Aims

• Chemical carcinogens

• Viral carcinogenesis

• Host defense against tumors

• Grading and Staging

• Laboratory Diagnosis

• Readings: Robbins; Chapter 6

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 ____________________________________.

Robbins & Cotran’s Pathologic Basis for Disease 7-48

Initiation and Promotion

Memory-Damage is permanent & irreversible

Initiation-Causes permanent DNA damage

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

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).

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.

Radiation Carcinogenesis

• UV rays from sunlight and ionizing radiation (includes X-rays, -rays, protons, neutrons, other particles).

• Can transform all cell types.

UV Radiation

• Can _______________________________ cell division.

• Can inactivate enzymes.

• Can induce gene mutations.– Pyrimidine dimers.

• Can kill cells.

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.

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

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

_________________.

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.

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

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.

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

Mutated Self Protein

• Various normal self proteins can be mutated by carcinogens (chemicals, radiation, etc.).

Robbins’ Basic Pathology 6-33

Antigens resulting from Mutant Oncogenes

• Mutants present only in tumor cells.

• No evidence that this occurs naturally.

Robbins’ Basic Pathology 6-33

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

Viral Antigens

• Viral genes (oncogenes) expressed in tumor cells.

Robbins’ Basic Pathology 6-33

Anti-Tumor Mechanisms

Robbins’ Basic Pathology 6-35 7th Ed.

Anti-Tumor Mechanisms

• Both cell-mediated and humoral immunity can have anti-tumor activity.

– Cytotoxic T cells.• Attack cells expressing peptide-

________________________________________.

Robbins’ Basic Pathology 6-35 7th Ed.

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.

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.

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

__________________________________________.

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)

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.

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.

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

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.

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.

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)

Next Time

• Skin Pathologies

• Reading: Robbins, Chapter 22

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.