Neoplasia: Carcinogenesis

Ayesha Sana (lecturer)

 Epidemiology
• Increasing / decreasing incidence
•Environmental and Geographic causes
•Death from Ca breast 4-5 fold higher in USA and Ca sto
mach 7 fold higher in japan
•Ca liver infrequent in USA but most lethal in Africa
•Exposure to sun light .
•Different cancer have different incidences in male and f
emales
•
 Epidemiology
• Extremes of age. Increasing age after 55-75. old
er persons have a greater propensity to develo
p neoplasms from lack of effective control mec
hanisms, accumulation of somatic mutations, d
ecline in immune competency. Cause of death i
n 10% children under 15 yrs
• Personal practices: diet -cigarette smoke - lung
cancer. Alcohol. Sexual practices
• Illegal, immoral, fattening - carcinogenic
 Occupational cancers
• carcinogenic Chemicals - man-made natural compounds (afl
atoxins - liver cancer)
• Aniline dyes - bladder ca. drugs
• Arsenic: metal smelting, medications –lung, skin ca
• Asbestos: roofing paper, floor tiles – lung git
• Benzene: printing, rubber, paint, dry cleaning -leukemia
• Beryllium: missile feul - lung
• Cadmium: plating, batteries - prostate
• Chromium: paints, pigments, preservative
• Ethylene oxide: ripening agent foods, textile- leukemia
• Nickel: plating, batteries, ceramics – lung nose
• Radon: decay of uranium containing minerals - lung
• Vinyl chloride: refrigerant, adhesive for plastic -liver
 Hereditary causes
• Genomic Instability
• Inherited defects in DNA repair genes. 5-10% tumors.
Impact of heredity is subtle or indirect. Genotype may inf
luence the likelihood of environmentally induced tumors
• 3 categories
• Autosomal recessive syndrome of defective DNA repa
ir. HNPCC syndrome (Hereditary non polyposis colon ca),
Xeroderma pigmentosum, defects in homologus recombi
nation DNA repair system (bloom syndrome)

