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Slide 1: 10/27/09 Neoplasia 4 Click to edit Master subtitle style Fe A. Bartolome, MD, FPASMAP Department of Pathology Our Lady of Fatima University
Slide 2: Chemical Carcinogenesis 10/27/09
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Slide 4: Chemical Carcinogenesis • 10/27/09 Initiation results from exposure of cells to a sufficient dose of a carcinogenic agent (initiator). Initiation alone is not sufficient for tumor formation. Initiation causes permanent DNA damage (mutations). It is rapid and irreversible and has “memory.” • •
Slide 5: Chemical Carcinogenesis • 10/27/09 Unrepaired alterations in the DNA are essential first steps in the process of initiation. ü For the change to be heritable, the damaged DNA template must be replicated ü For initiation to occur, altered cells must undergo at least one cycle of proliferation so that DNA change becomes fixed
Slide 6: Chemical Carcinogenesis • 10/27/09 Promoters (e.g. Phorbol esters, hormones, phenols, and drugs) can induce tumors in initiated cells, but they are nontumorigenic by themselves Tumors do not result when the promoting agent is applied before, rather than after, the initiating agent. The cellular changes resulting from application of promoters do not affect DNA directly and are reversible. • •
Slide 7: Chemical Carcinogenesis • 10/27/09 Application of promoters leads to proliferation and clonal expansion of initiated (mutated) cells ü Mutated cells with reduced growth factor requirements Process of tumor promotion includes multiple steps: proliferation of preneoplastic cells, malignant conversion, and tumor progression •
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Slide 10: Chemical Carcinogenesis: Initiators Direct-Acting Agents • 10/27/09 Require no metabolic conversion to become carcinogenic Most are weak carcinogens; some are chemotherapeutic drugs (e.g. Alkylating drugs) Risk of induced cancer is low. • •
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Slide 12: Chemical Carcinogenesis: Initiators Indirect-Acting Agents • 10/27/09 Requires metabolic conversion to an ultimate carcinogen before they become active Polycyclic hydrocarbons ü present in fossil fuels; animal fats during process of broiling meats; smoked meat and fish ü Principal active product: epoxides P and proteins •
Slide 13: Chemical Carcinogenesis: Initiators Indirect-Acting Agents • 10/27/09 Most of the known carcinogens are metabolized by the cytochrome P-450dependent mono-ozygenases ü Example: benzo[a]pyrene s light smokers with the susceptible genotype CYP1A1 with 7x higher risk of developing lung cancer
Slide 14: Chemical Carcinogenesis: Initiators Molecular Targets • 10/27/09 DNA is the primary target Any gene may be the target ° commonly mutated are RAS and p53 ü • Aflatoxin B1 t cause G:C t T:A transversion in codon 249 of p53
Slide 15: Radiation Carcinogenesis 10/27/09 Ultraviolet Rays • UV rays derived from sun 0 increased incidence of SCCA, basal cell carcinoma, and skin melanoma Degree of risk depends on: 1. Type of UV ray 2. Intensity of exposure 3. Quantity of light-absorbing protective coat of melanin •
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Slide 17: 10/27/09 UVB radiation is the main cause of sunburn and skin cancer although mounting evidence suggests UVA may also play a role. UVB does not penetrate the skin as deeply as UVA but
Slide 18: 10/27/09 UVB sunlight is directly absorbed by DNA resulting in single strand breaks and the formation of pyrimidine dimers.
