Lecture 38 - Neoplasia Iv
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Neoplasia By Prof. J.T. Anim Department of Pathology
Lecture IV
Topics
The neoplastic cell Causes of neoplasia Pathogenesis/mechanisms of neoplasia - oncogenesis Carcinogens and carcinogenesis
Biology of Neoplastic Cell
Morphological Changes
High nucleo-cytoplasmic ratio Irregular nuclear shape Prominent or multiple nucleoli Numerous protrusions on cell surface Disorganised cytoskeleton
Biology of Neoplastic cell
Biochemical alterations
Composition of cell surface
Cell surface properties
Enhanced mobility of receptors resulting from loss of cytoskeletal attachment to integral glycoproteins Expression of foetal, viral, or neo-antigens Shedding of antigens (and other glycoproteins) Increase in net negative charge on plasma membrane
Enzyme production and release
Loss of glycoprotein molecules Deletion of saccharide residues from glycolipids Loss of fibronectin
Increased protease activity (including collagenase and pl. activator) Increased release of alkaline phosphatase and glycosyl transferase
Transport – increased uptake of sugars and amino acids Cyclic nucleotides – increased cyclic GMP
Biology of Neoplastic Cell
Selection
Selective pressures confer advantages on some tumour cells → progressively more homogeneous population.
The host immune system Limits of space and nutrition Lethal mutations Post-mitotic arrest
Biology of Neoplastic Cell
Growth and division - modified by:
Intracellular factors
Polyamines, eg. spermidine, released in dividing cells Cyclic AMP inhibits cell growth Protein kinases control progression of cell cycle by regulating phosphorylation of histones
Extracellular factors
Nutrients Calcium ions Growth stimulating hormones and polypeptides - insulin stimulation or specific stimulation by:
Oestrogens – some breast and endometrial carcinomas Epidermal growth factor Platelet derived growth factor Sarcoma growth factors, etc
Cancer-associated galactosyl transferase acceptor (CAGA) inhibits growth of neoplastic cells Others – modify environment of cancer cells
Proteolytic enzymes reduce physical resistance by surrounding tissues Angiogenesis factors stimulate new blood vessel formation and nutrition
Biology of Neoplastic Cell
Behavioural characteristics in vitro
Immortality – can proliferate ad infinitum under ideal culture conditions Loss of contact inhibition – proliferation persists Increased motility – migrate more rapidly (may be due to altered cytoskeletal function) Decreased cell-to-cell adhesion – disturbances in arrangement of macromolecules on tumour cells Loss of substrate dependency – show a greatly diminished dependence on substrate attachment through binding proteins, eg. fibronectin, laminin
Aetiology of Tumours
The sequence of intra and extracellular mechanisms are unknown Genetic mutation and/or altered gene expression are critical factors in oncogenesis Genetic factors interact with environmental factors
The Transformed Cell
Autonomous generation of mitogenic signals Insensitivity to exogenous antigrowth signals Resistance to apoptosis Limitless replicative potential (immortalisation) Blocked differentiation Ability to sustain angiogenesis Capacity to invade surrounding tissues Potential to metastasise
Pathogenesis of Neoplasia
Non-lethal genetic damage
Role of regulatory genes
Mutation may be inherited in the germ line or acquired somatic (chemical, radiation, viruses) Leads to clonal expansion Oncogenes and tumour suppressor genes
Genes regulating apoptosis Genotypic and phenotypic multistep process
Stepwise acquisition of characteristics of a neoplasm – tumour progression
Oncogenesis
Oncogenes
Tumour suppressor genes
Cellular oncogenes – tumour promoting genes derived from normal growth promoting genes in normal cells (protooncogenes) Viral oncogenes (v-oncs) – a family of transforming genes, each of which is characteristic of a rapidly transforming oncornavirus Growth inhibiting genes – encode negative transcriptional regulators of cell cycle, signal transducing molecules, cell surface receptors
Mutator genes (caretaker genes)
