1. Aims Chemical carcinogens Viral carcinogenesis
Lecture #31 Handout
Aims
Chemical carcinogens
Viral carcinogenesis
Host defense against tumors
Grading and Staging
Laboratory Diagnosis
Readings: Robbins; Chapter 6

2. 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 ____________________________________.

3. Initiation and Promotion
Lecture #31 Handout
Initiation and Promotion
Initiation
-Causes permanent DNA damage
Memory
-Damage is permanent & irreversible
Robbins & Cotran’s Pathologic Basis for Disease 7-48

4. Initiation and Promotion
Lecture #31 Handout
Initiation and Promotion
Applications of Promoters do not effect DNA directly and are Reversible
- They require previous initiation to cause tumors
Robbins & Cotran’s Pathologic Basis for Disease 7-48

5. Carcinogenic Chemicals
Lecture #31 Handout
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).
Robbins & Cotran’s Pathologic Basis for Disease table 7-11
& Robbins Basic Pathology Table 6-4

6. Chemical Carcinogenesis
Lecture #31 Handout
Chemical Carcinogenesis
Most chemical carcinogens are procarcinogens and require metabolic activation to form the ultimate carcinogen.
Balance between metabolic activation and inactivation.
Robbins & Cotran’s Pathologic Basis for Disease 7-49

7. Radiation Carcinogenesis
UV rays from sunlight and ionizing radiation (includes X-rays, g-rays, protons, neutrons, other particles).
Can transform all cell types.

8. UV Radiation Can _______________________________ cell division.
Can inactivate enzymes.
Can induce gene mutations.
Pyrimidine dimers.
Can kill cells.

9. 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.

10. Viral Carcinogenesis DNA viruses RNA 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

11. Lecture #31 Handout
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 _________________.
Robbins & Cotran’s Pathologic Basis for Disease 7-51

12. Human T-cell Leukemia Virus Type 1
Lecture #31 Handout
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.
Robbins’ Basic Pathology 6-32

13. Lecture #31 Handout
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
Robbins’ Basic Pathology 6-17

14. Host Defense Against Tumors
Tumor specific-shared antigens
Mutated Self Protein.
Antigens resulting from mutations (oncogenes).
Overexpressed or Underexpressed antigens.
Viral antigens.

15. Tumor-Specific Shared Antigens
Lecture #31 Handout
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

16. Lecture #31 Handout
Mutated Self Protein
Various normal self proteins can be mutated by carcinogens (chemicals, radiation, etc.).
Robbins’ Basic Pathology 6-33

17. Antigens resulting from Mutant Oncogenes
Lecture #31 Handout
Antigens resulting from Mutant Oncogenes
Mutants present only in tumor cells.
No evidence that this occurs naturally.
Robbins’ Basic Pathology 6-33

18. Overexpressed Antigens
Lecture #31 Handout
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

19. Viral Antigens Viral genes (oncogenes) expressed in tumor cells.
Lecture #31 Handout
Viral Antigens
Viral genes (oncogenes) expressed in tumor cells.
Robbins’ Basic Pathology 6-33

20. Anti-Tumor Mechanisms
Lecture #31 Handout
Anti-Tumor Mechanisms
Robbins’ Basic Pathology th Ed.

21. Anti-Tumor Mechanisms
Lecture #31 Handout
Anti-Tumor Mechanisms
Both cell-mediated and humoral immunity can have anti-tumor activity.
Cytotoxic T cells.
Attack cells expressing peptide-
________________________________________.
Robbins’ Basic Pathology th Ed.

22. Anti-Tumor Mechanisms
Lecture #31 Handout
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 th Ed.

23. Anti-Tumor Mechanisms
Lecture #31 Handout
Anti-Tumor Mechanisms
Macrophages.
Activated macrophages can be cytotoxic to tumor cells.
Phagocytosis.
cytokine secretion.
Antibody.
Targeting for compliment.
ADCC.
Robbins’ Basic Pathology th Ed.

24. 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
__________________________________________.

25. 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)

26. 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.

27. 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.

28. 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

29. 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.

30. 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.

31. Laboratory Diagnostics
Immunocytochemistry of a malignant tumor to identify its tissue of origin. (Anticytokeratin antibody to identify epithelial origin)
Robbins & Cotran’s Pathologic Basis for Disease 7-56

32. Next Time
Skin Pathologies
Reading: Robbins, Chapter 22

33. Objectives
Describe the process and pathway of chemical carcinogenesis.
Initiation & Promotion
Describe the types of carcinogenic radiation.
Describe the various types & causes of viral carcinogenesis.
DNA Viruses (papilloma virus, EBV, Hepatitis B)
RNA Viruses (HTLV-1)
Describe host defenses against tumors.
Various forms of antigen presentation
Anti-Tumor Mechanisms (Cytotoxic T cells, Natural Killer cells, Macrophages, Antibodies)
Describe the basics of tumor grading & staging.
Describe the laboratory techniques used in diagnosing cancer.