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Cancer biology (introduction (what is cancer? (benigne/maligne (maligne…

- - - - lung
      - bowel
      - breast
        
        although they arise from the same tissue type, still variety is huge
  - - - loss of growth control
        
        growth is gradual
        
        mutations
        
        epigenetic changes
        
        activating element
        
        KRAS (90%)
    - - maligne
        
        cancer cells invade
        
        metastatic disease
        
        major factor to death
        
        features
        
        spread
        
        methastasize
        
        growth rate is high
        
        variable differentation
        
        life threatening
        
        characteristics
        
        Hanahan & Weinberg, 2000, Cell
        
        sustain proliferative signalling
        
        evading growth supressors
        
        activating invasion and methastasize
        
        1 more item...
        
        Hanahan and Weinberg, 2011, Cell
        
        emerging hallmarks
        
        deregulation cellular energetics
        
        avoiding immune destruction
        
        enabling characteristics
        
        genome instability and mutation
        
        tumor-promoting inflammation
        
        colorectal cancer
        
        vogelstein method
        
        normal epithelium
        
        hyperplastic epi
        
        4 more items...
        
        branched model becoming more popular as it is possible to sequence
        
        ''darwinian evolution''
        
        daughter cells acquire different mutations
      - benigne doesn't methastazise
        
        benigne
        
        local
        
        slow growth rate
        
        well differentiated
        
        not life threatening
  - - - genes are checked and targeted to those special mutations
  - - - even living in the isolated bubble, so to speak
    - - mutations occurring in the coding section of the genome
    - - mutations happening in non-coding areas
  - - - 10 years later methastasize
        
        tumor dormancy
        
        alteration in immunological status?
- - - - tendency to certain routes
  - - - raf
        
        MEK
        
        ERK
        
        mutations
        
        resulting in promoting cell proliferation
  - - - truncations
    - - chromosomal translocation
        
        increases the expression of myc
        
        in normal cells levels are low
        
        oncogenic myc
        
        point mutations preventing mic degradation
        
        accumulation of myc
        
        over expressed in 70% cancers
  - - - on and off conformation
        
        intramolecular phosphorylation
      - target is to discover and build inhibitors
        
        resistance
        
        mutation blocking the active site
        
        up regulation of another kinase
        
        down regulation of phosphatase
        
        redundant kinases at initial treatment
        
        mutation downstream to kinase
- - - - observational
        
        cohort studies
        
        pros/cons
        
        complex, time-consuming
        
        confounding effects
        
        other parameters affect
        
        issues happening simultaneously but may not cause one another
        
        take a healthy population, give 50% of them gum
        
        10 years after collection of the data
        
        nurse's health studies
        
        case control studeis
        
        groups are being chosen by their status
        
        cons
        
        people become bias as they already see the result, such as the location of the tumor
        
        cell phone brain tumor
      - experimental
- - - - kataegis
        
        clustered mutations
      - chromothipsis
        
        chromosomal rearrangement
    - - transition
      - transversion
      - insertion
      - deletion
      - missense mutation
      - nonsense mutation
    - - 50-80 overall
    - - promoter area
      - coding area
        
        deadly and difficult to correct
    - - chemicals
        
        carcinogens
        
        nitrosamines
      - radiation
        
        UV radiation
        
        skin cancers
        
        most typical
      - infectious pathogens
        
        viruses
        
        virus damages the DNA
        
        HPV
      - endogenous carcinogenic reactions
        
        result of producing oxidized products
      - carcinogenic reactions
        
        APOBECs
        
        removes uracil
        
        DNA polymerase
        
        endogenous reaction
    - - usually in G1 phase
  - - - aberrant regulation of CC
      - uncontrolled proliferation
      - carcinogenesis
    - - CKDs
        
        kinase=tyrosine, serine, threonine, histidine
      - cyclins
        
        interact with CDKs
        
        after
        
        interaction with inhibitory proteins
        
        degradation of cyclins by the ubiquitin-mediated proteasomal degradation
        
        types of E3 obi ligases
        
        2 more items...
        
        INK4 family and p21 of inhibitors
        
        INK family
        
        1 more item...
        