DNA mismatch repair genes – exercise surveillance over integrity of the genetic information by participating in cellular responses to DNA damage. Loss of their function → DNA susceptible to progressive accumulation of mutations
Proto-oncogenes
Growth factors – sis, int-2, IGF-1 Growth factor receptors with protein kinase – erb-2, fms, met, trk, ret Abnormally functioning growth factor receptors – neu Factors that act in the transduction of signals arising from ligandreceptor interactions G proteins – ras Guanosine 5-triphosphatase activators (GTPase) – gap, brev Membrane-associated cytoplasmic kinases – src, yes, fgr Non-membrane associated cytoplasmic kinases – raf, mos, pim1, fps DNA-binding proteins concerned in transcription Heterodimeric transcription factors – fos-jun, myc-max Transcription factors – myb, rel, ets Cell cycle proteins - cyclins
•
Growth factors
•
Transmembrane growth factor receptors (tyrosine kinase)
•
Membrane associated kinases
•
ras GTPase family
•
Cytoplasmic kinases
•
Nuclear transcriptional factors
Cellular compartments in which oncogene or protooncogene products reside
Gene products of protooncogenes and steps involved in cell division
Activation of Cellular Oncogenes
Mutation of proto-oncogene
Increased expression of the protooncogene
Leads to constitutively activated abnormal protein
Overproduction of a normal gene product
Insensitivity of normal auto- inhibitory and regulatory constraints
Mechanism of activation - mutation
Mechanism of activation - translocation
Mechanism of activation - amplification
Mechanism of activation
Summary of oncogene activation
Mechanism of Oncogene Action
Growth factors Cell surface receptors Intracellular signal transduction pathways DNA-binding nuclear proteins (transcription factors) Cell cycle proteins (cyclins and cyclindependent protein kinases) Inhibitors of apoptosis (bcl-2)
Viral Oncogenes
Viral oncogenes originate from cellular proto-oncogenes The current view is that v-oncs arise as a result of transcription from a cellular proto-oncogene, and that this cellular genetic material has been incorporated into the viral genome
Viral Oncogenes
A number of v-oncs code for proteins that possess the ability to phosphorylate tyrosine kinase in certain cells Oncogene from the avian erythroblastosis virus (erb b) codes for a protein homologous with a portion of the cellular receptor for epidermal growth factor. Another oncogene, sis from the simian sarcoma virus, codes for a protein homologous with PDGF
Tumour Suppressor Genes
Encode negative transcriptional regulators of cell cycle Encode signal transduction molecules Encode cell surface receptors Both alleles must be inactivated to produce the deficit that allows tumour development Heterozygous state is sufficient to protect against cancer Loss of heterozygosity predisposes to tumour development
Tumour Suppressor Genes
Certain hereditary tumours are associated with mutation or loss of alleles in germline cells
Retinoblastoma (RB gene) 13q14 Wilms’ tumour (WT-1) 11p13 Neurofibromatosis type 1 (NF-1) 17q11.2 Familial adenomatous polyposis coli (FAPC) 5q15-22
Tumour suppressor gene – the retinoblastoma gene
Tumour Suppressor Genes
The p53 tumour suppressor gene
Mutation appears to be the commonest abnormality related to tumour suppressor genes in human neoplasms. Causes arrest in G1 phase in cells with damaged DNA to allow time for excision and repair p53 protein can induce apoptosis (eliminates cells harbouring genomic abnormalities)
Mechanism of action of p53 gene
HPV and tumour suppressor genes: Both RB and p53 proteins can be inactivated by protein products of oncogenic human papillomavirus types 16 and 18
Properties of oncogenes and tumour suppressor genes
Oncogenesis - Summary
Summary of genomic mechanisms of cancer
Oncogenesis – Multistep Process
Initiation
Promotion
Change in genome of target cell. If not repaired, is permanent and heritable Rapid, dose-related, affects small proportion of target cells Biochemical events in normal and initiated cells → altered pattern of gene expression → expression of cells with new phenotype (preneoplastic cells) Continued effect of promoting agent → clonal expansion
Progression Metastasis
Initiation and promotion: A multistep process
Evolution of colorectal cancer through the adenoma-carcinoma sequence.
