Hallmarks Of Cancer PDF

HALLMARKS OF CANCER, Selfsufficiency in growth signals Insensitivity to growth-inhibitory signals Esr’a Jameel Nsour, MD. Faculty of medicine Al-Balqa’ applied university E-mail: [email protected] 1 HALLMARKS OF CANCER • All cancers display eight fundamental changes in cell physiology: 1....

HALLMARKS OF CANCER, Selfsufficiency in growth signals Insensitivity to growth-inhibitory signals Esr’a Jameel Nsour, MD. Faculty of medicine Al-Balqa’ applied university E-mail: [email protected] 1 HALLMARKS OF CANCER • All cancers display eight fundamental changes in cell physiology: 1. Self-sufficiency in growth signals 2. Insensitivity to growth-inhibitory signals uncon t Growth 3. Altered cellular metabolism 4. Evasion of apoptosis 5. Limitless replicative potential (immortality) 6. Sustained angiogenesis 7. Invasion and metastasis 8. Evasion of immune surveillance 2 as g hyperplasin sifted controlled Self-sufficiency in growth signals • Proto-oncogenes: normal cellular genes whose products promote cell proliferation • Oncogenes: mutant or overexpressed versions of proto-oncogenes that function autonomously without a requirement for normal growth-promoting signals 3 • Oncoproteins (products of oncogenes) promote uncontrolled cell proliferation by several mechanisms: IE Growth factors genes mutations: Stimulus-independent expression of growth factor and its receptor, setting up an autocrine loop of cell proliferation (e.g., PDGF–PDGF receptor in brain tumors) Htidperivet to of Growth factor receptors genes mutations: • Amplification of epidermal growth factor (EGF) receptor family genes such e in breast cancer.. as HER2 • blocking the extracellular domain of this receptor with anti-HER2 antibodies… target therapy www.f EF.ie 4 to b chemotherapy Mutations in genes encoding signaling molecules (e.g RAS, ABL) : 00  RAS is the most commonly mutated oncogene in human Notsuppression cancers: • RAS is normally flips between wind resting GDP-bound state and active GTP bound state; • mutations block hydrolysis of GTP to GDP, leading to unchecked signaling – so uncontrolled cellular proliferation keepRAS a GDP: Guanosine diphosphate, GTP: Guanosine triphosphate 5 4 hi I  ABL is a proto-oncogene that have a tyrosine kinase activity • Translocation (9, 22) will result to fusion of portions of the ABL tyrosine kinase gene (on chromosome 9) and the BCR protein gene (on chromosome 22) • This will create a BCR-ABL fusion gene which will encode an uncontrolled active tyrosine kinase activity ---- so uncontrolled proliferation • Seen in chronic myeloid leukemia (CML) • BCR-ABL kinase inhibitor called (imatinib mesylate (Gleevec)) is a drug to treat CML (target therapy) G CML the target 6 Overproduction or unregulated activity of transcription factors: • Nuclear Transcription Factors: • Results from uncontrolled activation of oncoproteins (e.g RAS, ABL) • So overexpression of growth-promoting genes (e.g MYC gene). • MYC will activate the transcription of other growth-promoting genes (e.g cyclindependent kinases (CDKs) e.g • Dysregulation of MYC results from a (8;14) translocation seen in Burkitt lymphoma I II o 7 Transcriptionfactor overactivation Cyclins and Cyclin-Dependent Kinases: • Normally, “cyclins - cyclin dependent kinases (CDKs)” complex will stimulate the progression of cell division and so proliferation. • Normally, the “Cyclin-CDK” complex is inhibited by cyclin dependent kinase inhibitors (CDKIs). So • Gain-of-function mutations involving CDK4 or cyclin-D • Loss-of-function mutations involving (cyclin dependent kinase inhibitors) CDKIs. Will cause uncontrolled cell cycle progression and cancers e.g, Melanoma, brain, lung cancers 8 HALLMARKS OF CANCER • All cancers display eight fundamental changes in cell physiology: 1. Self-sufficiency in growth signals oncogense 2. Insensitivity to growth-inhibitory signals suppressor 3. Altered cellular metabolism 4. Evasion of apoptosis 5. Limitless replicative potential (immortality) 6. Sustained angiogenesis 7. Invasion and metastasis 8. Evasion of immune surveillance 9 Insensitivity to Growth Inhibitory Signals: Tumor Suppressor Genes • Whereas oncogenes encode proteins that promote cell growth, the products of tumor suppressor genes apply brakes to cell proliferation i Retinoblastoma gene (RB) TP53 gene product p53 Transforming Growth Factor-β Pathway (TGF-β PATHWAY) Contact inhibition APC-β-CATENIN PATHWAY 10 Retinoblastoma gene (RB): Governor of the e Cell Cycle RAS oncogene • RB, a key negative regulator of the cell cycle, is directly or indirectly inactivated in most human cancers • RB protein regulate the G1/S checkpoint, before DNA replication starts --- so it has an anti-proliferative effects • It is now accepted that loss of normal cell cycle control is necessary to malignant transformation and that at least one of the four key regulators of the cell cycle (p16, cyclin D, CDK4, RB) is mutated in most human cancers. IF 11 (RB).. Cont’d • In its active form, RB is hypophosphorylated binds to E2F transcription factors so prevents transcription of genes like cyclin E which is needed for DNA replication, and so the cells are arrested in G1. 