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79 Cards in this Set
- Front
- Back
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transformation of nL cells to neoplastic cells involves endo-/exogenous factors:
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1. chemical & physical agents
2. viruses 3. activation of ca promoting genes 4. inhibition of ca suppressing genes 5. genes involved in DNA repair & regulation of apoptosis |
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procarcinogen
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chemicals that are not carcinogenic unless activated or acted upon in some way such as by metabolism
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cocarcinogen
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not carcinogen, but enhances the effects of carcinogens when administered concomitantly
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initiator
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agents that alter genetic constitution of cells predisposing them to neoplastic transformation
ex. most mutagens |
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promotor
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agents that are not carcinogenic but enhance the effects of carcinogens when administered afterwards or concomitantly
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mutagen
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agents that can permanently alter the genetic constitution of a cell. Many but not all fnxn as initiators of transformation
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Ames test
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a screening test for mutagenicity involving the appearance of mutants in cultures of bacT (Salmonella sp.)
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epigenetics
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study of changes in genetic expression independent of changes in DNA sequence
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proto-oncogene
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nL genes that code for proteins involved in the control of cell growth and reproduction
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oncogene
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abnL gene that arises from the mutation of a proto-oncogene. They code for an altered version or excess quant. of growth control proteins
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tumor suppressor genes
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genes whose protein products suppress the development of ca
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angiogenic factor
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factor that promotes the development of blood vessels
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field cancerization
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since areas of tissue are often subjected to carcinogens, the entire area is at risk for the development of ca and accounts for the high incidence of second primary tumors in certain ca, esp squamous cell carcinomas. These second primary tumors are often a/w a lower rate of survival than the original tumor
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cigarette smoking
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smoke contains many carcinogens; causes carcinoma of lung, mouth, larynx and bladder
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chewing tobacco
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oral ca
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aniline dyes
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bladder ca
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alkylating agents
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acute leukemia
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smoked foods (nitrosamine)
nitrite (food preserver) barbequed or overcooked meats (benzopyrene) |
adenocarcinoma of the stomach
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alcohol
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carcinoma of mouth, pharynx, esophagus and liver
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asbestos
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still found in certain industries like mechanics who are doing brake work (mesothelioma, lung and laryngeal ca)
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plastic (polyvinyl chloride)
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angiosarcomas of the liver
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moldy foods (aflotoxins)
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liver ca (moldy peanuts)
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benzene
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acute leukemia
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arsenic
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lung and bladder ca (naturally in environment, water supply, etc)
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direct acting carcinogens
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do not require metabolic conversions, but act directly at site of application of portal of entry
-rare: benzyl chloride and nitrogen mustard |
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indirect acting carcinogens
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most chemical carcinogens require metabolic conversion from procarcinogen to carcinogen
ex. mucosa of bladder contains glucouronidase that converts beta-naphthlamine glucuronide -> carcinogen beta-naphthylamine |
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mouse skin studies
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initiation - application of carcinogen to skin not enough to cause ca, but cause changes in DNA
promotion - application of another substance (not carcinogen) enhances carcinogenicity of agent and tumor develops (phorbol esters) |
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rat liver studies
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initiation - same as above
promotion - altered cells do not exhibit autonomous growth, but remain dependent on presence of promoting agent progression - growth becomes autonomous & development of ca is independent of presence of carcinogen or promoter ca - capacity to invade & metastasize |
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non ionizing radiation
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UV, visible light, infrared, microwaves, RF waves, ELF waves do not have sufficient energy to cause ionization
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exception of non ionizing radiation
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UV - directly related to frequency of skin ca such as squamous/basal cell carcinoma and melanomas
-- induce dimer formation b/w neighboring thyamine pairs in DNA so DNA repair mechanisms minimize damage |
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ionizing radiation
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gamma rays, XR, high energy UV and some subatomic particles (alpha particles and protons) cause ionization and direct damage to DNA
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ex of ionizing radiation
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- ca in XR pioneers who did not know about damage
- inc. skin ca and leukemia in radiologist - lung ca in uranium miners - thyroid ca in pts receiving head & neck radiation - acute & chronic myeloid leukemia in atmoic bomb survivors - osteosarcoma in radium watch dial workers |
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FB carcinogenesis
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inert materials resulted in development of sarcomas in animals, but asbestos only one in humans
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mechanisms in development of ca from infxous agents
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1. induction of chronic inflammation
2. immune suppression 3. viral oncogenesis |
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ex of induction of chronic inflamm.