        p21(Cip/Kip) family
        
        goes from partial activation to full activation
        
        Wee1 #
        
        Cdc25
        
        phosphatase
      - inhibitory proteins
      - proteins involved checkpoints
    - - G1
        
        mitogen triggers
      - G2
      - S
      - M
        
        cyclin B
        
        CDK1
      - division due to EC signals
        
        mitogens
        
        any substance that makes cells proliferative
        
        also artificial
        
        synthetic mitogen
        
        GFs
        
        chemicals
        
        GF
    - - R
        
        CDK4/6
        
        forms a complex with cyclin D
        
        activates RB
        
        conformation change
        
        RB gene
        
        tumor supressor
        
        E2F
        
        transcription factor family
        
        when this is crossed, the cell division cannot be stopped
        
        deregulation
        
        RB alterations
        
        RB+
        
        RB-
        
        amplification of #
        
        cyclin D1
        
        altering this cancer can proceed
        
        therapeutic methods
        
        loss of p16 INK4
      - G1/S #
        
        checking the DNA integrity
        
        p53
        
        activation results to deciding the pathway
        
        normal
        
        DNA repair
        
        CtIP
        
        S, G2, M
        
        apoptosis
        
        cancerous
        
        cell cycle continues
        
        p53 mutations
        
        BRCA 1/2 mutations
        
        recruited in homologous repairment in normal cells
        
        risk to certain types of cancers
        
        2 more items...
        
        activation of p38 MAPK pathway after UV-mediated DNA damage
        
        down regulation of
        
        ATR
        
        1 more item...
        
        CHK1
        
        1 more item...
        
        cancer cells can go on
        
        normal cells would undergo apoptosis
        
        if DNA mutations
        
        if DNA damage NHEJ
        
        specific complexes that recognize the error
        
        Ku70 and Ku80
        
        quick repair, it will be checked later on
      - G2
        
        DNA replication and its control by p53
        
        DNa is already synthetized
        
        checked if there is any errors
        
        p53 independent
        
        p53 dependent
      - M
        
        choromosome separated properly
        
        spindle assembly checkpoint
        
        huge protein complex
        
        D, E, A, B is the order for the CDK to be active in cell cycle
        
        separin is regulated by securin
        
        unattached kinetochore activates SAC signal
        
        MCC binds and inhibits anaphase
        
        two kinases
        
        aurora kinases
        
        A
        
        more on the poles
        
        interacts with BRCA and p53
        
        B
        
        more in the center area of the mitotic spindle
        
        interactions microtubule proteins
        
        expressed of different phase of mitosis
        
        cell doesn't like to hang in the mitosis phase
        
        1 more item...
        
        overexpressed in late stages of cancer
      - vital mechanism
        
        cell can undergo cell cycle
        
        cancerous
        
        cancer cells can bypass the checkpoints
        
        defects in the DNA repair mechanism
        
        cannot check whether the DNA is conserved or not
  - - - programmed cell death
        
        pathways
        
        extrinsic
        
        signal comes from outside
        
        flip
        
        intrinsic #
        
        triggered intracellulary
        
        apoptosome
        
        mitochondria
        
        mitochondria membrane space
        
        release of cytochrome C triggers apoptosome complex
        
        effectors
        
        BCL-2
        
        pro-survival
        
        1 more item...
        
        pro-apoptotic
        
        3 more items...
        
        chemoresistance?
        
        p53 activation
        
        activation of p53 by
        
        stress stimuli, for example
        
        how will cell decide to activate
        
        caspase 8 triggers the intrinsic pathway
        
        type one and two
        
        type two has the protein that has to be activated first in order to continue with the apoptosis
        
        cross talk between extrinsic and intrinsic
        
        caspases
        
        aspartate area is cleaved
        
        initiator
        
        8,10,2,9
        
        executioner
        
        3,6,7
        
        targeting caspases
      - apoptotic vesicles are engulfed by macrophages
      - cancerous cells targeted to go apoptosis
      - apoptosis and cancer
        
        manipulation of amount of antiapoptotic molecules
        
        nactivating proapoptotic cell death components
        
        ways
        
        disruption of the first apoptotic signal FAS and DR5 response
        
        alteration in FAS receptors
        
        amplification of decoy receptor 3
        
        mutations in TRAIL DR5 receptors
        
        disruption on the balance of BCL2 proteins #
        
        inactivation of BAX and BAK
        
        dysregulation of inhibitor of apoptosis
        
        down regulation of negative regulator of XIAP
        
        mutations of caspase proteins
        
        mutatin in the p53 pathway
        
        confers the survival advantage to cell by disrupting apoptosis
        
        targeting apoptosis as therapeutic strategy
        
        TRAIL
        
        solid tumor
        
        halflife is short
        
        CYTOTOXICITY IS HIGH
        
        targeting IAPs
- - - - stopping uncontrolled growth
  - - - loss of RB may be important for cancer progression
  - - - first tumor suppressor to be identified
- - - - leukemia sarcoma was transmitted via injection of purified sarcoma tissue
    - - competent cells are infected
        
        species specific!
        
