Tumorbiology: Effectofenvironmental factors, Cancerimmunology Flashcards
Effect of environmental factors on tumor formation
• General patho mechanism: carcinogen→damaged genetic material →tumor formation
I.)Chemical carcinogens
II.)Physical carcinogens: radiation, (mechanical effects) III.)Biological carcinogens: oncogenic bacteria, virus, parasitic worms, (chronic inflammation, aging)
I.)Chemical carcinogens: mode of action
• Carcinogens can act:
1.Directly
2. Indirectly: carcinogenicity develops following structural changes in the organism such as by activity of CYP enzymes, glutation-S-transferase.
• Carcinogen chemical or its metabolite: electrophile → binds to the electron-rich molecules of the cell (mostly DNA) → DNA damage → changes in cell division and differentiation, etc → tumor formation (A particular carcinogen acts mostly on a particular organ!)
I.)Chemical carcinogens: types
- Carcinogen can be
1.Initiator: DNA of the cells will be primarily modified(mutated)
• Alkylating agents (immunosuppressive drugs & cytostatics)
• Polycyclic aromatic hydrocarbons: metabolic activation is needed (tobacco, charcoal broiled meat, smoked meat)
• Aromatic amines & azo dyes: metabolic activation needed
• Mycotoxin(AflatoxinB1)
• Nitrosamines and –amides: intestinal microbes produce from nitrate and nitrite (source of nitrate & nitrite: preservatives, cured meat, drinking water)
• Asbestos, silicate, talcum, vinyl-chloride monomer (PVC), metals: chromium, nickel, arsenic
2.Promoters are the chemicals which cannot cause DNA damage but act on cells after application of initiators
• Mostly produced in the body (hormones, free radicals,H2O2 , bileacids etc.)
• If for some time there is no promoter action, the primarily produced DNA modification will be reversed and the tumor formation fails following the next promoter action.
II. Radiation
• The carcinogenic effect of radiation has been proven in all spp in vivo+in vitro
• Consequence: double & simple DNA strand breaks, damaged bases, covalent crosslinks inside and between the DNA strands (pyrimidine dimer), DNA-protein crosslinks, protein-protein crosslinks
• Types of radiation:
1. Sun light UVB (280-320 nm) → mutagenic, UVC (200-280 nm) is mutagenic also, but atmospheric ozone can protect partly against this radiation. Consequence of DNA damage: mutationofthenuclearDNA,mutationsintumorsuppressorgenes,enzymeinactivation,etc.
2. Ionizing radiation (very low wavelength): electromagnetic CT, PET (X-ray, gamma-ray) and particle radiation(proton, electron, alpha)
• Consequence in the cells:H2O→H+ +OH-, followed by DNA damage + mutation
• Ionising radiation sources: radioactive nucleus,(Hiroshima), cosmic radiation
• PET=Positron emission tomography (x-ray),CT=computed tomography(gamma-ray)
III. Biological carcinogens
- Virus: chicken Rous sarcoma virus (1911), hepatitis B, C virus, Bittner mouse mammary tumor virus (MMTV), Human papilloma (HPV) virus, Epstein-Barr virus, HIV type 1, Human T-cell lymphotropic virus
- Bacteria : Helicobacter pylori
- Helminths: Opisthorchis viverrini, Clonorchis sinensis, Spirocerca lupi (canine esophageal carcinoma)
- Consequence: virus can be integrated in the genome, Changes gene expression: mutations & epigenetic effects
role of MMTV=Bittner virus in the development of MMT (mouse mammary tumor)
• MMT cells were cultured in vitro or injected in newborn mouse (2500 or 7500 cells/animal IP).Bittner virus could be detected both in the cell culture & developed abdominal tumor (after 80 days)
MMTV: Reverse transcribing RNA viruses (retroviruses) use the enzyme to reverse-transcribe their RNA genomes into DNA, which is then integrated into the host genome and replicated along with it
Most important CD antigens of lymphocytes
CD4 (Th cell), CD8 Tc cell), CD20
Immunological background of tumor formation
1) Atg presentation by dendritic cells
2) Th & Tc cells
3) perforin + granzyme produced by the CTL (cytotoxic T lymphocytes) and NK (natural killer cells) can kill tumor cells .However, tumor-specific Tcells do not allow to enforce anti-tumor action of CTLs + NKs
Classification of tumor antigens
- Tumor-Specific Antigens(TSA), present only on tumor cells (specific vaccines)
- Tumor-Associated Antigens(TAA),which are present on some tumor cells & some normal cells (weak immune response against vaccines).
