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70 Cards in this Set
- Front
- Back
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X-linked isoenzyme markers as evidence of monoclonality of neoplasms
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Because the X of each cell is randomly inactivated, if the tumor was originally from a monoclonal population, then all the cells will have the same inactivated X. Which they do.
Path-RC-278 |
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Four classes of genes implicated in cancer
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‐ Growth promoting protooncogenes
‐ Growth inhibiting cancer suppressor genes ‐ Genes that regulate cell death/apoptosis ‐ DNA repair gene mutations Path-Neo3-ppt-5 |
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11 Essential alterations for
Malignant Tranformation |
• Self sufficiency in growth signals
• Insensitivity to growth‐inhibitory signals • Evasion of apoptosis • Defects in DNA repair • Limitless replicative potential • Sustained angiogenesis • Ability to invade and metastasize • (Escape from immunity and rejection) • One or more genes that regulate each of these traits mutated in every cancer • Pathways; specific genes differs • Conditioning defects: ‐ Lack of robustness of DNA repair ‐ Loss of protection apoptosis and normal senescence Path-Neo3-ppt-10 |
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Oncogenes
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• Activation of a single allele results produces self‐sufficiency in growth
Activation via • Mutation • Amplification – increased number of gene copies • Overexpression of gene product • Activation by translocation Path-Neo3-ppt-13 More on card doesn't seem revolutionary |
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Growth Factors which Produce Cancer
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Oncogenes amplified or overexpressed
PDGF-Beta from SIS gene [overexp]: glioblastoma FGF from HST gene [overexp]: gastric and Kaposi Sarcoma Others include: TGF-a, CSF-1 and HGF Path-Neo3-ppt-19 |
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PDGF-Beta
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an oncogene
product of SIS gene [//overexpression] produces glioblastoma Path-Neo3-ppt-19 |
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FGF
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an oncogene
product of HST gene [//overexpression] produces Kaposi sarcoma Path-Neo3-ppt-19 |
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Growth factor receptors
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always transmembrane with tyrosine kinase domain
Path-Neo3-ppt-20 |
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Growth Factor Receptors and Cancers
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Oncogenic receptors dimerize and activate without binding to the growth factor
May be overexpressed, amplified or product of point p mutation; gene re‐arrangements • Epidermal growth factor receptor family ‐ ERB B1 : product EGFR ‐ ERB B2 : product Her‐2 neu • FLT‐3 FMS‐like tyrosine kinase 3 ‐ leukemia • RET Neurotrophic growth factor receptor : endocrine tumors • KIT: gastrointestinal stromal tumors; leukemias Path-Neo3-ppt-20 |
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ERB B 1
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• EGFR (epidermal growth factor receptor)
• Overexpressed in some carcinomas • Mutated in some carcinomas of lung, head and neck • Therapies based on EGFR: ‐ Monoclonal antibody targeted at mutated EGFR ‐ Tyrosine kinase inhibitors Path-Neo3-ppt-24 |
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ERB B2
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aka Her-2 neu, an Oncogenic version of EGFR (Growth Factor Receptor Oncogenes)
• Amplified in ~25% of breast cancers • Correlates with poor prognosis; increased incidence of metastases and death • Routinely tested on all breast cancers ‐ Tumors positive for Her‐2 respond to monoclonal antibody Path-Neo3-ppt-25 |
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FLT‐3
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Oncogenic [FMS‐like tyrosine kinase 3 Amplified] Growth Factor Receptor involved in leukemia
Path-Neo3-ppt-24 |
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RET
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Oncogenic [Neurotrophic growth factor receptor with a Point Mutation] involved in endocrine tumors
