benign: excessive proliferation; single mass malignant: cancer; invade surrounding tissue...

• Benign: Excessive proliferation; single mass• Malignant: Cancer; invade surrounding tissue• Classifications: carcinomas, sarcomas, others

Benign Versus Malignant Tumors

Tumor Progression

• Derived from single abnormal cell• Somatic mutations• Accumulation of multiple mutations in lineage• Evolutionary process

Evolution Of Tumor

• Natural selection• Cell acquiring further mutation

that enhances proliferation dominates tumor

• Heterogeneity reflects continuing evolution

Stages Of Progression

Properties of Cancer Cells

• Cell division• Failure to properly differentiate• Failure to undergo apoptosis• Defective checkpoint control• Genetic instability• Overcome replicative cell senescence• Cell growth, biosynthesis, Warburg effect • Metastasis

Warburg Effect

• Import vastly more glucose• Small fraction for oxidative

phosphorylation• Building blocks for

macromolecules

Metastasis

• Invade neighboring tissue; proliferate in new location

Mutagens

• Most agents that cause cancer damage DNA

• Chemical carcinogens, UV light, ionizing radiation, certain viruses

Epigenetic Changes

• Heritable gene inactivation through histone modification and DNA methylation

Cancer Stem Cells

• Small population of stem cells with indefinite self-renewal

• Give rise to rapidly dividing cells with limited self-renewal

Genes That Contribute To Cancer

• Proto-oncogenes: gain-of-function mutation in single allele drives tumor progression

• Tumor suppressor genes: loss-of-function mutations in both alleles drives tumor progression

Converting Proto-oncogenes To Oncogenes

• Mutation results in hyperactive or overexpressed protein

Inactivating Tumor Suppressor Genes

• Both alleles can undergo inactivating somatic mutations• Individual can inherit one inactive allele resulting in

increased susceptibility to cancer • Can be inactivated by epigenetic mechanisms

Normal Cellular Functions Of Cancer-Causing Genes

• Internal regulators of cell cycle progression and apoptosis

• Molecules involved in cell adhesion and movements

• Components of signaling pathways

Cancer Genomics

• About 300 cancer-critical genes• About 10 critical genetic or epigenetic

changes in typical cancer• Several key pathways commonly disrupted

Mechanisms Of Retinoblastoma

• Hereditary form: one inherited and one somatic mutation• Nonhereditary form: two somatic mutations

Alterations To Rb Pathway

• Overactivation of cyclin D or Cdk4 or inactivation of p16 functionally equivalent to inactivation of Rb

Ras Proto-oncogene

• Converted to oncogene by point mutation that abolishes GTPase activity

• Downstream effects independent of growth factor stimulation

p53 Tumor Suppressor Gene

• Functions in checkpoint pathway for DNA damage or other cell stresses

• Can either induce apoptosis or block cell division• Inactivation leads to further genetic alterations

Bcl-2 Proto-oncogene

• Blocks apoptosis• Overexpression can contribute to cancer• Discovered from chromosomal translocation

in B-cell lymphoma

Genes Contributing to Metastasis

• Changes that promote metastasis largely unknown

• Rho-family GTPases: proto-oncogene, actin-based cell motility

• E-cadherin: tumor suppressor, cell adhesion at adherens junctions

Commonly Mutated Genes in Colorectal Cancer

Apc Tumor Suppressor Gene

• Inherited mutation in familial adenomatous polyposis coli

• Most colorectal tumors have somatic mutations

• Functions in Wnt signaling pathway by inhibiting -catenin

Sequence of Genetic Changes in Colorectal Tumor Progression

• General sequence in which common mutations often occur

DNA Repair Genes• Inactivation increases mutation rate• Increased cancer susceptibility from inheriting one inactive

alleleDisease Defective ProcessHereditary nonpolyposis mismatch repaircolon cancer

Xeroderma pigmentosum nucleotide excision repair(susceptibility to skin cancer)

BRCA-1, BRCA-2 mutations repair by homologous(susceptibility to breast cancer) recombination

Chronic Myeloid Leukemia

• Chromosomal translocation joining Bcr and Abl• Hyperactive Abl tyrosine kinase

Treatment By Bcr-Abl Inhibitor

• Gleevec: small molecule inhibitor