Hallmarks of CancerSix fundamental changes • Self sufficiency in growth factors • Insensitivity to growth-inhibitory signals • Evasion of apoptosis • Limitless replicative potential • Sustained angiogenesis • Ability to invade and metastasize
Tumor Suppressor Genes • A class of genes that normally suppress cell proliferation. Examples are p53 and Rb.
Tumor Suppressor Genes • Antigrowth signals can prevent cell proliferation by 2 mechanism: • 1-Cause the dividing cell go to Go phase • 2-The cell enter post-mitotic differentiated pool & lose replicative potential • The molecular level of antigrowth signals exert their effects on G1-S checkpoint of the cell cycle, controlled by Rb gene
Insensitivity to growth-inhibitory signals • Mutations that inactivate the tumor suppressor gene products can release cells from growth suppression and lead to hyper proliferation.
Tumor Suppressor Genes • In 1974 Knudson proposed tow- hits hypothesis • Both alleles of the tumor suppressor gene must be inactivated by mutation for hyperproliferation to occur. • Cell become malignant if it homozygous for the mutant gene Recessive cancer gene
Tumor Suppressor GenesRetinoblastoma Gene • RB gene13q14--- 1st TSG discovered • Present in every somatic cell in active(hypoph.) & inactive (hyperphosphorelated )form • Act as a brake prevent cell from moving from G1S • When GF stimulate cell, The cyclin D,E &CDK-phosphorelation of RBinactivation-release the brake.
Tumor Suppressor GenesRetinoblastoma Gene • 60% of retinoblastoma (Rb) are sporadic • 40% are familial, an autosomal dominant trait The 2 alleles on chromosome 13q14 must be inactivated
Tumor Suppressor Genes • Heterozygous-----one Rb gene is not mutant no cancer) • Homozygous------two Rb genes are mutant =cancer Loss of hrterozygosity of normal Rb gene
TP53 • Seen in > 70 % of human cancers • Both alleles has to be mutated • Usually mutation is aquired/ Viruses as HepB,EBV,HPV • Can be inherited (one allel is mutated) as Li Fraumeni syndrome (25 fold increase risk of ca by age 50) Ataxia telangiectasia-> can not repair x-ray caused DNA damage, ATM protein (damage sensor) is mutated so inactivate TP53 ( TP53 is normal)
APC Gene • APC gene loss lead to tumor development, both copies must be lost. • Seen in70-80% of sporadic colon ca • APC may be normal but B catenin mutated • Inherited mutation of one allele will develop 100-1000 of adenomatous polyps in the colon by the age of 10 or 20ys. One or more polyps will develop colon ca by the age of 40ys (Familial Polyposis coli) • APC mutation lead to adenoma and more mutation are needed for ca to develop