• Over expressed/ Aberrantly Expressed Cellular Proteins
-Tumor Antigens Produced by Oncogenic Viruses
• Oncofetal Antigens
- alphafetoprotein: hepatocellular cancer
• Altered Cell Surface Glycolipids and Glycoproteins
-Her2= human epidermal growth factor receptor 2:breast cancer
- EGFR=epithelial growth factor receptor
- Tyrosinase: melanoma
• Cell Type-Specific Differentiation Antigens
- PSA=prostate specific antigen: prostate cancer
- CEA=carcinoembryonic antigen: adenocarcinomas of colon, breast, lung, & other epithelial cancers
- MUC1=transmembrane type I molecule: almost in all human epithelial adenocarcinomas
• 1A10 & SB2: in the serum of dogs: canine mammary carcinoma
• CA-125= Cancer antigen125: epithelial ovarian cancers. CA-125 has not found application in vetmed
Failure of host defenses against tumor antigen
• tumours may continue to grow despite the presence of TAAs. Deficient host response to the TAA, include the following:
- Specific immunologic tolerance to TAAs in a process that involves Atg presenting cells: no appropriate Atg presentation occurs in tumor cells!!
• Suppression of immune response by chemical, physical, or viral agents (eg, helper T-cell destruction by HIV)
• Suppression of the immune response by the tumor itself:
- Tumor does not produce: HLA (human leukocyte-antigen complex), LMP-2 & LMP-7proteases, and /orTAP-1 & TAP-2 transporters. These factors are needed for complete Atg presentation
- Tumor does not produce: MHC (major histocompatibility gene complex)
- Dendritic cells of tumor aren’t mature
- Concentration of Trp & Arg is low in the surrounding of tumors, however these ass are needed for immune response
- High concentration of immun suppressor mediators such as IL-10, TGF + low concentration of CD8 (tumor killing function) supporting mediators such as IL- 7,IL-12,IL-15
• Immunologically protecting stroma around the tumor
Immune response in cancer: specific role of dendritic cells, 1st step
- Dendritic cells: specialized Atg presenting cells
- To produce active, tumor-killing CTL (cytotoxic T-lymphocytes) are needed: interaction of naïve CD8 cells and mature dendritic cells, further other co-stimulating and co-inhibiting stimuli
- However in tumors unmatured dendritic cells can be found → decreased activity of CTL
- Decreased activity of CTL →tumor progression
Immune response in cancer: specific role of Treg (regulatory T-cells), 2nd and 3rd steps
• Changes of different stimulation markers in tumors→ activation of PD1 (programmed death) element of T cells by immature tumor dendritic cells → T cells → differentiation in Treg → apoptosis of T cells & inhibition of CTL (cytotoxic T-lymphocytes)
• Decreased activity of CTL in the tumors from:
- immature (tumor) dendritic cells → more IL-10 + TGF → differentiation in Treg
- Treg → further increase of IL-10 + TGF synthesis → decreased synthesis/function of CTL
- High Treg concentration in tumor →decreased tumor elimination → tumor progression
Immune response in cancer: tumor specific TLs(CD8+ cells)has no cytotoxic action, 3rd step
• Tumor TLs (CD8+ T lymphocytes) don’t produce interferon, perforin + granzyme (they have antitumor activity) => in tumors CTL/CD8 „cell-killing” function will not occur.
The reasons are the followings:
• Differentiation of T-cells into Treg
• Immunosuppressive mediators
• Existing inhibitory surface receptors on the CD8+ cells
• Few Trp and Arg in tumors. Decrease of Trp concentration due to increased activity of IDO (indolamine 2,3 dioxygenase) - Trp-metabolizing enzyme - in tumor cells. Decrease of Arg concentration is due to increased arginase activity in tumor cells.
Summary
during elimination phase the effector cells of immune system, CTL + NK cells recognize (w/ the help of dendritic & CD4+ T cells) and kill (w/ of CTL/CD8+)the tumor cells.
Anti-tumor immunotherapy= immunoncology: „active immunization”
- Tumor cells: weak immune response, because they do not express HLA (human leukocyte atg complex) which are needed for atg presentation & in the tumor cells can not be found real Atg presenting cells
- Active immunization by tumor specific antigens (TSA), tumor associated Atg (TAA) or by the tumor cells
- Weak antitumor effect & as SE :autoimmunity