0 5 12 (RB).. Cont’d • Growth factor signaling leads to cyclin D expression, activation of cyclin D–CDK4/6 complexes • This will cause inactivation of RB by phosphorylation, and thus release of E2F transcription factor… so release of Cyclin E -so uncontrolled DNA replication, and so Loss of cell cycle control 13 Inactive Always cancer (RB).. Cont’d Ressive • Like other tumor suppressor genes, both copies of RB must be dysfunctional for tumor development to occur. • Retinoblastoma tumor ( most common intraocular cancer in children) (sporadic type and familial type) • In cases of familial retinoblastoma, one defective copy of the RB gene is present in the germ line, so that only one additional somatic mutation is needed to completely eliminate RB function. RNAi • Many oncogenic DNA viruses, like HPV (human papilloma virus), F encode proteins (e.g., E7)t that bind RB and give a nonfunctioning RB… a this may cause cervical cancer in females.. e f 14 (RB).. Cont’d cells 58m Retinoblastoma tumor: • Sporadic or • Familial e 15 TP53: Guardian of the Genome • The p53-encoding tumor suppressor gene, TP53, is the most commonly mutated gene in human cancer. • The p53 protein is a transcription factor that prevents neoplastic transformation.By sensationthe DNA to RBgene sprite • In nonstressed, healthy cells, p53 has a short half-life (20 minutes) because of its association with MDM2( MDM2: a protein that targets anti p53 p53 for destruction). • In stressed cells (e.g DNA damage, anoxia and others): the p53 will be released from MDM2, So we have an activated p53 (increasing its half-life) Non deviding 16 TP53.. Cont’d It • Activated p53 will drive transcription of CDKN1A (p21) and so prevents RB phosphorylation (i.e keeping RB activated) , and so causing a G1-S block in the cell cycle … gives the cells “breathing time” to repair DNA damage mis • If DNA damage cannot be repaired, p53 induces cellular senescence (a form of permanent cellIII cycle arrest) or apoptosis tis gene • p53-induced apoptosis ,of cells with irreversible DNA damage, is the ultimate protective mechanism against neoplastic transformation 17 TP53.. Cont’d sessive • Of human tumors, 70% demonstrate biallelic mutations in TP53. • Li-Fraumeni syndrome: inherit one defective copy of TP53 in the germ line, such that only one additional mutation is required to lose normal p53 function so patients can develop a wide variety of tumors. • Oncogenic DNA viruses such as HPV, hepatitis B and others encode Itsgive a nonfunctioning p53… so proteins that bind to p53 and development of many tumors. 18 Transforming Growth Factor-β Pathway (TGFβ PATHWAY) ph • TGF-β has an anti-proliferative effect: • Normally; TGF-β bind to TGF-β receptors I and II… So activation of CDKIs (inhibitors) and suppression of MYC (growth factor) • Mutations in TGF-β receptors I and II will cause a decrease in the TGF-β function … so development of tumors (e.g colon, stomach, endometrium) 19 compesatory hyperplasia CONTACT INHIBITION was 3 9 6tissue • In the growth of non-transformed cells: cells stop proliferating once they form confluent monolayers because of interactions between transmembrane proteins called Cadherins: • (e.g E-cadherin (E for epithelial)) males give Antiprofitsighed Layercomplete • E-cadherin is lost in malignant cells --- so no contact growth inhibition (seen in lobular breast cancer) F Lesscohesivecells 20 APC-β-CATENIN PATHWAY RompxD G • The APC gene exerts anti-proliferative actions by regulating the destruction of the cytoplasmic protein β-catenin (β-catenin is a part of WNT growth signaling pathway). • With a loss of APC, β-catenin is not cytopia destroyed, and it will be translocated to the nucleus (instead of cytoplasmic location), where it acts as a growthpromoting transcription factor. e No proliferation proliferation proliferation 21 APC-β-CATENIN PATHWAY.. Cont’d • Germ line mutation in the APC gene… seen in familial adenomatous polyposis (FAP)syndrome. • In FAP syndrome: • Development of hundreds of colonic polyps at a young age and future development of colonic cancer in one or more of these polyps. 0 EF.it 22 BAD EXAMPLES SMOKERS 23