Oncogenesis - Genetic
Account for less than 5% of tumours
Chromosomally determined syndromes
Single gene abnormalities
Down’s syndrome – acute leukaemias Klinefelter’s syndrome – breast cancer Gonadal dysgenesis – gonadal tumours Xeroderma pigmentosum (aut dom) lack of enzymes for excision and repair of DNA Familial adenomatous polyposis coli and related syndromes (aut dom) inheritance of malfunctioning APC gene
Increased risk with no precursor syndrome
Phaeochromocytoma – childhood form (50%) or as part of MEN IIa (Sipple’s) and MEN IIb
Oncogenesis - Chemical
Many chemical agents become carcinogenic only after conversion in the body of the host to biologically active forms The parent substance = remote carcinogen Its metabolites = proximate carcinogens Final molecular species that interacts with host DNA = ultimate carcinogen Most chemical carcinogens are also mutagens
Polycyclic hydrocarbons
1775 Percival Potts: scrotal cancer in chimney sweep’s boys
Moderate-powerful carcinogens in this group:
Coal tar – polycyclic hydrocarbons 7,12-dimethylbenzanthracene 3,4-benzpyrene 1,2,5,6-dibenzanthracene 3-methylcholanthrene
Site of application affects type of neoplasm produced Act by binding to host cytoplasmic and nuclear macromolecules. Are activated by oxidases to water-soluble, more reactive epoxides Greater DNA binding = greater carcinogenic potential Hydrocarbons in cigarette smoke related to lung cancer. Predisposition to lung cancer may be related to inducibility of aryl hydrocarbon hydroxylase
Aromatic Amines and Azo Dyes
Aniline dye workers in Germany – 1895 Carcinoma of bladder
Later: aniline dye manufacture, rubber & cable industry, manufacture of certain paints & pigments, textile dyeing, laboratory work 2-Naphthylamine and benzidine
Hydroxylation in liver – aminonaphthol – detox as glucuronide Aminonaphthol released in bladder by βglucuronidase in urothelium
Nitrosamines and Nitrosamides
Nitrosamines are remote carcinogens
Activation into alkylating agents Can be formed in GIT (nitrites – nitrous acid + amines) Nitrites present in pickled, salted, smoked foods
Nitrosamides do not require enzymatic activation
Ethyl-nitrosourea
Direct-acting Alkylating Agents
Can bind to DNA directly
Mustard gas Propiolactone Cyclophosphamide Melphalan busulphan
Their interaction with DNA – useful as antitumour agents, but also increases risk of other neoplasms (leukaemias, lymphomas)
Naturally Occurring & Occupational
Aflatoxin (A flavus) – produces point mutation at codon 249 of p53 gene – hepatocellular carcinoma Asbestos – mesothelioma Arsenic – cancer of skin, lung Ionizing radiation – leukaemia, lung, bone Nickel – lung, paranasal sinuses Benzene – leukaemia Vinyl chloride – angiosarcoma of liver Hardwood dust – adenocarcinoma of paranasal sinuses Bischlormethylether – small cell carcinoma of lung
Oncogenesis – Physical Agents
Ultraviolet irradiation
Ionizing radiation
BCC, SCC, melanoma Abnormal thymine dimers in DNA of epidermal cells; lack of efficient excision repair of abnormal DNA Free radical damage to target cell genome
Foreign materials
Certain plastics – connective tissue tumours
Oncogenesis - Hormones
Human breast cancer
Carcinoma of endometrium
Early menarche – late menopause Oestrogen effect
Others
Carcinoma of prostate Clear cell adenocarcinoma of vagina
Oncogenesis - Viruses
DNA oncogenic viruses - Encode proteins that bind regulatory proteins
Papova group
Herpesvirus group
Papillomavirus: proved to cause neoplasm – >80 types, mostly associated with benign lesions, warts (condyloma). >20 types associated with cancer esp. 16 and 18. Major oncoproteins E6 binds to p53 and E7 binds to RB releasing their inhibitory effect on cell cycle. Polyomaviruses mainly animal tumours (rats, mice, hamsters) SV40 (simian vacuolating virus – no human neoplasm) Human herpesvirus 8 - Kaposi’s sarcoma
Epstein-Barr virus: EBV genes EBNAs and LMPs involved in immortalization of infected B lymphocytes
Burkitt’s lymphoma Nasopharyngeal carcinoma
Hepatitis group – HBV, HCV
Oncogenesis - Viruses
Oncogenic RNA Viruses
Adult T cell leukaemia (Japan, Carribbean)
HTLV-I is tropic for CD4 T lymphocytes (leukaemia in <5%). Oncogenic stimulation mediated by viral transcription activation protein tax HTLV-II – few cases of lymphoproliferative disorders.