Path-Neo3-ppt-24 |
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KIT
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Oncogenic Growth Factor Receptors [with a point mutation] casues GI stromal stumors and leukemia
Path-Neo3-ppt-24 |
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RAS
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Signal Transducing Protein
• Most common oncogene mutation, mutated in up to 20% of all human tumors • Frequent in adenocarcinomas: most pancreatic, colon carcinomas • Common in hematologic malignancies • RAS oncogene arises as point mutations esp. in response to chemical injury • Inactive RAS is bound to GDP • Growth Signal, GTP binds, transduction via RAS/RAF/MAP pathway • RAS inactivated by: ‐ intrinsic GTPase activity of normal RAS ‐ GAP (GTPase‐activating proteins) NF‐1 (a tumor suppressor) • Mutated RAS evades GAP; persistent signal transduction Path-Neo3-ppt-31 |
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cABL
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• Nonreceptor tyrosine kinase
• cABL activation by translocation: t(9; 22), fusion of ABL with BCR; results in persistent signal transduction, Self‐sufficiency in growth signals • Characteristic of chronic myelogenous leukemia (CML); some acute lymphoblastic leukemias • Effective treatment Imatinib Path-Neo3-ppt-36 |
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JAK2
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• JAK2 tyrosine kinase activated by point mutation in negative regulatory domain
• STAT, transcription factor, activated : Self‐sufficiency in growth signals: = proliferation of myeloid cells in bone marrow Path-Neo3-ppt-38 |
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Go check this slide out
Seriously do it |
Path-Neo3-ppt-41
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MYC
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Nuclear transcription factor
• Widely expressed in normal cells • Activates transcription by DNA binding • Competence gene expressed early in cell cycle; among other things: ‐ renders cells competent to receive final signals for mitosis • Oncogenic MYC is continuously expressed/overexpressed • Burkitt lymphoma (a B cell lymphoma) ‐ MYC constitutively activated by t(8:14) • Amplified in many cancers including lung; breast • N‐MYC amplified in neuroblastoma correlates with poor prognosis • L‐MYC amplified ‐ small cell ca. lung Path-Neo3-ppt-24 |
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How is oncogenic MYC detected?
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‐ Karyotype, FISH for translocation
‐ Karyotype/ FISH for double minutes; homogenous staining regions (HSR) on karyotypes. Path-Neo3-ppt-45 |
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Cell Cycle Prgoression
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Path-Neo3-ppt-50
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What oncogene cell cycle regulators are commonly dysfunctional in cancers?
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• Cyclin D and CDK4 abnormalities common in many cancers (G1-S checkpoint= point of no return, normally check for DNA damage)
• Cyclin D overexpression in carcinomas of several organs: breast, others • Cyclin D1 activated by translocation in one type of lymphoma • CDK4 gene amplification in glioblastomas, melanomas Path-Neo3-ppt-54 |
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Tumor Suppressor Genes
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Usually : loss of both alleles is involved in transformation
also involved in cell differentiation Path-Neo3-ppt-56 |
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Gate keeper genes
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regulate cell growth: brakes to cell proliferation
Path-Neo3-ppt-58 |
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Loss of Heterozygosity
3 prominent examples |
‐ RB: familial retinoblastomas
‐ WT1: Wilm’s tumor (nephroblastoma) ‐ VHL: von Hippel Lindau: clear cell renal carcinoma Path-Neo3-ppt-59 |
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CpG
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CpG islands are common in promoter regions of genes:
---inactivates 2nd X chromosome; ---genomic imprinting; ---stabilizes coding DNA sequences Hypermethylation of CpG islands Contributes to neoplasia via silencing tumor suppressor genes eg Rb, VHL, BRCA‐1; mismatch repair genes Path-Neo3-ppt-60 |
