• Genetic disease due to rapid uncontrolled proliferation of cells within tissues of eukaryotes
• Most develop due to mutations in somatic cells
• Mutations create oncogenes and inactive tumor suppressing genes
• Determining specific oncogene and tumor suppressor gene mutations help in diagnosis of cancer type
• Multiple mutations lead to formation of neoplasia (tumors)

Types of tumors:
    (1)  Benign: Do not spread away from primary tumor
    (2)  Malignant:

• Spreads away from primary tumor
• Spreads via
  
• the blood stream or lymphatic ducts,
• cells lodge in the nearest narrow tube,
• usually where there are capillaries, and tumors grow. 
• Spreads by crossing body cavities in fluids,
• this type of spread is seen in abdomen, thorax,
• and brain that is called metastasis spread.

Tumors develop due to mutations in:

• Oncogenes
• Tumor suppressor genes

• 100 different types identified
• Normal counterparts - Proto-onocogenes
• a class of proteins active only when proper regulatory signals activate them
• What happens in oncogene mutations?
  
• Activity of mutant oncoprotein becomes uncoupled from normal regulatory pathway
• Leads to continuous unregulated expression
• Categorized according to uncoupling of regulatory function
• Gain of Function
  
• positive control of cell cycle
• negative control of apoptosis

• Base-pair substitution (gly to val) at amino acid 12
• Creates oncoprotein  in human bladder cancer
• What Happens?
• Oncoprotein always binds GTP even without phosphorylation of Ras
• Ras oncoprotein constantly signaling cell proliferation

(2)  Loss of Protein Domains

 Deletion of parts of normal protein can also produce an oncoprotein

 Ex.: v-erbB oncogene (found in erythroblastosis tumor virus infecting birds)

• Encodes a mutated RTK Þ EGFR (Epidermal Growth Factor Receptor)
• Recall- RTK (receptor tyrosine kinases):
• Receptor/ligand complex that requires dimerization to activate signaling
• The cytoplasmic domain is activated- phosphorylates tyrosine residues on target protein
• Autophosphorylation initiates signal transduction cascade
• Modification of transcriptional activators and repressors

• This lacks the extracellular binding domain & some regulatory parts of cytoplasmic domain
• Oncoprotein is able to dimerize in the absence of ligand (EGF)
• Constitutive EGFR dimer is always autophosphorylated
• Continuously initiates a signal transduction cascade

 (3)  Gene Fusions

 Causes the most remarkable type of structural alteration to a protein

 Classic Ex.: Philadelphia chromosome

•  Diagnostic feature of Chronic Myelogenous Leukemia (CML)
• Translocation between chromosomes 9 and 22
• Break points of translocation among CML patients are very similar
• Cause the fusion of bcr1 and abl
• The abl proto-oncogene encodes a cytoplasmic tyrosine-specific protein kinase
• The Bcr1-Abl oncoprotein has permanent protein kinase activity

 Some oncogenes cause Misexpression :

• When the oncoprotein and normal protein have identical structure
• Protein is expressed in cell types where it is normally absent
• Ex.: B-cell oncogene translocations (diagnostic of B-lymphocyte tumors)
• No protein fusion
• Causes a gene (near a break point) to be turned on in the wrong tissue
  

• Ex.: Follicular lymphoma

• Translocation between chromosomes 14 and 18
• Enhancer from an immunoglobulin gene is fused with bcl2 (negative regulator of apoptosis)
• Causes large amounts of Bcl2 to be expressed in B lymphocytes
• Apoptosis blocked, mutations accumulate over long cell life (promote proliferation)

• Genes that slow down cell division, repair DNA, tell cells when to die
• Nonfunctioning genes cause cells to grow out of control that leads to cancer
• Genes can be inherited or acquired
• Cause cancer when they are inactive

Functions

• Genes that control cell division
• There are two copies of every gene; if one copy is mutated and one is normal – no cancer develops
• Both mutated; loss of heterozygosity – cancer develops

• Genes that control cell death
• p53 genes destroy cells when the DNA is badly damaged

• Genes that repair DNA
• DNA proofreading genes; malfunction – DNA is mutated and can lead to cancer

• Indirect Effects
• Inherited tumor phenotype
• p53 tumor suppressor gene

Indirect effects:

• Retinoblastoma – codes for mutated Rb gene protein
• Sporadic retinoblastoma is most common

• Mutation in the retina is not inherited
• Multiple tumors in one eye
• rb mutation(s) inactivate the Rb gene
• Cancer develops by chance during developmental stages

• Inherited retinoblastoma (hereditary binocular retinoblastoma, HBR)
• Tumors in both eyes

Why does the absence of RB gene promote tumor growth?

• Back to cell cycle!
• Rb binds to E2F, preventing transcription of genes for S phase
• Inactive Rb, can’t bind E2F so genes are transcribed
• Continuous growth w/out Rb gene!!

• Recessive tumor-promoting mutation
• 50% of tumors lack functional p53 gene
• p53
• Transcriptional regulator
• Activated by DNA damage
• Can “stall” the cell cycle or induce apoptosis
• W/out p53, apoptosis is not activated and cell cycle continues indefinitely

The Complexities of Cancer

• Mutations arise from alterations in cell cycle or apoptosis
• Benign tumors can become malignant
• Malignant tumors evolve by successive mutations
• More work on tumors is needed

 
A Cure?

• Chronic myelogenous leukemia (CML)
• Overexpression of tyrosine kinase
• Gleevec successfully treats 90% of CML patients
• ST1571  inhibits tyrosine kinase
• Prevents phosphorylation of target proteins
• Inhibits cell proliferation in bcr-abl cell lines
• Long term effects unclear

 Conclusion