Dr. Hiba Wazeer Al Zou’bi Neoplasia 6 Dr. Hiba Wazeer Al Zou’bi

ETIOLOGY OF CANCER: 1. Chemical Carcinogens A-Diret-Acting Agents: - Require no metabolic conversion to become carcinogenic - Weak carcinogens. - Alkylating agents and acylating agents

b. Indirect-Acting Agents: - Require metabolic conversion to an ultimate carcinogen mediated by the cytochrome P-450–dependent monooxygenases. 1- Benzo[a]pyrene present in cigarette smoking causes lung cancer. 2- Polycyclic hydrocarbons, produced from smoked meats and fish and fossil fuels. 3- Aromatic amines and azo dyes (β-naphthylamine) associated with with urinary bladder cancer (in the aniline dye and rubber industries).

c. Natural planet and microbial products: Aflatoxin B1 produced by Aspergillus, that grows on improperly stored grains and can cause hepatocellular carcinoma.

Mechanisms of Action of Chemical Carcinogens Most chemical carcinogens are mutagenic. All direct and ultimate carcinogens contain highly reactive electrophile groups that form chemical adducts with DNA, proteins and RNA. The commonly mutated oncogenes and tumor suppressors are RAS and TP53. Initiator (Mutagen)– A chemical inducing irreversible DNA damage Promoter- A chemical augmenting effect of initiator by promoting cell growth

II. Radiation Carcinogenesis A- Therapeutic irradiation of the head and neck can give rise to thyroid cancers years later. Causes chromosome breakage, translocations, and, less frequently, point mutations. Double stranded DNA breaks seem to be the most important form of DNA damage B- Natural UV radiation derived from the sun can cause skin cancers . - Damage DNA by forming pyrimidine dimers - Patients with the inherited disease xeroderma pigmentosum there is a increased predisposition to skin cancers .

III. Viral and Microbial Oncogenesis Oncogenic RNA Viruses: HTLV1 (Human T cell lymphotropic virus-1) Induces T cell Leukemia /Lymphoma, endemic in Japan Leukemia develops only in about 3% to 5% of infected persons aftera long latent period of 20 to 50 years. Transmitted sexually,blood or milk Mode of action: Virus TAX gene attaches to CD4+ T cells TAX interacts with several transcription factors, such as NF-κB, so transactivate the expression of genes that encode cytokines, cytokine receptors, and costimulatory molecules Directly bind and activate cyclins Suppresses action of TP53 & CDKI

2- Oncogenic DNA Viruses: 1- Human Papillomavirus (HPV) causes: a. Skin warts (Benign squamous papilloma) b. Genital warts caused by low risk HPV (6 and 11) c. Squamous cell carcinoma of the uterin cervix caused by high-risk HPVs (16 and 18) Mode of action HPV have transforming early genes (E6,E7) E6 inactivates p53no apoptosis E7 binds to Rb releasing E2F transcription effect  activates cyclins, & inhibit CDKI High risk groups have a stronger affinity of early genes to E2F

2. Epstein-Barr Virus (EBV) : a. Burkitt lymphoma b. Lymphomas in patients with AIDS c. Nasopharyngeal carcinoma. d. Hodgkins lymphoma.

Mode of action of EBV EBV has LMP1 (Latent memrbrane protien) gene - Induces B cell proliferation by activating signaling pathways, as NF-κB and JAK/STAT - Prevents apoptosis by activating BCL2 Another EBV-encoded protein, EBNA2, transactivates several host genes, including cyclin D. In immunologically normal person EBV-driven polyclonal B cell proliferation is readily controlled, and patient either remains asymptomatic or experiences a self-limited episode of infectious mononucleosis Evasion of the immune system seems to be a key step in EBV-related oncogenesis. Impairs immune competence, allowing sustained B cell proliferation.

3. HBV and HCV : Between 70% and 85% of hepatocellular carcinomas worldwide are due to infection with HBV or HCV. The oncogenic effects of HBV and HCV are multifactorial, but the dominant effect seems to be immunologically mediated chronic inflammation, with hepatocellular injury, stimulation of hepatocyte proliferation, and production of reactive oxygen species that can damage DNA. - A key molecular step seems to be activation of the nuclear factor-κB (NF-κB) pathway in hepatocytes caused by mediators derived from the activated immune cells, lead to blocks apoptosis, allowing the dividing hepatocytes to incur genotoxic stress and to accumulate mutations.