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Slide 21: Radiation Carcinogenesis 10/27/09 Ionizing Radiation • Electromagnetic (x-rays, gamma rays) and particulate (α particles, β particles, protons, neutrons) radiation are all carcinogenic Lead to formation of reactive oxygen species or free radicals •
Slide 22: Radiation Carcinogenesis 10/27/09 Ionizing Radiation • High vulnerability: acute and chronic myeloid leukemia; thyroid cancer (only in the young) Intermediate: breast, lungs, salivary glands Resistant: skin, bone, GIT • •
Slide 23: 10/27/09 DNA is damaged due to ionization or excitation caused by radiation. Clustered DNA damage would be produced where the density of ionization/excitation is high,
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Slide 26: Microbial Carcinogenesis 10/27/09
Slide 27: Microbial Carcinogenesis 10/27/09
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Slide 29: Microbial Carcinogenesis 10/27/09 Oncogenic RNA Viruses: HTLV type 1 • Only human retrovirus firmly implicated in causation of cancer in humans (T-cell leukemia/lymphoma) Does not contain an oncogene Viral integration shows clonal pattern V site of integration identical within all cells of a given cancer • •
Slide 30: Microbial Carcinogenesis 10/27/09 Oncogenic RNA Viruses: HTLV type 1 • With tax regulatory gene 1. stimulates viral mRNA transcription 2. activate transcription of several host cell genes involved in proliferation and differentiation of T cells ü FOS gene – immediate early gene ü Genes encoding IL-2 & its receptor ü Gene for myeloid growth factor granulocyte-macrophage colonystimulating factor
Slide 31: Microbial Carcinogenesis 10/27/09 Oncogenic RNA Viruses: HTLV type 1 • With tax regulatory gene 3. Inactivates the cell cycle inhibitor p16/INK4a and enhance cyclin D activation 4. Activate NFκβ e apoptotic genes 5. Interfere with DNA repair functions 6. Inhibits ATM-mediated cell cycle checkpoints activated by DNA damage
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Slide 34: Microbial Carcinogenesis 10/27/09 Oncogenic DNAViruses: HPV • High-risk HPVs: types 16 and 18 C squamous cell CA of cervix and anogenital region; penile cancer; oropharyngeal CA HPV genome integrated into host genome H site of integration random but pattern of integration is clonal •
Slide 35: 10/27/09 Naturally occurring cancers associated with papillomaviruses [10, 13]. Species Humans Cancer Skin carcinomas Lower genital tract cancers Malignant progression of respiratory papillomas Cattle Sheep Cottontail rabbit Alimentary-tract carcinoma Eye and skin carcinoma Skin carcinoma Skin carcinoma Predominant viral types HPV-5, -8 HPV-16, -18, -31, -33 HPV-6, -11 HPV-4 Not characterized Not characterized Cotton rabbit papillomavirus (CRPV) Shehata Cancer Cell International 2005 5:10 doi:10.1186/1475-2867-5-10
Slide 36: Microbial Carcinogenesis 10/27/09 Oncogenic DNAViruses: HPV • Viral genome integration 0 interruption of viral DNA within E1/E2 open reading frame a loss of E2 viral repressor and overexpression of oncoproteins E6 and E7
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Slide 39: Microbial Carcinogenesis 10/27/09 Oncogenic DNAViruses: EBV • Associated with African form of Burkitt’s lymphoma, a subset of Hodgkin lymphoma, nasopharyngeal Ca and some gastric carcinoma Infects B cells and possibly epithelial cells of the oropharynx via complement receptor CD21 •
Slide 40: Microbial Carcinogenesis 10/27/09 Oncogenic DNAViruses: EBV • Infection of B cells is latent · no viral replication and destruction of cells Involves the “hijacking” of several normal signalling pathways •
Slide 41: Microbial Carcinogenesis Oncogenic DNAViruses: EBV • 10/27/09 EBV gene LMP-1 (latent membrane protein-1): 1. acts as oncogene Y behaves like a constitutively active CD40 receptor ì stimulate B cell growth 2. Activate NFκβ and JAK/STAT signalling pathways 3. Promote B cell survival and proliferation 4. Activate BCL2 – prevent apoptosis 5. Induce expression of pro-angiogenic factors (VEGF, FGF-2, MMP9, COX2)
Slide 42: Microbial Carcinogenesis 10/27/09 Oncogenic DNAViruses: EBV • EBV gene EBNA-2 1. Encodes a nuclear protein that mimics a constitutively active Notch receptor 2. Transactivates several host genes c cyclin D and src family of protooncogenes
Slide 43: Microbial Carcinogenesis Oncogenic DNAViruses: EBV • 10/27/09 EBV genome contains a viral cytokine vIL-10 hijacked from the host genome 0 prevent macrophages and monocytes from activating T cells Impair immune competence o allow sustained B-cell proliferation Cause translocations that activate cMYC oncogene • •