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Cell Cycle Inhibitors
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• Tumor suppressor genes
• CIP/WAF family: p21, p27, p57 ‐ Block actions of several cyclin/CDK complexes ‐ p21 induced by p53 ‐ p27 responds to TGF‐ß • INK4 family: p15; p16; p18; p19 ‐ p16INK4 binds to cyclin D‐CDK4 ‐‐ inhibitory to RB • CDKI (inhibitor) mutations are common; permissive for cell proliferation • Inhibitor p16 ‐ somatic inactivation by mutation /deletion in wide variety of carcinomas ‐ germ‐line mutations found in 20% of familial melanoma ‐ inactivated by hypermethylation in HPV related cancers: cervical cancer Path-Neo3-ppt-63 |
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Retinoblastoma gene
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• Gene product is a DNA binding protein found in every cell type
• Activated RB is a brake on advancement of G1‐‐> S checkpoint • Activated/inactivated by phosphorylation • Active= hypophosphorylated RB, inhibits transcription factor E2F • Inactive = hyperphosphorylated RB, releases E2F to transcribe S phase genes • Phosphate groups removed during M phase • Many oncogenic viruses act by neutralizing activities of RB • RB mutated/inactive in many tumors including retinoblastoma and osteosarcoma Path-Neo3-ppt-67 |
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Oncogenic viruses which neutralize RB
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- SV40 and polyomavirus
- Adenovirus EIA protein - Human papilloma virus (HPV) high risk (for malignancy) types‐ E7 protein Path-Neo3-ppt-70 |
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Inactivating RB
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• RB function abnormal/inactive by:
‐ RB mutation; RB deletion ‐ Gene silencing by hypermethylation ‐ Cyclin D, CDK4 activation ‐ p16INK4a inactivation Path-Neo3-ppt-71 |
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p53
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Very Important
Too big to make a card or think about at 2:37 in the morning. Sorry kiddo. Go back and look it up. Path-Neo3-ppt-75 |
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LiFraumeni Syndrome
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• Germ line heterozygous p53 mutation confers 25x risk of cancer by age 50
• Many different types of cancers occur: ‐ breast ‐ sarcoma, brain tumors, leukemia and ‐ adrenal cortical Path-Neo3-ppt-81 |
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Senescence
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loss of cell’s ability to complete mitosis due to irreversible arrest of cell cycle
• Protective response in cells in which oncogenes have been activated • Characteristic feature of benign tumors • Cells remain viable • Major critical arbiters : p53 and Rb Path-Neo3-ppt-84 |
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APC
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Tumor suppressor genes
Adenomatous polyposis coli‐ß catenin pathway • APC degrades ß catenin • ß‐catenin binds to E‐cadherin‐ maintains cell to cell cohesion/adhesiveness • ß‐catenin part of WNT signaling pathway translocates to nucleus as transcription activator • Homozygous loss occurs in precancerous colon polyps; colon cancers; hepatic cancers • Mutated in familial adenomatous polyposis syndrome • APC mutations in 70‐80% of sporadic colon cancers • ß‐catenin mutations occur in some of the colon cancers that lack APC mutations • APC chromsome 5q21 Path-Neo3-ppt-88 |
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Cadherins
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Tumor suppressor gene
• Loss favors malignant phenotype ‐ disaggregated cells invade, metastasize • Common in many visceral cancers and breast cancer • Germline mutation of E cadherin predisposes for gastric cancer Path-Neo3-ppt-93 |
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Transforming Growth Factor ß
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Tumor suppressor gene
• Stimulates CDKI’s p21 and p15 • Inhibits transcription of CDKs, cyclins, MYC • Signaling pathway SMAD • TGF‐ß mutations/signaling pathway mutations occur in pancreatic cancers and colon and gastric cancers Path-Neo3-ppt-93 |
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NF‐1 gene
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Tumor Suppressor Gene
