aims chemical carcinogens viral carcinogenesis host defense against tumors grading and staging...
TRANSCRIPT
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Aims
• Chemical carcinogens
• Viral carcinogenesis
• Host defense against tumors
• Grading and Staging
• Laboratory Diagnosis
• Readings: Robbins; Chapter 6
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Chemical Carcinogenesis
• Two step process (initiation and promotion)• Initiation
– Results from exposure to carcinogenic agent.– Causes permanent (irreversible) DNA damage.– Not sufficient for tumor formation.
• Promotion– Can induce tumors from initiated cells.– Not tumorigenic by itself.– Does not affect DNA directly.– Is ____________________________________.
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Robbins & Cotran’s Pathologic Basis for Disease 7-48
Initiation and Promotion
Memory-Damage is permanent & irreversible
Initiation-Causes permanent DNA damage
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Robbins & Cotran’s Pathologic Basis for Disease 7-48
Initiation and Promotion•Applications of Promoters do not effect DNA directly and are Reversible
- They require previous initiation to cause tumors
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Robbins & Cotran’s Pathologic Basis for Disease table 7-11 & Robbins Basic Pathology Table 6-4
Carcinogenic Chemicals
• Diverse in structure.
• Both natural and synthetic.
• Direct or Indirect (procarcinogens).
• All are highly reactive electrophiles that react with electron rich sites in cells (DNA, RNA, and proteins).
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Robbins & Cotran’s Pathologic Basis for Disease 7-49
Chemical Carcinogenesis
• Most chemical carcinogens are procarcinogens and require metabolic activation to form the ultimate carcinogen.
• Balance between metabolic activation and inactivation.
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Radiation Carcinogenesis
• UV rays from sunlight and ionizing radiation (includes X-rays, -rays, protons, neutrons, other particles).
• Can transform all cell types.
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UV Radiation
• Can _______________________________ cell division.
• Can inactivate enzymes.
• Can induce gene mutations.– Pyrimidine dimers.
• Can kill cells.
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Ionizing Radiation
• Both electromagnetic (x-rays & rays) and particulate ( particles, particles, protons, & neutrons) are carcinogenic.
• The most frequent radiation induced cancers are leukemias (except chronic lymphocytic leukemia) with thyroid cancers in the young being the 2nd most common.
• Skin, bone, and GI cancers are relatively resistant to ionizing radiation induced cancers.
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Viral Carcinogenesis• DNA viruses
– Form stable associations with host cells genome.– Papillomaviruses
• Involved in the pathogenesis of warts to carcinoma.
– Epstein-Barr virus• Involved in the pathogenesis of Burkitt lymphoma and Hodgkin disease.
– Hepatitis B virus• Involved in the pathogenesis of liver cancer.
• RNA viruses– Human T-cell Leukemia virus type 1
• T cell leukemia/ lymphoma
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Robbins & Cotran’s Pathologic Basis for Disease 7-51
Epstein-Barr Virus
• EBV serves as one factor in the development of Burkitt lymphoma.
• Other factors include:– Translocation between
chromosome 8 and 14. – Mutation of oncogene
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Robbins’ Basic Pathology 6-32
Human T-cell Leukemia Virus Type 1• Transmitted by sexual
intercourse or blood transfusions.
• Endemic to Japan and the Caribbean.
• First infected T cells proliferate due to autocrine and paracrine cytokine stimulation.– Due to viral protein, TAX,
which increased IL-2 and IL-2r expression, while inhibiting tumor suppressor genes.
• Ultimately one T cell clone mutates during the great amount of replication.
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Robbins’ Basic Pathology 6-17
Hallmarks of Cancer
• Most cancers will acquire these properties during their development.– Evade apoptosis– Self sufficient growth signals– Insensitive to anti growth signals– Metastasis– Limitless replication– Sustained angiogenesis
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Host Defense Against Tumors
1. Tumor specific-shared antigens
2. Mutated Self Protein.
3. Antigens resulting from mutations (oncogenes).
4. Overexpressed or Underexpressed antigens.
5. Viral antigens.
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Tumor-Specific Shared Antigens
• MAGE family of genes are antigens usually silent in normal cells and expressed in tumor cells.– Also expressed by immunologically privileged tissue in testis.
Robbins’ Basic Pathology 6-33
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Mutated Self Protein
• Various normal self proteins can be mutated by carcinogens (chemicals, radiation, etc.).
Robbins’ Basic Pathology 6-33
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Antigens resulting from Mutant Oncogenes
• Mutants present only in tumor cells.