 Hereditary factors
• Autosomal dominant cancer syndromes:
• Inheritance of single mutated gene
• Chromosomes which have absent or defective anti-onco
genes that control growth. 40%Retinoblastomas familial,
Germ line mutation of tumor suppressor genes
• Associated with specific phenotype marker
• Familial cancers of uncertain origin
• Pattern of inheritance unclear. Ca colon, breast, ovary, b
rain.
• Early age at onset, two or more close relatives effected,
multiple or bilateral. Not associated with specific marker
phenotypes
 Etiology of cancer
Carcinogenic agents
• Three classes
• Chemical
• Radiation
• microbial
• Many agents may act in concert to produce m
ultiple genetic abnormalities
 Chemical carcinogens
• Direct acting & Indirect acting
• Direct acting
• Require no metabolic conversion
• Generally weak carcinogens
– Alkylating agents:
• β propiolactone,
• dimethyl sulphate,
• anticancer drugs like chlorambucil Cyclophosph
amide
– Acylating agents:
• Diethyl carbamyl chloride
• 1-acetyl imidazole
 Chemical carcinogens
• Indirect acting: Require metabolic conversion. Enzymati
c pathways involved e.g. P-450-dependent monooxygena
se. Polymorphic enzyme, Specific allele of enzyme inherit
ed
• Polycyclic and heterocyclic aromatic hydrocarbons: tobac
co combustion, fossil feuls, smoked meat and fish and an
imal fat in broiling meat. HC form addition products with
cellular molecules.
• Benz(a) anthracene, Benzo(a)pyrene (tobacco)
• Aromatic amines, amides, azo dyes: (food &colors)
• 2-Naphthylamine, Benzidine
• Acetyl amino fluorine
• Dimethylaminoazobenzene
 Chemical carcinogens
• Indirect acting
• Natural plant and microbial products:
• Aflatoxin B1 (Aspergillus)
• Griseofulvin
• Betel nuts
• Safrole
• Others:
• Nitrosamines (pickled food) and amides
• Vinyl chloride, nickel, chromium
• Insecticides, fungicides
• Polychlorinated biphenyls
• Nitrites food preservative
 Chemical carcinogenesis
Mechanism of action:
Mutagenic. Contain highly reactive electrophile
groups that form chemical adducts with DNA,
RNA and proteins. Any gene can be target but
commonly mutation in RAS & TP53 genes
• There are two steps:
• Initiation and Promotion
 Chemical carcinogenesis Initiation
An initiating carcinogenic agent has highly reacti
ve electrophile groups that irreversibly damages c
ell DNA - mutagenic. E.g. alkylating agents like c
yclophosphamide, polycyclic aromatic hydrocarb
ons like epoxides found in smoked foods, aromati
c amines or azo dyes used in food & coloring, Afl
atoxins in moldy peanuts, nitrosamines in pickled
foods.
 Chemical carcinogenesis Promotion
Initiator is followed by promoter which acts (reve
rsibly) to cause proliferation of neoplastic cell clo
ne. There appears to be "dose-threshold" concentr
ation of promoter below which neoplasia will not
occur. Not mutagenic
Examples: phenols, hormones (Estrogen), drugs (
diethyl-stilbesterol, chemicals (cyclamates used a
s sweeteners).
 Microbial carcinogenesis
• Oncogenic DNA Viruses:
– Hepatitis B virus Hepatocellular carcinomas. Immunologi
cally mediated chronic Inflammation, stimulation of hep
atocyte cell proliferation, production of reactive Oxygen
species
– Epstein Barr virus EBV African Burkitt's lymphoma, Hodg
kins lymphoma, nasopharyngeal ca
– Human papilloma virus HPV – E 6& 7 proteins bind to p5
3 and RB. Squamous cell carcinomas of cervix and anoge
nital squamous papillomas
– Kaposi sarcoma herpesvirus KSHV (HHV8)
 Microbial carcinogenesis
• Oncogenic RNA V:
– Human T cell lymphotropic virus HTLV-1
– Hepatitis C virus Hepatocellular carcinomas
 Microbial carcinogenesis
• Helicobactor pylori:
• Immunologically mediated chronic Inflammati
on, stimulation of gastric cell proliferation, pro
duction of reactive Oxygen species
• Cag A genes
• gastric Adenocarcinoma, MALT lymphoma
 Radiation carcinogenesis
• Sun light - Ultraviolet light - induces pyrimidine dimers i
n DNA. Squamous cell ca, melanoma, basal cell ca
• Ionizing radiation – chromosome break, translocation, i
nduces mutations in DNA.
• Gamma radiation - leukemia, thyroid, lung, colon, and b
reast cancers.
• X-rays – melanoma, squamous cell ca skin
• Nuclear fission – leukemia, thyroid, breast, colon and lu
ng ca
 Radiation carcinogenesis
• Radiation, either as low level long-term environmental
gamma rays or as higher dose therapeutic radiation, ca
n also produce genetic mutations, Chromosome breaka
ge, translocations, point mutations, Double stranded D
NA breaks,
• Australia, new zealand greater sunlight. induces pyrimid
ine dimers in DNA, repaired by nucleotide excision repa
ir pathway. Excessive exposure, overwhelms repair syste
ms. Xeroderma pigmentosum
• Sun bathing - melanoma
 Carcinogenesis: Molecular basis
• Fundamental principles
• Non lethal genetic damage /mutation
• due to
– Environmental agents radiation, chemical, virus
– Inherited in germ line
• tumors arise from clonal expansion of single progenito
r cell that have incurred genetic damage
 Molecular basis of carcinogenesis
• Principal target are four classes of regulatory genes.
– Genes promoting cell growth proto-oncogenes
– Genes inhibiting cell growth tumor suppressor ge
nes. (recessive)
– Genes regulating apoptosis (dominant)
– Genes regulating DNA repair
 Molecular basis of carcinogenesis
• Proto-oncogenes: normal cellular genes whose products
promote cell proliferation.
Oncogenes: mutant alleles of proto-oncogenes that funct
ion autonomously without a requirement for normal gro
wth-promoting signals. (dominant). When expressed the
y induce a transformed phenotype in cells
• Tumor suppressor genes: prevent uncontrolled growth. If
damaged, allow transformed phenotype to develop.
• Both alleles must be damaged for transformation to occu
r. Haploinsuffuiciency in some cases. Two groups
• Governors: RB mutation removes break on cellular prolif
eration
• Guardians: TP53 sense genomic damage. Either stop proli
feration or induce apoptosis. Loss permits mutations in g
enes – mutator phenotype
 Molecular basis of carcinogenesis
– Genes regulating apoptosis (dominant)
– Genes regulating DNA repair
• Both may act like proto-oncogenes or tumor s
uppressor genes
 Carcinogenesis: Molecular basis
• Genetic damage with DNA alterations leads to point m
utations of genes, translocations of genetic material be
tween chromosomes and gene reduplication with ampl
ification. These alterations transform proto-oncogenes
into oncogenes.
• The proto-oncogenes may play a role in growth promot
ion and regulation in normal cells, perhaps in embryog
enesis, but are typically "turned off" in adults. They are
"turned on" by transformation
 Cellular Transformation
•Some factor causes a cell to be transformed to a neoplasti
c cell that is not controlled by normal body processes.
•Probably most transformed cells die because they are too
abnormal to function or are abnormal enough for the body'
s immune system to destroy them.
•If the factors promoting neoplasia persist, a transformed c
ell may some day give rise to a clone that does continue to
grow.
•Some neoplastic growth is influenced by host factors. Est
rogenic hormones aid growth of breast fibroadenomas or c
arcinomas and uterine leiomyomas because the tumor cells
have hormone receptors.
 Clonality
Neoplastic cells tend to be monoclonal, or similar in ge
netic makeup, indicating origin from a transformed cel
l. Non-neoplastic proliferations (reactions to inflammat
ion) have cells that are polyclonal in origin.
The concept of "tumor progression" holds that subclon
es may arise over time from the original malignant clo
ne. Subclones may differ from original clone in charac
teristics such as invasiveness, metastatic potential, and
response to therapy.
 Characteristics of
Transformed (Neoplastic) Cells