• Neurofibromatosis type I occurs with one germline mutant allele for NF‐1 gene • Codes for neurofibromin ‐ GTPase activating protein (GAP) ‐‐ Inactivates RAS • Loss of 2 alleles leads to continuously active RAS • Sporadic and familial neurofibromas; neurofibrosarcoma and other neoplasms Path-Neo3-ppt-94 |
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NF‐2 gene
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Tumor Suppressor Gene
• Neurofibromatosis II similar to but less common than type I; germline mutation ‐ bilateral acoustic neuromas • Sporadic mutations / inactivation associated • with schwannomas; meningiomas • Gene product: merlin – neurofibromin 2 ‐ homologous to RBC cytoskeletal protein ‐ cell‐cell junctions and signaling functions ‐ mechanism of carcinogenesis is unknown Path-Neo3-ppt-95 |
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VHL gene
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Tumor Suppressor Gene
• Von Hippel Lindau (VHL) syndrome due to germline mutation of VHL gene ‐ Hereditary renal cell carcinoma, pheochromocytoma (adrenal medulla tumor); hemangioblastomas of CNS • Both VHL gene alleles inactive (mutation; promoter hypermethylation) in the most common form of sporadic renal cell carcinoma • Hypoxia inducible factor, HIFa bound by VHL for ubiquitination; degradation in presence of oxygen • HIFa regulates VEGF, PDGF: ‐ angiogenesis is increased when VHL is lacking (mutated) VHL has additional tumor suppressor activities Path-Neo3-ppt-98 |
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PTEN
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Tumor Suppressor Gene
• Phosphate and tensin homologue • Potent tumor suppressor gene • Second most frequent gene mutation in cancers • Dephosphorylates proteins and lipids • Impacts multiple signaling pathways, including p53 and RAS • Brake on pro‐survival/pro‐growth pathway PI3K/AKT • Cowden syndrome: familial mutation benign skin appendage hamartomas; increased risk for cancers, esp. beast • Sporadic monoallelic loss: breast, colon, prostate, lung and brain tumors • Homozygous mutations: endometrial Path-Neo3-ppt-100 |
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WT‐1
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Tumor Suppressor Gene
• Chromosome 11 p13 • Activities based isoform and extent of association with other proteins • Tumor suppressor activity : growth arrest • Oncogenic activity; ‐ Transcription activator of genes involved in renal and gonadal development ‐ RNA processing ‐ Anti‐apoptotic activity • Homozygous inactivation in familial Wilm’s tumor: nephroblastoma, pediatric renal Ca. • Inactivation in 15% of sporadic Wilm’s • May be over expressed in Wilm’s tumor • Overexpressed in the most common adult malignancies Path-Neo3-ppt-105 |
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Tumor Suppressor Genes
Litany |
• E‐cadherin
• TGF‐ß; SMAD2 and SMAD4 • NF‐1; NF‐2 • APC/ß catenin • PTEN • RB • p53 • WT‐1 • p16INK4a • BRCA1; BRCA 2 Path-Neo3-ppt-107 |
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pro‐apoptotic signals,
anti-apoptotic signals |
‐ pro‐apoptotic signal: BAX, BAK
‐ anti‐apoptotic signal: BCL2; BCL‐XL ‐ balance regulated by BH3 only proteins BAD, BID, PUMA Path-Neo3-ppt-111 |
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Evasion of Apoptosis
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• Cancer cells may have reduced FAS (CD96); evade apoptosis
• Cancer cells may inhibit caspase 8 via FLIP • BCL‐2 overexpression ‐ characteristic of B‐cell follicular lymphoma, ‐ t(14:18) activates transcription of BCL‐2 ‐ lymphoma is indolent (slow growing) • P53 mutation: BAX not transcribed Path-Neo3-ppt-113 |
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BCL‐2 overexpression
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‐ characteristic of B‐cell follicular lymphoma,
‐ t(14:18) activates transcription of BCL‐2 ‐ lymphoma is indolent (slow growing) Path-Neo3-ppt-113 |
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Autophagy and Cancer
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• Impaired autophagy associated with cellular accumulation of toxic material
• Autophagy facilitation: PTEN; tuberous sclerosis proteins (TSC) • Autophagy inhibitors: Akt; Bcl‐2, mTOR Path-Neo3-ppt-114 |
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Hereditary nonpolyposis colon cancer
syndrome |
• Hereditary risk for colon and other cancers