• No evidence that this occurs naturally.
Robbins’ Basic Pathology 6-33
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Overexpressed Antigens
• Present in both normal cells and tumor cells.– Low levels in normal cells result in non-detection
by T cells.
Robbins’ Basic Pathology 6-33
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Viral Antigens
• Viral genes (oncogenes) expressed in tumor cells.
Robbins’ Basic Pathology 6-33
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Anti-Tumor Mechanisms
Robbins’ Basic Pathology 6-35 7th Ed.
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Anti-Tumor Mechanisms
• Both cell-mediated and humoral immunity can have anti-tumor activity.
– Cytotoxic T cells.• Attack cells expressing peptide-
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Robbins’ Basic Pathology 6-35 7th Ed.
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Anti-Tumor Mechanisms
– Natural Killer cells.
• May provide first line of defense as no prior sensitization is necessary.
• Attack tumor cells with lowered levels of MHC class I.
• Can also participate in ADCC.
Robbins’ Basic Pathology 6-35 7th Ed.
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Anti-Tumor Mechanisms
– Macrophages.• Activated macrophages can be cytotoxic to tumor
cells.– Phagocytosis.
– cytokine secretion.
– Antibody.• Targeting for compliment.• ADCC.
Robbins’ Basic Pathology 6-35 7th Ed.
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Grading & Staging of Tumors
• Grading of a cancer is based on the degree of differentiation of the tumor cells and the number of mitoses within the tumor.– Correlates with the neoplasm’s aggressiveness
• Tumors are classified as grades I-IV with increasing
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Grading & Staging of Tumors
• Staging is based on the size of the primary lesion, its extent of spread to regional lymph nodes, and the presence or absence of blood-borne metastases.
• Staging has proved to be of greater clinical value than grading
• There are 2 systems used– TNM classification system – AJC system (American Joint Committee on Cancer
Staging)
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Grading & Staging of Tumors
• TNM System– T for tumor (T1-T4 for increasing size), N for
lymph node involvement (N0-N3, for increasing range and # of nodes involved), M for metastases (M0-M2)
– Varies for each form of cancer
• AJC System– Cancers divided into stages 0-IV which
incorporates the size of the lesion as well as nodal involvement and metastases.
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Laboratory Diagnostics• Histology and Exfoliative Cytology (smears) are
the most commonly used techniques in the diagnosis of cancer– Excision or Biopsy
• Appropriate preservation of the sample is critical (preservative or freezing)
– Fine needle aspiration• Sample is aspirated by a needle and stained before
examination
– Cytologic (Papanicolaou) smears• Cancer cells have a decreased adhesiveness and are
morphologically different.
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Laboratory Diagnostics
• Pap Smear
– Normal cells are large and flat
– Cancer cells have large hyperchromatic nuclei, polymorphic nuclei, and mitotic cells.
Robbins’ Basic Pathology 6-34
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Laboratory Diagnostics• Newer techniques are continually being added to
improve diagnosis of various cancers.
– Immunohistochemistry• Allows for categorization of undifferentiated
malignant tumors, determination of site of origin of metastatic tumors, and detection of molecules with therapeutic significance.
– Molecular diagnosis• Useful in diagnosis as well as predictive and therapetic
aspects of cancers.
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Laboratory Diagnostics
• Newer techniques are continually being added to improve diagnosis of various cancers.
– Flow cytometry• Can rapidly measure cell characteristics like
membrane antigens and DNA content of tumor cells
– Tumor markers• These are biochemical markers of various cancer
types.
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Laboratory Diagnostics
Robbins & Cotran’s Pathologic Basis for Disease 7-56
Immunocytochemistry of a malignant tumor to identify its tissue of origin. (Anticytokeratin antibody to identify epithelial origin)
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Next Time
• Skin Pathologies
• Reading: Robbins, Chapter 22
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Objectives1. Describe the process and pathway of chemical
carcinogenesis.1. Initiation & Promotion
2. Describe the types of carcinogenic radiation.3. Describe the various types & causes of viral
carcinogenesis.1. DNA Viruses (papilloma virus, EBV, Hepatitis B)2. RNA Viruses (HTLV-1)
4. Describe host defenses against tumors.1. Various forms of antigen presentation2. Anti-Tumor Mechanisms (Cytotoxic T cells, Natural Killer
cells, Macrophages, Antibodies)5. Describe the basics of tumor grading & staging.6. Describe the laboratory techniques used in diagnosing
cancer.