• Growth not inhibited by contact with surrounding cell

s and is not dependent on anchorage to solid surface.
• may attain immortality / ability to divide indefinitely
• Are discohesive and transplantable-favoring invasion
and metastasis.
• Can bind to laminin and fibronectin in connective tiss
ues, secrete collagenases or proteases and invade.
 Tumor Genetics
Neoplasms have a greater tendency to
• Point mutations activate / inactivate gene product
• Karyotypic abnormalities such as translocations, d
eletions. Leukemias and lymphomas are famous for t
his. Philadelphia (Ph1) chromosome of chronic myel
ogenous leukemia
•t(8:14) translocation in Burkitt's lymphomas.
• gene amplifications (activators of proto-oncogenes
). Neuroblastoma and breast ca
•Aneuploidy: number of chromosoes not multiple of
23
 Epigenetic modifications
• Reversible heritble changes in gene expression t
hat occur without mutations.
• DNA methylation, post translational modificatio
n of histones. Gene silencing
• Selective Hypermethylation and hypomethylatio
nin cancer cells
 Micro RNAs (MiRNA) or oncomirs

• Non coding SS, 22 nucleotides

• Negative regulator genes. Inhibit gene expression pos
t transcriptionally by repressing translation or mRNA
cleavage.
• Increase expression of RAS ,MYC oncogenes or reduci
ng expression of tumor suppression genes
• Control cell growth, differentiation, survival.
 Carcinogenesis multi-step process
at genetic and phenotypic levels
• Mutation in no single gene is sufficient to cause cancer
• Phenotypic attributes characteristic of malignancy develop
when multiple mutations involving multiple genes accumul
ate.
• Cancers can arise from non-neoplastic precursor lesions
• Tumor progression: The stepwise accumulation of mutation
s and increasing malignancy.
• Phenotypic attributes include excessive growth, local invasi
veness, ability to form metastases
 Carcinogenesis multi-step process
at genetic and phenotypic levels
• Multiple mutations in different cells result in heterogenei
ty – subclones with different characteristics - growth rate
, invasiveness, drug susceptibility, Antigenecity
• Immune and non immune selection pressures. Highly ant
igenic are destroyed by immune system. Tumors with red
uced growth factor requirements are selected
• Tumor that recur after chemotherapy are almost resistan
t to drug
• So genetic evolution and selection explains the propertie
s of cancers