1. Benign Versus Malignant Tumors
Benign: Excessive proliferation; single mass
Malignant: Cancer; invade surrounding tissue
Classifications: carcinomas, sarcomas, others

2. Tumor Progression Derived from single abnormal cell Somatic mutations
Accumulation of multiple mutations in lineage
Evolutionary process

3. Evolution Of Tumor Natural selection
Cell acquiring further mutation that enhances proliferation dominates tumor
Heterogeneity reflects continuing evolution

4. Stages Of Progression

5. 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

6. Warburg Effect Import vastly more glucose
Small fraction for oxidative phosphorylation
Building blocks for macromolecules

7. Metastasis
Invade neighboring tissue; proliferate in new location

8. Mutagens Most agents that cause cancer damage DNA
Chemical carcinogens, UV light, ionizing radiation, certain viruses

9. Epigenetic Changes
Heritable gene inactivation through histone modification and DNA methylation

10. Cancer Stem Cells
Small population of stem cells with indefinite self-renewal
Give rise to rapidly dividing cells with limited self-renewal

11. 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

12. Converting Proto-oncogenes To Oncogenes
Mutation results in hyperactive or overexpressed protein

13. 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

14. 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

15. Cancer Genomics About 300 cancer-critical genes
About 10 critical genetic or epigenetic changes in typical cancer
Several key pathways commonly disrupted

16. Mechanisms Of Retinoblastoma
Hereditary form: one inherited and one somatic mutation
Nonhereditary form: two somatic mutations

17. Alterations To Rb Pathway
Overactivation of cyclin D or Cdk4 or inactivation of p16 functionally equivalent to inactivation of Rb

18. Ras Proto-oncogene
Converted to oncogene by point mutation that abolishes GTPase activity
Downstream effects independent of growth factor stimulation

19. 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

20. Bcl-2 Proto-oncogene Blocks apoptosis
Overexpression can contribute to cancer
Discovered from chromosomal translocation in B-cell lymphoma

21. 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

22. Commonly Mutated Genes in Colorectal Cancer

23. Apc Tumor Suppressor Gene
Inherited mutation in familial adenomatous polyposis coli
Most colorectal tumors have somatic mutations
Functions in Wnt signaling pathway by inhibiting b-catenin

24. Sequence of Genetic Changes in Colorectal Tumor Progression
General sequence in which common mutations often occur

25. DNA Repair Genes Inactivation increases mutation rate
Increased cancer susceptibility from inheriting one inactive allele
Disease Defective Process
Hereditary nonpolyposis mismatch repair
colon cancer
Xeroderma pigmentosum nucleotide excision repair
(susceptibility to skin cancer)
BRCA-1, BRCA-2 mutations repair by homologous
(susceptibility to breast cancer) recombination

26. Chronic Myeloid Leukemia
Chromosomal translocation joining Bcr and Abl
Hyperactive Abl tyrosine kinase

27. Treatment By Bcr-Abl Inhibitor
Gleevec: small molecule inhibitor