NEOPL ASIA
(2)
LECTURE BY
D R . A I S H A K H AT O O N
A S S I S TA N T P R O F E S S O R
D E P T. O F PAT H O L O G Y, F V S . U A F
2
ETIOLOGY OF
NEOPLASIA
LEARNING OBJECTIVES
• Define neoplasia and understand its etiology.
• Identify genetic and environmental causes of neoplasia.
• Explain the role of key genes and molecular pathways.
• Recognize the importance of multistep carcinogenesis
CAUSES OF NEOPLASIA
• Etiology involves both intrinsic (genetic) and extrinsic
(environmental) factors
GENETIC FACTORS
1.Inherited Mutations:
BRCA1/2 (breast/ovarian cancer), APC (colorectal cancer)
2.Somatic Mutations:
Oncogenes (e.g., RAS, MYC) and tumor suppressors (e.g., TP53, RB1)
3.Epigenetic Changes:
DNA hypermethylation silencing repair genes (e.g., MGMT in colorectal
cancer)
GENETIC FACTORS
• Classes of Regulatory Genes Involved:
• Proto-oncogenes (growth-promoting)
• Tumor suppressor genes (growth-inhibiting)
• Genes regulating apoptosis
• DNA repair genes
Environmental Causes
ENVIRONMENTAL CAUSES
Factor Examples Associated Cancers
Tobacco smoke, aflatoxins, Lung, liver,
Chemicals
asbestos mesothelioma
Radiation UV light, ionizing radiation Skin, leukemia, thyroid
Cervical, lymphoma,
Viruses HPV, EBV, HBV
liver
Lifestyle Obesity, alcohol, diet Colorectal, breast
MOLECULAR BASIS OF
CARCINOGENESIS
Accumulation of multiple mutations (multistep carcinogenesis)4.
• Hallmarks of cancer:
• Self-sufficiency in growth signals
• Insensitivity to growth-inhibitory signals
• Evasion of apoptosis
• Defects in DNA repair
• Limitless replication
• Sustained angiogenesis
• Invasion and metastasis
EXAMPLES OF CARCINOGENIC
AGENTS
• Chemical Carcinogens: Direct-acting, procarcinogens (require
metabolic activation)
• Radiation: UV (causes pyrimidine dimers), ionizing (causes DNA
breaks).
• Oncogenic Viruses: HPV (E6/E7 proteins inactivate p53/RB), EBV,
HBV
A large number of agents cause genetic damage
and neoplastic transformation of cells
Chemical carcinogens
Chemical carcinogenesis is a multistep process.
• Direct acting chemicals
• Indirect acting chemicals (procarcinogens): Require metabolic
conversion in vivo to produce ultimate carcinogens capable of
transforming cells.
• Complete carcinogens: Foreign chemical sufficient to cause
cancer, either as a direct or indirect
carcinogen
• Incomplete carcinogens: When it requires a tumor promoter
to cause cancer
① Initiation of carcinogenesis
Chemical carcinogens diverse in structure, fall into one of two
categories:
a. Direct-acting chemical carcinogens
b. Indirect-acting chemical carcinogens (procarcinogens)
Both are highly reactive electrophiles that can react
with nucleophilic (electron-rich) sites in the cells.
These reactions are non-enzymatic and result in the
formation of covalent adducts between the chemical
carcinogen and nucleotide in DNA.
② Promotion of carcinogenesis
Promoters induce tumors in initiated cells, but they are
non-tumorigenic by themselves.
Promoters render cells susceptible to additional
mutations by causing cellular proliferation.
CARCINOGEN
Metabolic activation
Excretion
Electrophilic
intermediates
INITIATION DNA repair
Normal cell
Binding to DNA:
Adduct formation
Cell death
Permanent DNA lesion:
Initiated cell
Cell proliferaion:
Altered differentiation
PROMOTION
PRENEOPLASTIC CLONE
Additional
Proliferation mutations
MALIGNANT NEOPLASM (Quoted from Robbins
《 Pathology Basis of disease》)
CHEMICAL CARCINOGENS
INITIATORS
• DIRECT • “PRO”CARCINOGENS
• β-Propiolactone • Polycyclic and Heterocyclic Aromatic
• Dimeth. sulfate Hydrocarbons
• Diepoxybutane • Aromatic Amines, Amides, Azo Dyes
• Direct acing alkylating agents • Natural Plant and Microbial Products
(cyclophosphamide, chlorambucil, – Aflatoxin B1→ Hepatomas
nitrosoureas, and others) – Griseofulvin→ Antifungal
• Acylating Agents – Cycasin→ from cycads
– 1-Acetyl-imidazole – Safrole→ from sassafras
– Dimethylcarbamyl chloride – Betel nuts→ Oral SCC
CHEMICAL CARCINOGENS
PROMOTORS
• HORMONES
• BILE SALTS
• PHORBOL ESTERS (TPA), activate kinase C
• PHENOLS
• DRUGS, many
“Initiated” cells respond and proliferate
FASTER to promotors than normal cells
RADIATION CARCINOGENESIS
① UV light is clearly implicated in causation of skin cancers
Ionizing radiations (x rays), atomic bomb have produced a
variety of forms of malignant neoplastic, especially in leukemia
lymphoma, thyroid cancers
Squamous cell carcinoma in animals due to long exposure to sun
Some breeds of cattle like Hereford Cattle more susceptible to UV
light
Certain plastics when implanted in tissues induces sarcomas
POSSIBLE MECHANISM OF ACTION
Radiation may inhibited cell division, inactive enzymes, induce
mutations.
• Excite local water present in the tissues and lead to formation of
free radicals which then cause DNA damage
• Nucleoproteins are damaged by radiation, the breaks occur at
disulfide bonds.
VIRAL CARCINOGENESIS
① RNA oncogenic viruses
② DNA oncogenic viruses
① RNA oncogenic viruses
– Which containing viral oncogene (src, abl, myb) may directly transform human
oncogenes
– Viruses an enzyme reverse transcriptase by which they synthesize a DNA
copy of their RNA genome
– This DNA copy of their genome is inserted into the host genome
Examples: Retroviruses
② DNA oncogenic viruses
– Transforming DNA viruses form stable association with the host
cell genome and are important for cell transformation.
– Either undergoes proliferation inside the host cell with eventual disruption of
the cell or the virus transform the cells but not kill the cell
– Oncogenic DNA viruses contain oncogenes
Examples: adenovirus, herpesvirus, papovavirus and poxvirus.
Summary
•Neoplasia: Abnormal, uncontrolled cell growth forming tumors
Causes of neoplasia:
➢Genetic factors: Mutations in oncogenes, tumor suppressor genes (e.g., TP53, RAS),
and DNA repair genes contribute to tumor initiation and progression.
➢Environmental factors: Exposure to carcinogens such as tobacco smoke, radiation,
certain viruses (HPV, EBV), and chronic inflammation increases cancer risk.
➢Multistep carcinogenesis: Neoplasia develops through accumulation of multiple
genetic and epigenetic alterations over time.
