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Neoplasia
Dr Omar Chughtai
Cancer
• Uncontrolled growth of abnormal cells
The Study of Cancer
• Research:– Pathologists– Molecular Biologists and Geneticists
• Diagnose: – Pathologists– Radiologists
• Treat: – Oncologists– Surgeons
Nomenclature
• Neoplasm: new growth• Tumor: swelling caused by inflammation;
now almost always used to refer to neoplastic masses
Nomenclature
Metaplasia Dysplasia
Characteristics of Neoplasms
• Differentiation and Anaplasia• Rate of Growth• Invasion of Surrounding Tissue• Metastatic Potential
Differentiation and Anaplasia
• Differentiation: How similar tumor cells are to normal cells – Benign Tumors: Well-differentiated–Malignant Tumors: Range of differentiation
• Anaplasia: The lack of differentiation
Differentiation and Anaplasia
• Pleomorphism: – Variable cell size / shape
Differentiation and Anaplasia
• Abnormal Nuclear Morphology: – Variable nuclear
size / shape– dark
(hyperchromatic)– prominent nucleoli– clumped
chromatin
Differentiation and Anaplasia
• Mitoses: Increased in number, abnormal in shape
Differentiation and Anaplasia
• Loss of Polarity: No longer arranged neatly
Differentiation and Anaplasia
• Tumor Giant Cells:
Differentiation and Anaplasia
• Tumor Necrosis:
Rate of Growth
• Tumors are clonal
Rate of Growth
• Cell Proliferation: – Doubling Time is same as normal tissue or even
longer
• Growth Fraction: – Very high initially– Decreases as tumor size grows
• Cell Loss: – Apoptosis, Lack of nutrients, Necrosis
Rate of Growth
• Fast Growing Tumors have high cell turnover– High cell proliferation– High cell loss– Susceptible to
chemotherapy
Rate of Growth
• Slow Growing Tumors– Low cell proliferation– Low cell loss– Resistant to
chemotherapy
Local Invasion
• Benign Tumors: – Discrete, well-circumscribed mass– Don’t infiltrate surrounding tissue– Fibrous capsule
Local Invasion
• Malignant Tumors: – Poorly demarcated– Infiltrate surrounding tissue– No capsule
Metastasis
• Tumor implants discontinuous from the primary tumor
Metastasis – Peritoneal Cavity
Metastasis – Hepatic Metastasis
Metastasis – Lymph Node
Nomenclature
BENIGN• Relatively harmless• Will remain localized• Local surgical removal
• Epithelial: – Adenoma– Papilloma
• Mesenchymal– Fibroma– Leiomyoma
MALIGNANT• Harmful• Potential to spread widely• Surgical removal is not
enough• Epithelial: carcinoma
– Adenocarcinoma– Squamous cell carcinoma
• Mesenchymal: sarcoma– Fibrosarcoma– Leiomyosarcoma
Epidemiology
• Second most common cause of death • In the United States, one in five deaths is due
to cancer• In Pakistan, . . . .
Most Common Cancers
Men1. Prostate2. Lung3. Colorectal
Women1. Breast2. Lung 3. Colorectal
Cancer Mortality Trends
• Decreased deaths in men from– Ca Lung: Decreased smoking– Prostate: PSA screening– Ca Colon: Colonoscopy screening
• Decreased deaths in women from – Ca Breast: Self exam, Mammography– Ca Cervix: Pap Smear
Cancer Mortality Trends
• Increased deaths in men and women from – Hepatocellular Ca: Hepatitis C
• Increased deaths in women: – Ca Lung: Smoking
Cancer Incidence
Cancer Mortality - Men
Cancer Mortality - Women
Geography and Environment
• Ca Stomach deaths are 7-8 times higher in Japan than in the US
• Ca Lung deaths are higher in the US than in Japan
Geography and Environment
Obesity and Cancer
Age and Cancer
Genetic Predisposition to Cancer
• Cancers are caused by genetic mutations– Sporadic– Inherited
Inherited Cancer Syndromes
• Person inherits one autosomal dominant mutant gene
• Carriers of the mutated gene have a significantly increased risk of developing cancer
• Familial Adenomatous Polyposis• Retinoblastoma
Defective DNA Repair
• Autosomal recessive• Cells have decreased ability to recover from
DNA damage• Xeroderma pigmentosum• Ataxia-Telangiectasia
Familial Cancers
• Clustering of certain cancers in families• Early age at onset• Two or more first-degree relatives with the
same cancer• Siblings: 2-3 X risk of cancer• Multiple / Bilateral tumors• Multiple low-penetrance genes
Precancerous Conditions
Molecular Basis of Cancer
• Nonlethal Genetic Damage
• Clonal Expansion of Mutated Cell
• Accumulation of Mutations
Nonlethal Genetic Damage
• Proto-oncogenes• Tumor Suppressor Genes• Genes that regulate Apoptosis• Genes involved in DNA repair
Tumor Progression
Accumulation of Mutations
Growth Factors
• Normal: Paracrine stimulation• Cancer cells: Synthesize the same growth
factors to which they are responsive (Autocrine loop)
Factor Gene Mode Tumor
PDGF-beta PDGFB Overexpressed Astrocytoma
TGF-alfa TGFA Overexpressed Sarcomas
Growth Factor Receptors
• Normal: Receptors are transiently activated• Mutated: Constitutive activation without the
need for Growth Factor binding!
