Neoplasia 6-3-2011

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