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1. hep B & C viruses and liver ca
2. liver flukes and liver ca 3. blood fluke and bladder ca 3. H pylori and gastric ca |
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immune suppression
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esp w/ chronic suppression like AIDS
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viral oncogenesis
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currently, only virus proven to cause ca is HTLV
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viruses a/w human ca
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1. epstein-barr
2. hep B & C 3. HPV 4. human herpes virus 8 5. HTLV-1 |
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Epstein-barr: DNA virus a/w:
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1. Burkitt's lymphoma - endemic Africa
2. Nasopharyngeal carcinoma 3. B cell lymphomas in immunosupp 4. Hodgkin's ds |
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HBV & HCV
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DNA & RNA viruses respectively a/w liver CA
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HPV: DNA virus a/w:
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1. cervical carcinoma (16 & 18)
2. penile carcinoma 3. anal carcinoma 4. certain head & neck ca |
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HHV 8: DNA virus a/w:
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Kaposi's sarcoma
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HTLV: RNA virus a/w:
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T lymphoblastic leukemias
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mechanisms in viral carcinogenesis (2 types)
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1. DNA viruses
2. RTV |
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DNA viruses
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directly integrate viral DNA into host genome resulting in mutant cells
- viral products inhibit tumor suppressor genes such as p53 & Rb |
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RTV
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with RT, viral genomic RNA sequences transcribed into DNA & integrated into host genomes resulting in mutant cells
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viral oncogenes (v-oncs)
exs |
certain RTs cause ca in animals
V-src = rouse sarcoma virus in chickens V-sis - simian sarcoma virus V-fms - feline sarcoma virus |
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viral oncogenes also exhibit homology for DNA sequences of human & other eukaryotic species. They are known as:
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proto-oncogenes - nL components of genome
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how to oncogenes
1. resemble 2. differ from proto-oncogenes |
1. they code for the production of proteins involved in cell growth
2. an altered version or excess quant., thereby disrupting the cell's growth signal pathways |
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one-hit hypothesis
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changes in only one pair of proto-oncogenes can result in neoplastic development
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ex of 1 hit hypothesis
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1. production of excess nL protein
2. production of excess abnL protein |
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excess nL protein
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gene amp - reduplication of proto-oncogene can result in 1000s of copies
1. overexpression of n-myc (code for TF that regulate exp of various other genes in cellular proliferation) 2. over expression of HER-2 aka Erb-2 |
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excess abnL protein
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several ca's involve point mutations in signal transduction genes. Code for abnL factors that are always on and don't require binding GF to be activaed
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examples of abnL proteins
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Ras - nL functions in signaling p-ways to relay signals from cell surface recep. involved in growth and repro
mutant Ras - autonomous Ras always on, continuously activated p-way, uncontrolled growth |
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tumor suppressor genes (anti-oncogenes)
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in contrast to oncogenes, tumor suppressor genes promote cellular proliferation when they are inactivated by mutation or deletion or muted by epigenic mechanisms
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Two hit hypothesis
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inactivation of both copies of a tumor suppressor gene is required for ca to develop
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tumor suppressor genes (define)
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nL genes that inhibit cell proliferation by acting on cell cycle in G1
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ex of tumor suppressor genes
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1. p53
2. retinoblastoma (Rb) 3. adenomatous polyposis coli (APC) 4. TGF-beta p-way 5. phosphatase & tensin (PTEN) gene 6. tumor suppressor genes & oncogenetic DNA viruses |
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p53
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**mutations or deletions of p53 are considered to be the most common genetic change in human ca**