• colon cancers occur in the cecum, right side; need not arise from polyps ‐ Inherited defect in one of two alleles for mismatch repair gene ‐ acquired defect of second allele predisposes for development of cancer • Mismatch repair genes: MLH‐1; MSH‐2 and others • Microsatellite instability can be detected, tandem repeats of up to 6 nucleotides • Sporadic mutations occur in 15% of all colon cancers Path-Neo4-ppt-120 |
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Xeroderma Pigmentosum
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Defective Nucleotide Excision Repair
• Increased risk of skin cancer with UV exposure • UV light causes cross linking of pyrimidines preventing normal DNA replication • Inherited defect of nucleotide excision repair (NER) process ‐ several different gene and protein mutations Path-Neo4-ppt-123 |
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Genes Involved in DNA Repair by Homologous Recombination
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• Genes involved: BRCA 1 and BRCA 2, ATM
• Inherited defects: hypersensitivity to DNA damage: Ataxia telangiectasia (ATM) • Sensitivity to DNA cross‐linking agents: Fanconi anemia • Predisposition to cancer and developmental defects Path-Neo4-ppt-126 |
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BRCA‐1 and BRCA‐2
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Genes Involved in DNA Repair by Homologous Recombination
• Mutations of one allele occur in familial breast ovarian cancer syndromes • Protein products regulate transcription • BRCA‐BRCA 1 regulates estrogen receptor activity; co‐activator of androgen receptor • Both involved in homologous recombination DNA repair • Mutations may occur in Fanconi anemia Path-Neo4-ppt-128 |
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Short Telomere
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• In somatic cells, Telomeres shorten with each division
• p53 dependent checkpoints activated by short telomere‐‐> proliferative arrest (senescence) or apoptosis Path-Neo4-ppt-131 |
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Telomerase
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Activated in 90% of cancer cells: provides limitless replicative potential
(Not normally present in somatic cells) Path-Neo4-ppt-132 |
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Development of Sustained Angiogenesis
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• Tumors cannot grow beyond 1‐2 mm in diameter or thickness unless vascularized
• Neovascularization= new blood vessel formation ‐ provides nutrients, growth factors ‐ necessary for metastatic spread • Pro‐ and antiangiogenesis factors are produced by tumor; its matrix and inflammatory cells • Angiogenic switch occurs when proangiogenesis factors predominate Path-Neo4-ppt-136 |
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Mechanisms of Tumor Angiogenesis
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• Two pathways
‐ recruitment of endothelial cell precursors ‐ sprouting of of existing capillaries • Tumor vessels are tortuous, irregular and leaky (due to increased VEGF) and grow continuously • Vasculogenic mimicry: vessel like structures lined by tumor cells Path-Neo4-ppt-137 |
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Proangiogenic Factors
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• VEGF (vascular endothelial growth factor)
‐Transcription controlled by ‐‐hypoxia‐ inducing factor HIF‐1a ‐‐RAS‐MAP; MYC ‐ Increases ligands that activate Notch pathway • Basic fibroblastic growth factor (bFGF) released by proteases from ECM • Inhibitor of VEGF is used as cancer therapy: Path-Neo4-ppt-139 |
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Antiangiogenesis Facotirs
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produced or induced by tumor cells
• Thrombospondin‐1: induced by p53 • Agents produced in response to tumor by proteolytic cleavage of ECM (collagen, plasminogen, tranthyretin) ‐ angiostatin ‐ endostatin ‐ vasculostatin Path-Neo4-ppt-140 |
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Ability to Invade and Metastasize
Invasion of Extracellular Matrix |
• Detachment of tumor cells from one another (dissociation)
---Loss of E‐Cadherins ---Reduced catenin protein (link with cytoskeleton) • Degradation of ECM • Attachment to novel ECM components • Migration of tumor cells Path-Neo4-ppt-148 |
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Tumor Degredation of the ECM
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• Matrix metalloproteinases eg type IV collagenase (MMP9)