Slide 44: Microbial Carcinogenesis Oncogenic DNAViruses: HBV and HCV • 10/27/09 Genomes do not encode any viral oncoproteins No consistent pattern of integration in liver cells Immunologically-mediated chronic inflammation with hepatocyte death n regeneration and genomic damage • •
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Slide 49: Microbial Carcinogenesis Helicobacter pylori • 10/27/09 First bacterium classified as a carcinogen Implicated in gastric adenocarcinoma and gastric lymphomas Involves increased epithelial cell proliferation in a background of chronic inflammation contain genotoxic agents such as ROS • •
Slide 50: Microbial Carcinogenesis Helicobacter pylori • 10/27/09 • Contains a “pathogenicity island” that contains cytotoxin-associated A (CagA) gene ü Penetrates into gastric epithelial cells a initiate signalling cascade that mimics unregulated growth factor stimulation Additional mutations may be acquired (e.g. (11:18) translocation) c cause constitutive activation of NF-κβ
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Slide 54: Tumor Immunity Immune surveillance • 10/27/09 A normal function of the immune system is to survey the body for emerging malignant cells and destroy them ü (+) lymphocytic infiltrates around tumors and in LN draining sites of cancer ü Increased incidence of cancer in immunocompromised individuals ü Demonstration of tumor-specific T cells and antibodies
Slide 55: Tumor Immunity Tumor antigens • • 10/27/09 Poorly immunogenic Initially classified as: 1. Tumor-specific antigens ü Present only on tumor cells and not on any normal cells Tumor-associated antigens ü Present on tumor cells and also on some normal cells 1.
Slide 56: Tumor Immunity Tumor antigens • 10/27/09 Modern classification based on molecular structure and source 1. Products of mutated genes ü Synthesized in cytoplasm of tumor cells s enter class I or class II MHC pathways ü Not present in normal cells s do not induce self-tolerance
Slide 57: Tumor Immunity 10/27/09 Tumor antigens Overexpressed or aberrantly expressed cellular proteins ü May be normal cellular proteins abnormally expressed in tumor cells a elicit immune response 2.
Slide 58: Tumor Immunity 10/27/09 Tumor antigens Antigens produced by oncogenic viruses ü Most potent: proteins produced by latent DNA viruses (e.g. HPV and EBV) 3.
Slide 59: Tumor Immunity Tumor antigens Oncofetal antigens (CEA, AFP) ü Proteins that are expressed at high levels on cancer cells and in normal developing (fetal) but not adult tissues ü Genes silenced during development and activated during malignant transformation 10/27/09 4.
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Slide 61: Tumor Immunity Tumor antigens 5. 10/27/09 Altered cell surface glycolipids and glycoproteins ü Include gangliosodes, blood group antigens, and mucins present at higher levels in cancer cells than on normal cells ü Melanomas: high levels of gangliosides GM2, GD2, and GD3 ü Target for cancer therapy with specific antibodies
Slide 62: 10/27/09 Loss of normal topology and polarization of epithelial cells in cancer results in secretion of mucins into the bloodstream. The tumor cells invading the tissues and bloodstream
Slide 63: 10/27/09 Cancer cells entering the bloodstream form complex thromboemboli with platelets and leukocytes, which are thought to facilitate arrest at ectopic sites, assist interactions with the endothelium, and help in evasion of the immune system. Current data suggest that this phenomenon can be explained by interactions between platelet and/or endothelial P-selectin and carcinoma mucins.
Slide 64: Tumor Immunity Tumor antigens 6. 10/27/09 Cell type-specific differentiation antigens ü Specific for particular lineages or differentiation stages of various cell types ü Typically normal self-antigens u do not induce immune response ü Potential targets for immunotherapy and for identifying the tissue of origin of tumors
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Slide 67: Tumor Immunity 10/27/09 Anti-tumor Effector Mechanisms 1. Cytotoxic T lymphocytes ü ü Play a protective role against virusassociated neoplasms Demonstrated in blood and tumor infiltrates of cancer patients
Slide 68: 10/27/09 In this diagram the various mechanisms elicited by stress for stimulating innate and adaptive immunity against cancer are illustrated.