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% deleted/mutated/blocked in colorectal, breast, lung and other cas
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70-80%
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mechanism of p53
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1. minor DNA damage -> p53 product levels rise and prevent cell from entering S phase
2. if DNA damage severe, p53 product induces apoptosis 3. acts as guardian of genome, restricting cellular proliferation |
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Rb
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first tumor suppressor gene ID'd
1. malignant tumor in retina in children <5 2. hereditary Rb caused by mutation in single copy of Rb. Others prevent remains cells from becoming cancerous, but 1 or more in retina likely to spont cause ca 3. children who inherit Rb gene - x200 chances to develop mesenchymal tumors later |
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APC gene
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those born w/ mutant form of this gene develop numerous polyps in colon w/ inc risk of malignant transformation
- loss of APC proteins - up-regulation in cellular proliferation |
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TGF-beta p-way
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leads to up-regulation of groth inhibitory genes
- mutations a/w development of numerous ca - pancreatic & colorectal |
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PTEN gene
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1. nL fnxn - regulate p53 levels
2. mutations: 1st steps in development of many cas -cause Cowden syndrome |
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tumor suppressor genes and oncogenetic DNA viruses
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unlike RV, DNA viruses not homologous w/ any cellular genes. Both Rb and p53 proteins inactivated by binding viral proteins
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Evasion of apoptosis
- mechanism |
some ca able to evade destruction by apoptosis
mechanism - inactive or delete component in signaling p-way leads to apoptosis |
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molecular basis of multistep carcinogenesis
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1. oncogenes
2. tumor suppressor genes 3. apoptosis must all be involved before ca develops |
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evolution of benign colon adenomas into carcinomas
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1. nL epithelium to hyperprolif. epithelium & early adenoma
(loss/mutation of APC gene on 5q) 2. early adenoma to intermed. adenoma (nutation of ras gene on 12p) 3. intermed. adenoma to late adenoma (loss of SMAD 2&4 gene on 18q) 4. late adenoma to carcinoma (loss p53 gene on 17p) |
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Genomic instability syndromes
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indiv. born w/ inherited mutations in genes of DNA repair at inc risk of developing ca
1. excision 2. recombination 3. mismatch repair |
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xeroderma pigmentosa
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skin ca develop in these pts exposed to UV light b/c they have mutated nucleotide excision repair genes required for correcting DNA damage induced by UV light
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inherited ds w/ defects in DNA repair by homologous recombination
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ex. ataxia telagelectasia, bloom syndrome (other recessive disorders from prev lecture)
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BRCA-1 & BRCA-2 genes
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1. mutations - inc risk of developing breast and ovarian ca
2. children of parents w/ such mutations have 50% of inheriting mut 3. BRCA genes - inv. in repair of breaks in double stranded DNA 4. possible that utations may be inv in other ca |
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hereditary nonpolyposis colon ca
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a. MSH2, MSJ6 & MLH: inv. in repair of DNA
b. mut: single base mismatches or small insertions or deletions develop ca of colon or cecum w/o preneoplastic adenomatous polyp |
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telomerase activity & ca
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somatic cells - telomeres shorten until arrest in nondividing state called replicative senescence
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how do ca's evade replicative senescence
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by reactivating enzyme telomerase which prevents further shortening of telomeres - divide indefinitely
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angiogenesis in ca
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tumor cells produce angiogenic factors such as vascular endothelial GF and fibroblastic GF & also induce formation of antiangiogenic factors such as thrombospondin-1, angiostatin, endostatin, and vasculostatin
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how is the growth of tumors controlled
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by balance b/w angiogenic and antiangiogenic factors
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not needed during early growth, but needed during expansive growth:
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vascularization
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