Factor Gene Mode Tumor
PDGF Receptor PDGFRB Overexpressed Astrocytoma
EGF Receptor ERBB1 (EGFR) Overexpressed Sq Cell Ca Lung
ERBB2 Overexpressed Breast Ca
Stem Cell (Steel) Factor Receptor KIT Point Mutation Gastro-Intestinal
Stromal Tumor
Signal Transducing Proteins
• Located on inner surface of plasma membrane• Receive signals from Growth Factor Receptor• Transmit signals to the cell nucleus• Two most important members of this group: – RAS– ABL
RAS
• Most commonly mutated oncogene• One of a family of small GTP/GDP binding
Proteins• Normal activation is transient• Upon Activation, GDP is replaced by GTP• GTP is hydrolyzed to GDP by intrinsic GTPase• GTPase activity is accelerated by GTPase-
Activating Proteins
RAS
• Point mutations interfere with hydrolysis of GTP
• RAS is trapped in the activated state
• Cell ends up in a state of continuous proliferation
BCR-ABL Translocation
BCR-ABL Translocation
• ABL proto-oncogene:– Limited tyrosine kinase activity– Localizes to nucleus and promotes apoptosis in
cells with DNA damage
• BCR-ABL Hybrid Protein:– Much higher, uncontrolled tyrosine kinase activity– Can’t move into nucleus, thus can’t cause
apoptosis in cells with damaged DNA– Chronic Myeloid Leukemia
Signal Transducing Proteins
Factor Gene Mode Tumor
GTP Binding KRAS Point mutation Colon, Pancreas, Lung tumors
HRAS Point Mutation Bladder and Kidney tumors
NRAS Point Mutation Melanoma
Non-Receptor Tyrosine Kinase ABL Translocation Chronic Myeloid
Leukemia
The Cell Cycle
Transcription Factors
• MYC proto-oncogene: – Induced rapidly upon signal to divide– Activate CDK’s– Inhibits CDKI’s– Levels decline to baseline when cell cycle begins
Transcription Factors
• Mutated MYC oncogene: – Persistent expression /
overexpression– Leading to sustained
proliferation
Transcription Factors
Factor Gene Mode TumorTranscription Activators C-MYC Translocation Burkitt’s
LymphomaN-MYC Amplification Neuroblastoma
L-MYC Amplification Small Cell Ca Lung
Cell Cycle Regulators
• Cyclins D, E, A and B appear sequentially and bind to various CDK’s
• Cyclin-CDK complexes drive the cell through the cel cycle
• CDKI’s exert negative control over the cell cycle
Cell Cycle Regulators
Factor Gene Mode TumorCell Cycle Regulators Cyclin D Translocation Mantle Cell
LymphomaCyclin E Overexpression Ca Breast
Cyclin-Dependent Kinases CDK4 Amplification
Point MutationAstrocytoma Melanoma
CDK Inhibitors CDKN2A Deletion Ca Pancreas
Summary
• Cancer Progression• Oncogenes• Growth Factor• GF Receptors• Signal Transducing Proteins• Transcription Factors• Cell Cycle Regulators