Slide 69: Tumor Immunity Anti-tumor Effector Mechanisms 2. 10/27/09 Natural killer cells ü ü ü Capable of destroying tumor cells without prior sensitization c may form first line of defense vs. Tumor Activated by IL-2 and IL-5; may be activated by tumors that fail to express MHC class I antigens NKG2D proteins s activating receptors; recognize stress-induced antigens expressed on tumor cells
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Slide 71: Tumor Immunity Anti-tumor Effector Mechanisms 3. 10/27/09 Macrophages ü Activated by interferon-gamma secreted by T cells and NK cells Kill tumors by mechanisms similar to those used to kill microbes or by secretion of TNF ü
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Slide 73: Tumor Immunity Anti-tumor Effector Mechanisms 4. 10/27/09 Antibodies ü No evidence of protective effects of antitumor antibodies against spontaneous tumors Monoclonal antibody vs. CD20 (Bcell surface antigen) . treatment of lymphomas ü
Slide 74: Tumor Immunity 10/27/09 Tumor Evasion of Immune System 1. Selective outgrowth of antigennegative variants ü Elimination of strongly immunogenic subclones during tumor progression
Slide 75: Tumor Immunity 10/27/09 Tumor Evasion of Immune System 2. Loss or reduced expression of MHC molecules ü Failure to express normal levels of class I MHC molecules m escape CTLs but may trigger NK cells
Slide 76: Tumor Immunity Tumor Evasion of Immune System 3. 10/27/09 Lack of co-stimulation ü ü Express peptide antigens with class I molecules but without co-stimulatory molecules b prevent sensitization and render T cells anergic or undergo apoptosis Express arginase s arginine essential component of TCR s loss of T cell recognition
Slide 77: Tumor Immunity Tumor Evasion of Immune System 4. 10/27/09 Immunosuppression ü ü TGF-β secreted in large quantities by many tumors i potent immunosuppressant Immune response induced by the tumor may inhibit tumor immunity by activation of T-cell inhibitory receptor CTLA4
Slide 78: Tumor Immunity 10/27/09 Tumor Evasion of Immune System 4. Immunosuppression ü Production of COX2 m decreased IL-10 and increased IL-12 a immunosuppression and promotion of metastasis
Slide 79: Tumor Immunity Tumor Evasion of Immune System 5. 10/27/09 Antigen masking ü Cell surface antigens of tumors may be hidden, or masked, by glycocalyx molecules expressed in greater amounts in tumor cells
Slide 80: Tumor Immunity Tumor Evasion of Immune System 6. 10/27/09 Apoptosis of CTLs ü Some melanomas and hepatomas express FasL s kill Fas-expressing T lymphocytes that come in contact with them
Slide 81: Tumor Immunity Tumor Evasion of Immune System 7. 10/27/09 Dendritic cell defects a) b) c) Tumor secretion of growth factors T inhibit formation of DCs in bone marrow Increased IL-10 levels D decreased expression of CD80 and CD86 r decreased T cell activation Tumor secretion of nitric oxide and hydrogen peroxide DCs undergo cell death
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Slide 83: Clinical Aspects of Neoplasia • 10/27/09 Both malignant and benign tumors cause problems because of: 1. Location and impingement on adjacent structures 2. Functional activity (e.g. Hormone synthesis or development of paraneoplastic syndrome) 3. Bleeding and infections due to ulceration of tumor through adjacent surfaces 4. Symptoms due to rupture or infarction 5. Cachexia or wasting
Slide 84: Clinical Aspects of Neoplasia Local and Hormonal Effects • 10/27/09 Cancers arising within or metastatic to an endocrine gland w endocrine insufficiency Hormone production seen in neoplasms arising in endocrine glands e more typical of benign tumor Neoplasms in the gut g obstruction or intussusception • •
Slide 85: Clinical Aspects of Neoplasia 10/27/09 Local and Hormonal Effects • Non-endocrine tumors may elaborate hormones or hormone-like products paraneoplastic syndromes Melena and hematuria characteristic of neoplasms of the gut and urinary tract •
Slide 86: Clinical Aspects of Neoplasia 10/27/09 Paraneoplastic Syndromes • Symptom complexes in cancer-bearing individuals that cannot readily be explained, either by the local or distant spread of the tumor or by the elaboration of hormones indigenous to the tissue from which the tumor arose
Slide 87: Clinical Aspects of Neoplasia 10/27/09 Paraneoplastic Syndromes • Significance: 1. May present the earliest manifestation of an occult neoplasm 2. May represent significant clinical problems in the affected patients 3. May mimic metastatic disease which may complicate treatment
