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BHS 116.3 – Physiology III Notetaker: Vivien Yip Date: 4/24/2013, 1st hour Page1 Lecture 31 Chemical carcinogens, viral carcinogens, host defense against tumors, grading and staging Chemical Carcinogenesis - 2 step process o 1st step: Initiation Results from exposure to carcinogenic agent (chemical, radiation) Causes permanent irreversible DNA damage Not sufficient for tumor formation o 2nd step: Promotion Can induce tumors from previously initiated cells Not tumorigenic by itself Does not affect DNA directly (promoter itself) reversible usually a growth factor or some other cellular stimulus that activates DNA transcription with the damaged DNA Initiation and Promotion - Initiation o Causes permanent DNA damage - Memory o Damage is permanent and irreversible - Promoters o do not effect DNA directly and are reversible o require previous initiation to cause tumors Group 1- only initiation occurs, irreversible DNA damage, nothing follows it, no promotor, no tumor formed Group 2- initiation then sequential application of promoter following initiation, a lot of promoter in a short period of time tumor Group 3 – will have nothing after first set of initiation, then promoters are added and trigger tumor formation tumor (Key: a lot of promoters in short period of time in close proximity will cause tumor if the DNA has been initiated) Group 4- initiation has to occur prior to promoter no tumor Group 5- No initiation, only promoter no tumor Group 6- initiation occurs (irreversible DNA damage), promoter is applied in minimal amounts, spaced out over long period of time, not going to trigger tumor (require cluster of promoter application to get tumor) no tumor Carcinogenic Chemicals - diverse in structure - natural OR synthetic - direct OR indirect (procarcinogens) o procarcinogens require metabolic step to become carcinogenic* o i.e benzoapyrene is found in cigarette smoke BHS 116.3 – Physiology III Notetaker: Vivien Yip - Date: 4/24/2013, 1st hour Page2 o more indirect carcinogens than direct carinogens highly reactive electrophiles that react with electron rich sites in cells (DNA, RNA and proteins) Chemical carcinogenesis - most chemical carcinogens are procarcinogens and require metabolic activation to form the ultimate carcinogen - in most cases, carcinogens are detoxified in liver and excreted via urine/bile, usually not a problem - can be some direct carcinogens that can lead to DNA damage - also potentially some that are converted (procarcinogen more active carcinogen) o these intermediates can sometimes be detoxified via liver and excreted - some carcinogens can evade the liver and cause DNA damage - DNA repair genes can repair damaged DNA if carcinogen is able to act on it o can trigger apoptosis if DNA is mutated - Some carcinogens damage DNA beyond help of p53 and RAS will cause tumor since repair process is stopped - primary targets for mutation are RAS and p53 (most commonly affected*) - multistep process with checks and balance in place, carcinogens that evade this will cause a tumor Radiation carcinogenesis - UV rays from sunlight and ionizing radiations - X rays, gamma rays, protons, neutrons - Can transform all cell types - irreversible damage UV Radiation - Can inhibit cell division - Can inactivate enzymes - Can induce gene mutations pyrimidine dimers o major reason for DNA damage - Can kill cells, i.e. extensive sunburns Ionizing Radiation - Both electromagnetic (x rays and gamma rays) and particulate (alpha, beta particles, protons & neutrons) are carcinogenic - cause irreversible DNA damage - 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 tract are relatively resistant to ionizing radiation induced cancers Viral carcinogenesis - DNA VIRUSES o Form stable associations with host cells genome o Papillomaviruses BHS 116.3 – Physiology III Notetaker: Vivien Yip Date: 4/24/2013, 1st hour Page3 Involved in pathogenesis of warts to carcinoma new vaccine for cervical cancer (Gardisil) o Epstein barr virus Involved in the pathogenesis of Burkitt lymphoma and Hodgkin disease o Hepatitis B virus involved in pathogenesis of liver cancer - RNA VIRUSES o Human T cell leukemia virus type I T cell leukemia/lymphoma Epstein barr virus - EBV serves as one factor in the development of Burkitt lymphoma o Effects primarily B cells - viruses integrate their genome into host cell o cells will express viral genes (viral oncogenes) in host cell o cell becomes tumorogenic o get transformed B cells, some get recognized by cytotoxic T cells destroyed, will not proliferate to tumor cells o some that evade the immune system, express EPV antigens on their surface o one of the things triggered by the virus is chromosomal translocation b/w chromos 8 & 14 o Mutation of oncogene MYC gets expressed and trigger tumor formation, proliferation of a number of B cell tumors excessive proliferation of mutant B cell blood cell cancer, do not get actual tumors Human T cell leukemia virus type I (HTL) - RNA virus - Transmitted by sexual contact or blood transfusion - First infected T cells (CD4+) proliferate due to autocrine and paracrine cytokine stimulation o Due to viral protein, TAX, which increases IL2 AND IL2r (receptor) expression, while inhibiting tumor suppressor genes o CD4+ T cell will be producing high levels of IL2 (proliferation phase of CD4+ T cells when they activate) and IL2r cytokine released, binds to own receptor and triggers increased proliferation o TAX = oncogene in HTL virus - Ultimately one T cell clone mutates during the great amount of replication o results in malignancy BHS 116.3 – Physiology III Notetaker: Vivien Yip Date: 4/24/2013, 1st hour Page4 Hallmarks of Cancer - Most cancers will acquire these properties during their development over time as the tumor proliferates inside the body (to evade our immune system or being destroyed) o Evade apoptosis o Self-sufficient growth signals (can’t rely