Lecture IV
Topics
The neoplastic cell Causes of neoplasia Pathogenesis/mechanisms of neoplasia - oncogenesis Carcinogens and carcinogenesis
Biology of Neoplastic Cell
Morphological Changes
High nucleo-cytoplasmic ratio Irregular nuclear shape Prominent or multiple nucleoli Numerous protrusions on cell surface Disorganised cytoskeleton
Biology of Neoplastic cell
Biochemical alterations
Composition of cell surface
Cell surface properties
Enhanced mobility of receptors resulting from loss of cytoskeletal attachment to integral glycoproteins Expression of foetal, viral, or neo-antigens Shedding of antigens (and other glycoproteins) Increase in net negative charge on plasma membrane
Enzyme production and release
Loss of glycoprotein molecules Deletion of saccharide residues from glycolipids Loss of fibronectin
Increased protease activity (including collagenase and pl. activator) Increased release of alkaline phosphatase and glycosyl transferase
Transport – increased uptake of sugars and amino acids Cyclic nucleotides – increased cyclic GMP
Biology of Neoplastic Cell
Selection
Selective pressures confer advantages on some tumour cells → progressively more homogeneous population.
The host immune system Limits of space and nutrition Lethal mutations Post-mitotic arrest
Biology of Neoplastic Cell
Growth and division - modified by:
Intracellular factors
Polyamines, eg. spermidine, released in dividing cells Cyclic AMP inhibits cell growth Protein kinases control progression of cell cycle by regulating phosphorylation of histones
Extracellular factors
Nutrients Calcium ions Growth stimulating hormones and polypeptides - insulin stimulation or specific stimulation by:
Oestrogens – some breast and endometrial carcinomas Epidermal growth factor Platelet derived growth factor Sarcoma growth factors, etc
Cancer-associated galactosyl transferase acceptor (CAGA) inhibits growth of neoplastic cells Others – modify environment of cancer cells
Proteolytic enzymes reduce physical resistance by surrounding tissues Angiogenesis factors stimulate new blood vessel formation and nutrition
Biology of Neoplastic Cell
Behavioural characteristics in vitro
Immortality – can proliferate ad infinitum under ideal culture conditions Loss of contact inhibition – proliferation persists Increased motility – migrate more rapidly (may be due to altered cytoskeletal function) Decreased cell-to-cell adhesion – disturbances in arrangement of macromolecules on tumour cells Loss of substrate dependency – show a greatly diminished dependence on substrate attachment through binding proteins, eg. fibronectin, laminin
Aetiology of Tumours
The sequence of intra and extracellular mechanisms are unknown Genetic mutation and/or altered gene expression are critical factors in oncogenesis Genetic factors interact with environmental factors
The Transformed Cell
Autonomous generation of mitogenic signals Insensitivity to exogenous antigrowth signals Resistance to apoptosis Limitless replicative potential (immortalisation) Blocked differentiation Ability to sustain angiogenesis Capacity to invade surrounding tissues Potential to metastasise
Pathogenesis of Neoplasia
Non-lethal genetic damage
Role of regulatory genes
Mutation may be inherited in the germ line or acquired somatic (chemical, radiation, viruses) Leads to clonal expansion Oncogenes and tumour suppressor genes
Genes regulating apoptosis Genotypic and phenotypic multistep process
Stepwise acquisition of characteristics of a neoplasm – tumour progression
Oncogenesis
Oncogenes
Tumour suppressor genes
Cellular oncogenes – tumour promoting genes derived from normal growth promoting genes in normal cells (protooncogenes) Viral oncogenes (v-oncs) – a family of transforming genes, each of which is characteristic of a rapidly transforming oncornavirus Growth inhibiting genes – encode negative transcriptional regulators of cell cycle, signal transducing molecules, cell surface receptors
Mutator genes (caretaker genes)
DNA mismatch repair genes – exercise surveillance over integrity of the genetic information by participating in cellular responses to DNA damage. Loss of their function → DNA susceptible to progressive accumulation of mutations