Slide 88: Clinical Aspects of Neoplasia 10/27/09 Paraneoplastic Syndromes 1. Endocrinopathies ü ü Ectopic hormone production Cushing syndrome – most common endocrinopathy e 50% with small cell CA of lungs; due to excessive corticotropin production
Slide 89: Clinical Aspects of Neoplasia 10/27/09 Paraneoplastic Syndromes 2. Hypercalcemia ü ü Most common paraneoplastic synd. Two processes involved: 1. Osteolysis induced by cancer 2. Production of calcemic humoral substances in extra-osseous neoplasms
Slide 90: Clinical Aspects of Neoplasia 10/27/09 Paraneoplastic Syndromes 3. Acanthosis nigricans ü Gray-black patches of verrucous hyperkeratosis on the skin Genetically determined; juveniles or adults ü
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Slide 92: Clinical Aspects of Neoplasia 10/27/09 Cancer Cachexia • Progressive loss of body fat and lean body mass accompanied by profound weakness, anorexia, and anemia Weight loss results equally from loss of fat and lean muscle Due to increased basal metabolic rate despite reduced food intake • •
Slide 93: 10/27/09 LMF – lipid-mobilizing factor induce breakdown of adipose into fatty acids; PIF – proteolysis-inducing factor n induce protein degradation in skeletal muscles. Tumours convert glucose to lactate, which is transferred to the liver, where it is converted back into glucose. This cycle uses a large amount of energy, and might contribute to cachexia.
Slide 94: Grading and Staging Cancer Grading • 10/27/09 Based on degree of differentiation of the tumor cells and, in some cancers, the number of mitoses or architectural features Provides information about potential behavior of tumor Of less clinical value than staging • •
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Slide 97: Grading and Staging Cancer Staging • 10/27/09 Based on: 1. Size of primary lesion 2. Extent of spread to regional LN 3. Presence or absence of blood-borne metastases Gives an idea of how extensive or widespread the cancer is Determines treatment and outlook for recovery • •
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Slide 100: Laboratory Diagnosis 10/27/09 Histologic and Cytologic Methods • Sampling approaches: 1. Excision or biopsy ü Quick-frozen section desirable s determine the nature of a mass lesion or in evaluating the margins of an excised cancer
Slide 101: Laboratory Diagnosis 10/27/09 Histologic and Cytologic Methods • Sampling approaches: 2. Fine-needle aspiration ü Aspirating cells and attendant fluid with a small-bore needle ü Used for more readily palpable lesions in breast, thyroid, and LN ü Less invasive and more rapidly performed
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Slide 103: Laboratory Diagnosis Histologic and Cytologic Methods • 10/27/09 Sampling approaches: 3. Cytologic (Papanicolau) smears ü Screen for cervical carcinoma and also endometrial CA, bronchogenic CA, bladder and prostatic tumors, and gastric CA ü For ID of tumor cells in abdominal, pleural, joint, and cerebrospinal fluids
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Slide 105: Laboratory Diagnosis 10/27/09 Immunohistochemistry • Uses: 1. Categorization of undifferentiated malignant tumors ü ü (+) cytokeratins carcinoma (+) desmin a muscle cell origin
Slide 106: Laboratory Diagnosis Immunohistochemistry • 10/27/09 Uses: 2. Determination of site of origin of metastatic tumors ü Detect tissue-specific or organspecific antigens in a biopsy specimen of the metastatic deposit (e.g. PSA)
Slide 107: Laboratory Diagnosis Immunohistochemistry • 10/27/09 Uses: 3. Detection of molecules that have prognostic or therapeutic significance ü e.g. Detection of hormone receptors in breast cancer cells of prognostic and therapeutic value
Slide 108: Laboratory Diagnosis 10/27/09 Flow Cytometry • Rapidly and quantitatively measure individual cell characteristics (e.g. Membrane antigens, DNA content of tumor cells) Useful in ID and classification of tumor arising from T and B cells, and from mononuclear-phagocytic cells •
Slide 109: Laboratory Diagnosis 10/27/09 Molecular Techniques 1. Diagnosis of malignant neoplasms Prognosis of malignant neoplasms Detection of minimal residual disease Diagnosis of hereditary predisposition to cancer 1. 1. 1.
Slide 110: Tumor Markers 10/27/09 • Biochemical assays for tumorassociated enzymes, hormones, and other tumor markers in the blood Contribute to detection of cancer Useful in determining the effectiveness of therapy or appearance of recurrence • •
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