on growth factors secreted by the rest of the body) o Insensitive to antigrowth signals (our body uses this to destroy the potential tumor) o Metastasis (spread to other sites) o Limitless replication (highly active telomerase, CA cells can go through limitless replication) o Sustained angiogenesis (has to have its own blood supply, tumors can only survive through their own blood supply to sustain their highly metabolic activity) Host Defense Against Tumors - Our bodies are exposed to carcinogens all the time, we are very good at getting rid of these tumor cells, alerts are in place to activate immune system - 1.Overexpressed Antigen o Present in both normal and tumor cells o Low levels in normal cells result in non detection by T cells - 1.Aberrantly expressed o MAGE family of genes are antigens usually silent in normal cells and expressed in tumor cells o Also expressed by immunologically privileged tissue in testes o liver cells have genes for all cells, if something disrupts that cell so that it is expressing normally immune privileged antigens (testicular or ocular antigens, where it shouldn’t belong) on its surface, that will signal the immune something is wrong - 2.Mutated self protein o Various normal self proteins can be mutated by carcinogens (chemicals, radiation) o Protein is mutated - 3.Antigens resulting from mutant oncogenes o Mutants present only in tumor cells o Gene is mutated and produces a mutant protein o RAS becomes mutated and continuously hydrolyzes GDP to constantly become active o No evidence that this occurs naturally o Requires an initiator - 4.Viral Antigens o Viral genes (oncogenes) expressed in tumor cells by oncogenic virus Anti tumor mechanisms - Both cell mediated and humoral immunity can have antitumor activity o Cytotoxic T cells (CD8+) Attack cells expressing peptide-MHC class 1 previously activated by specific Ag will go after all those cells that expresses “non self Antigen” especially viruses, viral peptides are expressed via MHC 1 will end up triggering CD8 + cells - BHS 116.3 – Physiology III Notetaker: Vivien Yip - - - - Date: 4/24/2013, 1st hour Page5 NK cells o May provide first line of defense as no prior sensitization is necessary o Attack tumor cells with lowered levels of MHC class I (or lack of MHC I) o Can also participate in ADCC , Antibody Dependent Cell Cytotoxicity, Antibody produced against specific tumor antigen and binds to tumor cell, NK cell can recognize the antibody (Fc receptors), binding triggers destruction Macrophages o Activated macrophages can be cytotoxic to tumor cells Phagocytosis, especially through ADCC Cytokine secretion, draws in WBC to site Antibody o Targeting for complement activation o ADCC o can form MAC on tumor cell and lead to lysis CD4+ also plays a role in activating the B cell to cause class switch, activates macrophages Grading & Staging of tumors - Grading of a cancer is based on degree of differentiation of the tumor cells and the number of mitoses within the tumor o Correlates with the neoplasm’s aggressiveness - Tumors are classified as grades I-IV with increasing anaplasia o I- well differentiated (benign tumor, look exactly like tissue they originated from) o IV- completely undifferentiated (anaplastic, looks nothing like host organ malignant metastatic tumor) - Staging is based on the size of the primary lesion, 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, more accurate - 2 systems used: o TNM classification T for tumor (T1, small-T4, large for increasing size) N for lymph node involvement (N0, no involvement-N3, significant amount of lymph nodes for increasing range and # of nodes involved) M for metastases (M0, no metastases-M2, significant amount of metastases) Varies for each form of cancer o AJC system (American joint committee on cancer staging) Cancers divided into stages 0, benign – IV, metastatic tumor 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 - In order to get the tissue, we have various ways: o Excision or biopsy Appropriate preservation of the sample is critical (preservation/freezing) o Fine needle aspiration Sample is aspirated by a needle and stained before examination o Cytologic smears Cancer cells have a decreased adhesiveness (scraped off a lot easier) and are morphologically different - PAP Smear (papanicolaou) o Normal cells are large and flat and very adherent BHS 116.3 – Physiology III Notetaker: Vivien Yip Date: 4/24/2013, 1st hour Page6 Cervical tumor cells are not adherent and have a lot more cells present in the smear very easy to distinguish o Cancer cells have large hyperchromatic nuclei, polymorphic nuclei and mitotic cells - Newer techniques are continually being added to improve diagnosis of various cancers o Immunohistochemistry Allows for categorization of undifferentiated malignant tumors, determination of site of origin of metastatic tumors, detection of molecules with therapeutic significance stain sample with different antigens, i.e. lung biopsy (liver antigens present = originated in liver and metastasized in the lung) i.e. anticytokeratin antibody to identify epithelial origin o Tumor markers Biochemical markers of various cancer types o Molecular diagnosis Useful in diagnosis as well as predictive and therapeutic aspects of cancer screening tool for certain genes that lead to cancers Cancer Tx - Chemotherapy o Anti-mitotic drugs/drugs that interfere with DNA replication - Radiation tx o Causes a lot of collateral damage - Surgical removal - Biological therapy o Enhancement of immune system (interferons & interleukins) - Gene therapy - Targeted cancer therapy o Drugs that interfere w/ carcinogenesis, anti-angiogenesis drugs o prevent collateral damage - Radiofrequency ablation? o Novel technique, not FDA approved o Small amounts of metals that burns the tumor with radiofrequencies o Clicker Q Which of the following processes is reversible? - initiation of carcinogenesis - promotion of carcinogenesis