        based on these animal studies
        
        human cancer knowledge still increases
        
        same genes present in human cancers
      - categories
        
        acutely transforming retroviruses
        
        carry viral oncogenes
        
        enter the cell
        
        inducing cancer formation
        
        insertional mutagenesis
        
        accidentally inserting gene
        
        only occasional integration
      - virus kidnaps a cellular pro-oncogene
      - insertional mutagenesis
        
        can integrate to many sites before the first coding region
      - human perspective
        
        do not function as they function in animals
        
        interfere cell other ways to produce cancer
        
        examples
        
        HTLV-1
        
        human T cells leukemia virus, type 1
        
        HIV
        
        HCV
        
        hepatitis c virus
        
        tissue turnover increases
    - - use DNA replication machinery in cell but no integration
      - goal is to replicate genome
      - examples
        
        human papilloma viruses HPV
        
        benigne tumors
        
        maligne warts and carcinomas in uterine cervix
        
        subtypes
        
        cervical cancer specific
        
        HPV 16 and 18
        
        viral proteins E6 and E7 interfere cell cycle proteins (retinoblastoma RB =cell cycle protein ', prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide, p53 =guardian of the genome)
        
        epstein-barr
        
        nasopharyngeal carcinoma
        
        malaria areas
        
        burkitt's lymphoma
        
        hepatitis B virus
        
        increased risk for liver cancer
        
        activation of oncogenes
    - - all of these cases number of people actually developing cancer is rare
  - - - cronic inflammation
      - proteins produced by bacteria
        
        Cag A
        
        activates SHP-2
        
        mitosis
        
        cell migration
        
        cell adhesion
        
        detaching
        
        apoptosis
        
        gastritis
        
        increased
        
        cell turnover
        
        DNA rep
        
        mutation
  - - - local accumulation of fluid
      - plasma proteins
      - blood cells
    - - local immune response
      - physical injury
      - infection
    - - delivery of effector molecules
      - promote the repair processes
      - provide barrier
        
        spreading stops
    - - schistosomiasis -- bladder cancer
      - mechanisms
        
        inflammation cytokines chemokines
        
        apoptosis
        
        angiogenesis
        
        metastasis
        
        increased amounts of oxygen and nitrogen species agents ROS and NOS
        
        cancer is a wound that never heals
        
        NF-kß
        
        can be produced by
        
        also cancer cells can produce
        
        bacteria
        
        H pylori
        
        inflammatory cells activate
        
        cytokines
        
        carcinogens
        
        viruses
  - - - innate
      - adapted
    - - APC
        
        MHC I
      - specific cells
        
        MHC II
    - - altered self-cells
      - immune system is impaired
      - increased rate while population ages, as the immune system effectiveness decreases (and young individuals immune system is not highly developed)
        
        immunodeficiency patients
        
        increased number of cancers
        
        some tumor types
      - evidence that there is a immune response for cancer
        
        pathological sections
        
        sign of inflammatory response
        
        tumor infiltrating lymphocytes
      - animal studies
        
        animals can be vaccinated against tumors
        
        irradiated (dead) tumor cells
        
        animal receives live tumor cells
        
        no tumor formation
        
        animal receives tumor cells of different kind
        
        tumor formation
    - - decreased number of MHC cells on the cell surface that can be detected by immune cells
      - tumor specific antigens
        
        unique to tumor cells
        
        somatically mutated TSAs
        
        point mutation
        
        changes only one aa
        
        is it noticable
        
        fusion proteins
        
        passenger mutations=occur at the same time as cancer evolves, but happening at the same time
        
        could function as TSAs
      - tumor associated antigens
        
        not unique to tumor cells, but expressed in fetal period, CEA or AFP
        
        low levels in normal cells but high levels in tumor cells
        
        used as tumor markers
        
        patient follow up, should go down if the treatment is working
      - antigens that are over expressed in cancer cells
        
        hTERT
        
        growth factor receptors-- significance?
    - - strongly antigenic tumors
      - immune recognition a late event
      - poorly antigenic tumors
      - immunoevasion
        
        cancerous cells escape from immune system destruction
        
        tumor cells lose the tumor antigenst
        
        downreg of MHC I receptors
        
        NK-cells
      - immunoediting
        
        phases
        
        equilibrium
        
        only portion is destroyed
        
        tumor dormancy
        
        less immunogenic cell type will remain as the highly immunogenic cells are destroyed
        
        escape
        
        tumor cells evade attack by the immune system
        
        elimination
        
        tumor cells will be destroyed
- - - - grading
        
        staging
  - - - destroying cells via DNA damage
      - low oxygen levels
        
        resistance to radiation
      - G2-M phase is most productive phase
      - types
        
        preoperative
        
        postoperative
        
        palliative
      - side effects
        
        normal cells are also being affected
    - - chemicals targeted to DNA, RNA, prot to disrupt the cell cycle in rapidly dividing cancer cells
      - carcinogens
      - affects normal cells too
      - dosing
        
        effect of killing vs LD50
        
        combinational therapy
      - developing resistance
        
        theory of different populations of cells having different endogenic resistance against the drug
    - - removal of hormone production
      - inhibition of hormone synthesis
  - - - distinguishing mutations
        
        characterization
    - - loss of function changes must be corrected
    - - methylation inhibitors
      - histone deacylase inhibitors
      - telomerase inhibitors
    - - strategies
        
        passive or active
        
        monoclonal antibodies
        
        cytokines
        
        amounts can induce toxic side effects
        
        adoptive cell transfer
        
        isolate tumor cells
        
        tumor recognition in vitro
        
        culture tested with high active lymphocytes
        
        1 more item...
        