Proto-oncogenes
Growth factors – sis, int-2, IGF-1 Growth factor receptors with protein kinase – erb-2, fms, met, trk, ret Abnormally functioning growth factor receptors – neu Factors that act in the transduction of signals arising from ligandreceptor interactions G proteins – ras Guanosine 5-triphosphatase activators (GTPase) – gap, brev Membrane-associated cytoplasmic kinases – src, yes, fgr Non-membrane associated cytoplasmic kinases – raf, mos, pim1, fps DNA-binding proteins concerned in transcription Heterodimeric transcription factors – fos-jun, myc-max Transcription factors – myb, rel, ets Cell cycle proteins - cyclins
•
Growth factors
•
Transmembrane growth factor receptors (tyrosine kinase)
•
Membrane associated kinases
•
ras GTPase family
•
Cytoplasmic kinases
•
Nuclear transcriptional factors
Cellular compartments in which oncogene or protooncogene products reside
Gene products of protooncogenes and steps involved in cell division
Activation of Cellular Oncogenes
Mutation of proto-oncogene
Increased expression of the protooncogene
Leads to constitutively activated abnormal protein
Overproduction of a normal gene product
Insensitivity of normal auto- inhibitory and regulatory constraints
Mechanism of activation - mutation
Mechanism of activation - translocation
Mechanism of activation - amplification
Mechanism of activation
Summary of oncogene activation
Mechanism of Oncogene Action
Growth factors Cell surface receptors Intracellular signal transduction pathways DNA-binding nuclear proteins (transcription factors) Cell cycle proteins (cyclins and cyclindependent protein kinases) Inhibitors of apoptosis (bcl-2)
Viral Oncogenes
Viral oncogenes originate from cellular proto-oncogenes The current view is that v-oncs arise as a result of transcription from a cellular proto-oncogene, and that this cellular genetic material has been incorporated into the viral genome
Viral Oncogenes
A number of v-oncs code for proteins that possess the ability to phosphorylate tyrosine kinase in certain cells Oncogene from the avian erythroblastosis virus (erb b) codes for a protein homologous with a portion of the cellular receptor for epidermal growth factor. Another oncogene, sis from the simian sarcoma virus, codes for a protein homologous with PDGF
Tumour Suppressor Genes
Encode negative transcriptional regulators of cell cycle Encode signal transduction molecules Encode cell surface receptors Both alleles must be inactivated to produce the deficit that allows tumour development Heterozygous state is sufficient to protect against cancer Loss of heterozygosity predisposes to tumour development
Tumour Suppressor Genes
Certain hereditary tumours are associated with mutation or loss of alleles in germline cells
Retinoblastoma (RB gene) 13q14 Wilms’ tumour (WT-1) 11p13 Neurofibromatosis type 1 (NF-1) 17q11.2 Familial adenomatous polyposis coli (FAPC) 5q15-22
Tumour suppressor gene – the retinoblastoma gene
Tumour Suppressor Genes
The p53 tumour suppressor gene
Mutation appears to be the commonest abnormality related to tumour suppressor genes in human neoplasms. Causes arrest in G1 phase in cells with damaged DNA to allow time for excision and repair p53 protein can induce apoptosis (eliminates cells harbouring genomic abnormalities)
Mechanism of action of p53 gene
HPV and tumour suppressor genes: Both RB and p53 proteins can be inactivated by protein products of oncogenic human papillomavirus types 16 and 18
Properties of oncogenes and tumour suppressor genes
Oncogenesis - Summary
Summary of genomic mechanisms of cancer
Oncogenesis – Multistep Process
Initiation
Promotion
Change in genome of target cell. If not repaired, is permanent and heritable Rapid, dose-related, affects small proportion of target cells Biochemical events in normal and initiated cells → altered pattern of gene expression → expression of cells with new phenotype (preneoplastic cells) Continued effect of promoting agent → clonal expansion
Progression Metastasis
Initiation and promotion: A multistep process
Evolution of colorectal cancer through the adenoma-carcinoma sequence.