• Cathepsin D • Urokinase plaminogen activator • Degradation remodels and releases growth factors, stimulate VEGF; chemotaxis • Ameboid migration occurs Path-Neo4-ppt-151 |
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Invasion of Extracellular Matrix
Attachment and Migration |
• Increase in and loss of polarity of laminin and fibronectin receptors
• Locomotion via attachment to matrix (eg fibronetin); contraction of cells • Autocrine motility factor, chemotactic factors from ECM • Facilitated by proteases secreted by tumor and associated host cells (macrophages leukocytes) • Invadopodia: cell projections containing actin, integrins; MMPs, other enzmes • Neoplastic cells may assume mesenchymal phenotype to facilitate invasion ‐ epithelial‐mesenchymal transition • Stromal cells altered in response to tumor: co‐opted to support successful cancer Path-Neo4-ppt-156 |
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Intravasation
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vascular invasion by cancer
cells Path-Neo4-ppt-158 |
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Mechanisms of Metastasis
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• Adhesion to endothelium via adhesion molecule , CD44
• Extravasation: grow out through wall of vessel • Induction of angiogenesis (neovascularization) at new site • Growth in metastatic location Path-Neo4-ppt-161 |
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Preferred Metastatic sites
Prostate Bronchogenic Neuroblastomas Breast |
• Predictable for each tumor type
Prostate to lumbar vertebrae Bronchogenic carcinoma to adrenals, brain Neuroblastomas to liver, bone Breast: bone, liver, lung • Natural drainage explains some, not all sites Path-Neo4-ppt-163 |
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Homing
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Metastatic site tropism
• Endothelial cells of various organs express differing ligands for adhesion molecules • Chemokines of target tissues ‐ Cancer cells express specific chemokine receptor • Target organs may liberate chemoattractants: IGFs I, II • Target tissue may be nonpermissive: skeletal muscle; spleen, heart Path-Neo4-ppt-164 |
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Breast Cell Homing
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CXCR4 and CCR7 chemokine receptors
Ligands: CCL21 and CXCL12 only expressed in bone, liver, lungs Path-Neo4-ppt-165 |
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Detecting Metastases
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Circulating Cells Detectible via PCR
Path-Neo4-ppt-166 |
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Metastatic Dormance
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years/decades of survival of
micrometastases w/o clinical disease Path-Neo4-ppt-166 |
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Stromal Microenvironment in Cancer
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• Cross‐talk between ECM and tumor cells
provides paracrine growth signals • Inflammatory cells, Fibroblasts; may drive genetic changes in the tumor Path-Neo4-ppt-168 |
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Warburg Effect
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• “Eighth hallmark of cancer”
• Metabolism shifts to aerobic glycolysis • Advantage in hypoxic microenvironment • Mutations in many genes shown to shift metabolism ( PTEN; RAS; p53; MYC) • Metabolic shift increases supply of building blocks for cell division • Glucose hunger allows visualization by PET scanning ‐ 18F‐fluordeoxyglucose preferentially taken up by cancer cells, dividing cells, and CNS Path-Neo4-ppt-171 |
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PET scans and cancer
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• Metabolism shifts to aerobic glycolysis
• Glucose hunger allows visualization by PET scanning ‐ 18F‐fluordeoxyglucose preferentially taken up by cancer cells, dividing cells, and CNS Path-Neo4-ppt-173 |
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Molecular, Multistep Basis of
Carcinogenesis |
• Each cancer results from accumulation of multiple mutations
• To date, experiments show that no single mutation can fully transform a cell • Mutations appear to be incremental over time • Mutations associated with phenotypic changes [specific pathway for colon cancer, but that's not directly in objectives] Path-Neo4-ppt-176 |