The HBV encodes Hbxprot. Has dual action : Acts as growth promoting gene Hbx binds to p53  Inactivates suppressor function The HCV has HCV core Protein which may act through activating signal transduction  Proliferation

3- Helicobacter pylori: The first bacterium classified as a carcinogen H.Pylori Causes: 1. Adenocarcinoma of stomach. 2. Gastric lymphoma (MALT) , early eradication of H. pylori "cures" the lymphoma. - First described as a cause for peptic ulcer - There is an initial development of chronic inflammation/gastritis, followed by gastric atrophy, intestinal metaplasia of the lining cells, dysplasia, and cancer. This sequence takes decades to complete and occurs in only 3% of infected patients. In adenocarcinoma,H.pylori contains Cytotoxic Associated A gene (Cag A)  initiation of signaling cascade mimics unregulated GF stimulation  Cell proliferation Other strains cytokines & TNF MALTOMA

Tumor Antigens 1- Products of Mutated Oncogenes and Tumor Suppressor Genes Neoplastic transformation, lead to the expression of cell surface antigens that are seen as non-self by the immune system. Tumor antigens arise from β-catenin, RAS, p53, and CDK4 Many tumors may carry the same mutation, such antigens are shared by different tumors. In some cases, unmutated oncogenes are overexpressed in tumors, as HER2/NEU oncogene in a subset of breast cancers.

2- Products of Other Mutated Genes Mutated genes whose products are not related to the transformed phenotype and have no known function. Found more frequently in chemical carcinogen- or radiation-induced tumors 3- Overexpressed or Aberrantly Expressed Cellular Proteins Tumor antigens may be normal cellular proteins that are abnormally expressed in tumor cells and elicit immune responses.

4- Tumor Antigens Produced by Oncogenic Viruses Viruses produce proteins that are recognized as foreign by the immune system. The most potent of these antigens are proteins produced by latent DNA viruses (HPV and EBV). CTLs recognize antigens of these viruses - Vaccines against HPV antigens have been found to be effective in prevention of cervical cancers in women.

5- Oncofetal or embryonic Antigens - Carcino-embryonic antigen (CEA) and alpha fetoprotein. Are expressed during embryogenesis but not in normal adult. - Derepression of the genes that encode these antigens causes their reexpression in colon and liver cancers. - Although, they are not tumor-specific, they can serve as serum markers for cancer. For example , serum CEA is high in cases of colon cancer.

6- Altered Cell Surface Glycolipids and Glycoproteins - Most human tumors express higher than normal levels and/or abnormal forms of surface glycoproteins and glycolipids, which may be diagnostic markers and targets for therapy. - Include gangliosides, blood group antigens, and mucins. - Several mucins are of special interest , include CA-125 and CA-19-9, expressed on ovarian carcinomas, and MUC-1, expressed on breast carcinomas.

7- Cell Type–Specific Differentiation Antigens: - Tumors express molecules that normally are present on the cells of origin (differentiation antigens). - Important in identifying the tissue of origin of tumors. - For example, B cell–derived lymphoma : characteristic of this lineage, is the surface markers CD20. Antibodies against CD20 are used for immunotherapy of certain B cell lymphomas.

Antitumor Effector Mechanisms Immune surveillance : recognition and destruction of newly appearing tumor cells, which are seen as foreign by the host immune system. Cell-mediated immunity is the dominant antitumor mechanism 1- Cytotoxic T Lymphocytes Play a protective role, chiefly against virus-associated neoplasms (HPV-induced tumors). 2- Natural Killer Cells May provide the first line of defense against tumor cells. After activation with IL-2, NK cells can lyse a wide range of human tumors - T cells and NK cells apparently provide complementary antitumor mechanisms.

3- Macrophages Classically activated macrophages exhibit cytotoxicity against tumor T cells, NK cells, and macrophages may collaborate in antitumor reactivity, because interferon-γ, a cytokine secreted by T cells and NK cells, is a potent activator of macrophages. Activated macrophages may kill tumors by mechanisms similar to those used to kill microbes (e.g., production of reactive oxygen metabolites) or by secretion of (TNF). 4- Humoral Mechanisms Administration of monoclonal antibodies against tumor cells can be therapeutically effective

Immune Surveillance and Immune Evasion by Tumors The strongest argument for the existence of immune surveillance is the increased frequency of cancers in immunodeficient hosts. About 5% of persons with congenital immunodeficiencies develop cancers, a rate that is about 200 times reported rates for persons without such immunodeficiencies. Immunosuppressed transplant recipients and patients with acquired immunodeficiency syndrome have increased numbers of malignancies.

Most cancers occur in persons who do not suffer from any overt immunodeficiency. If immune surveillance exists, how do cancers evade the immune system in immunocompetent hosts? Several escape mechanisms have been proposed: 1- Selective outgrowth of antigen-negative variants. During tumor progression, strongly immunogenic subclones may be eliminated. 2- Loss or reduced expression of histocompatibility molecules. - Tumor cells may fail to express normal levels of human leukocyte antigen (HLA) class I, escaping attack by CTLs.

3- Immunosuppression - Many oncogenic agents (e.g., chemicals, ionizing radiation) suppress host immune responses. 4- Antigen masking Many tumor cells produce a thicker coat of external glycocalyx molecules, such as sialic acid–containing mucopolysaccharides, than normal cells. - This thick coat may block access of immune cells to antigen-presenting molecules, thereby preventing antigen recognition and cell killing. 5- Downregulation of co-stimulatory molecules - Costimulatory molecules are required to initiate strong T cell responses. - Many tumors reduce expression of these costimulatory molecules.