Oncogenesis - Genetic
Account for less than 5% of tumours
Chromosomally determined syndromes
Single gene abnormalities
Down’s syndrome – acute leukaemias Klinefelter’s syndrome – breast cancer Gonadal dysgenesis – gonadal tumours Xeroderma pigmentosum (aut dom) lack of enzymes for excision and repair of DNA Familial adenomatous polyposis coli and related syndromes (aut dom) inheritance of malfunctioning APC gene
Increased risk with no precursor syndrome
Phaeochromocytoma – childhood form (50%) or as part of MEN IIa (Sipple’s) and MEN IIb
Oncogenesis - Chemical
Many chemical agents become carcinogenic only after conversion in the body of the host to biologically active forms The parent substance = remote carcinogen Its metabolites = proximate carcinogens Final molecular species that interacts with host DNA = ultimate carcinogen Most chemical carcinogens are also mutagens
Polycyclic hydrocarbons
1775 Percival Potts: scrotal cancer in chimney sweep’s boys
Moderate-powerful carcinogens in this group:
Coal tar – polycyclic hydrocarbons 7,12-dimethylbenzanthracene 3,4-benzpyrene 1,2,5,6-dibenzanthracene 3-methylcholanthrene
Site of application affects type of neoplasm produced Act by binding to host cytoplasmic and nuclear macromolecules. Are activated by oxidases to water-soluble, more reactive epoxides Greater DNA binding = greater carcinogenic potential Hydrocarbons in cigarette smoke related to lung cancer. Predisposition to lung cancer may be related to inducibility of aryl hydrocarbon hydroxylase
Aromatic Amines and Azo Dyes
Aniline dye workers in Germany – 1895 Carcinoma of bladder
Later: aniline dye manufacture, rubber & cable industry, manufacture of certain paints & pigments, textile dyeing, laboratory work 2-Naphthylamine and benzidine
Hydroxylation in liver – aminonaphthol – detox as glucuronide Aminonaphthol released in bladder by βglucuronidase in urothelium
Nitrosamines and Nitrosamides
Nitrosamines are remote carcinogens
Activation into alkylating agents Can be formed in GIT (nitrites – nitrous acid + amines) Nitrites present in pickled, salted, smoked foods
Nitrosamides do not require enzymatic activation
Ethyl-nitrosourea
Direct-acting Alkylating Agents
Can bind to DNA directly
Mustard gas Propiolactone Cyclophosphamide Melphalan busulphan
Their interaction with DNA – useful as antitumour agents, but also increases risk of other neoplasms (leukaemias, lymphomas)
Naturally Occurring & Occupational
Aflatoxin (A flavus) – produces point mutation at codon 249 of p53 gene – hepatocellular carcinoma Asbestos – mesothelioma Arsenic – cancer of skin, lung Ionizing radiation – leukaemia, lung, bone Nickel – lung, paranasal sinuses Benzene – leukaemia Vinyl chloride – angiosarcoma of liver Hardwood dust – adenocarcinoma of paranasal sinuses Bischlormethylether – small cell carcinoma of lung
Oncogenesis – Physical Agents
Ultraviolet irradiation
Ionizing radiation
BCC, SCC, melanoma Abnormal thymine dimers in DNA of epidermal cells; lack of efficient excision repair of abnormal DNA Free radical damage to target cell genome
Foreign materials
Certain plastics – connective tissue tumours
Oncogenesis - Hormones
Human breast cancer
Carcinoma of endometrium
Early menarche – late menopause Oestrogen effect
Others
Carcinoma of prostate Clear cell adenocarcinoma of vagina
Oncogenesis - Viruses
DNA oncogenic viruses - Encode proteins that bind regulatory proteins
Papova group
Herpesvirus group
Papillomavirus: proved to cause neoplasm – >80 types, mostly associated with benign lesions, warts (condyloma). >20 types associated with cancer esp. 16 and 18. Major oncoproteins E6 binds to p53 and E7 binds to RB releasing their inhibitory effect on cell cycle. Polyomaviruses mainly animal tumours (rats, mice, hamsters) SV40 (simian vacuolating virus – no human neoplasm) Human herpesvirus 8 - Kaposi’s sarcoma
Epstein-Barr virus: EBV genes EBNAs and LMPs involved in immortalization of infected B lymphocytes
Burkitt’s lymphoma Nasopharyngeal carcinoma
Hepatitis group – HBV, HCV
Oncogenesis - Viruses
Oncogenic RNA Viruses
Adult T cell leukaemia (Japan, Carribbean)
HTLV-I is tropic for CD4 T lymphocytes (leukaemia in <5%). Oncogenic stimulation mediated by viral transcription activation protein tax HTLV-II – few cases of lymphoproliferative disorders.
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