Viruses
• 70% to 85% of hepatocellular carcinomas
• HBV is endemic in countries of the Far East and Africa correspondingly,
these areas have the highest incidence of hepatocellular carcinoma
• Oncogenic effects of HBV and HCV are multifactorial
• The dominant effect seems
1. Immunologically mediated chronic inflammation and hepatocyte death
2. hepatocyte proliferation during regeneration
3. genomic damage
• HBV gene - HBx can activate a variety of transcription factors and several
signal transduction pathways.
• Although not a DNA virus, HCV is also strongly linked to the
pathogenesis of liver cancer.
• The molecular mechanisms used by HCV-
Chronic liver cell injury and compensatory regeneration
Components of the HCV genome- HCV core protein activates a variety of
growth- promoting signal transduction pathways cusing tumorigenesis
Helicobacter pylori
• First bacterium classified as a carcinogen
• Causes gastric adenocarcinomas as well as gastric lymphomas.
• There is increased epithelial cell proliferation in a background of chronic
inflammation
• As seen in viral hepatitis, the inflammatory milieu contains numerous
genotoxic agents, such as reactive oxygen species.
• The H. pylori genome also contains genes directly implicated in oncogenesis
• Strains associated with gastric adenocarcinoma have a “pathogenicity island”
that contains cytotoxin-associated A (CagA) gene.
• CagA gene - penetrates into gastric epithelial cells
• initiation of a signaling cascade that mimics unregulated growth factor
stimulation.
Helicobacter pylori

H. pylori infection

chronic gastritis This sequence takes

decades to complete and
gastric atrophy occurs in only 3% of
infected patients

intestinal metaplasia of the lining cells

dysplasia

cancer
H. pylori associated gastric lymphomas are of B-cell origin
Molecular pathogenesis:
H. pylori factors Host genetic factors
H. pylori infection • polymorphisms in the
promoters of
inflammatory cytokines
H. pylori reactive T cells
such as IL-1β and TNF.

polyclonal B-cell proliferation

Acquire mutations

monoclonal MALToma
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