        cancer vaccines
        
        immune checkpoint blockade
        
        ipilimumab
        
        oncolytic viruses
        
        able to lyse the tumor cell
        
        adapting for balance?
        
        finding the balance, how to screen whether the ration satis the same
- - - - high energy radiation causing ionization
        
        particle
        
        wave
        
        UV
        
        affects
        
        skin
        
        eyes
        
        categories
        
        A
        
        stimulates cell prol
        
        B
        
        skin cancer
        
        2 more items...
        
        C
        
        artificial source
        
        ionizing radiation
        
        direct effect
        
        ions released
        
        indirect
        
        destruction of water into hydroxyl radicals
        
        sources
        
        natural
        
        artificial
        
        low energy
        
        microwaves
        
        cell phones
        
        electromagnetic radiation
    - - lifestyle factors
        
        smoking
        
        reversing your bad odds by quitting
        
        diet
        
        beneficial elements
        
        antioxidants
        
        vitamins A E and C
        
        plant phenols
        
        antagonize effects fo sex hormones
        
        dietary fiber
        
        accelerate gut emptying
        
        bing carcinogens
        
        gray area
        
        fat and meat
        
        food preparation
        
        overcooking meat
        
        obesity
        
        high-fat diet causing cancer
        
        malificent elements
      - consequences of DNA damage
        
        repair and return to normality
        
        extensive damage
        
        cytotoxicity and cell death
        
        fixation of the covalently bound DNA
        
        depending on the site and type
        
        no effect
        
        amino acid change
        
        truncated protein
        
        altered regulation
        
        genotoxic carcinogens
        
        PAHs
        
        aromatic amines
        
        nitrosamines/nitrosamides
        
        alkylating agents
        
        natural products
        
        aflatoxin
    - - prolonged hormonal stimulation would allow the cells to proliferate
        
        changes for acquiring a mutation increases
      - breast cancer
        
        having children at young age beneficial when thinking about breast cancer formation
  - - - dose
      - time scale
      - species
      - metabolism
- - - - phases
        
        proliferation and invasion of endothelial cells
        
        chemotaxis produced by cancer cells
        
        mediators
        
        activators
        
        inhibitors
        
        causes for imbalance
        
        metabolic stress
        
        1 more item...
        
        mechanical stress
        
        1 more item...
        
        immune /inlammatory responses
        
        mutations
        
        2 more items...
        
        maturation and differentiation of the sprouts
        
        therapeutic solutions
        
        targeting tumor angiogenesis
        
        cover all the cancer types
        
        destabilization of mature vessel
    - - normal
        
        network
      - cancerous
        
        chaotic
        
        not assebled in a sophisticated way
        
        cell-cell-interactions are a looser, enabling the cancer to spread in a more efficient way
        
        leakage
        
        blood flow patterns
- - - - problem: all patients don't develop metastasis
        
        0.01% of circulating tumor cells forms a metastatic tumor
        
        immune system?
        
        angiogenesis accelerates
    - - escape from the primary site
        
        breakage of cell-cell-adhesions, cell-ECM-adhesions
        
        EMT
        
        cancer
        
        involved in metastasis
        
        tumor cells turn into mesenchymal form
        
        intravasade
        
        1 more item...
        
        marker for mesenchymal cells vimentin
        
        E-cadherin is lost in cancer
        
        downregu
        
        decreased cell adhesion
        
        hallmark for EMT
        
        integrins in cancer
        
        are changed
        
        allows cell to migrate
        
        involved in angiogenesis
        
        degrade the path through ECM and stroma
        
        induce surroundings to produce proteinases
      - invade lymph or blood vessels (difficult)
        
        depending on the tumor type
        
        lymph
        
        breast
        
        blood
        
        liver
        
        singular or aggregates
        
        (body cavities)
        
        entry into blood stream or lymph vessels
      - travel via previous (easy)
        
        immune cells can attack
        
        99% of cancer cells are destroyed in the blood circ
      - invade out (extravasation) of the vessel to the tissue (difficult)
        
        stromal cells impact
        
        actually tumor cells utilize stromal cells to help them move in ECM
        
        going through endothelia and basal membrane
        
        tumor cells go where they are first passed, nearby targets
        
        seed and soil hypothesis
        
        able to grow where the environment is suitable
        
        GF
        
        receptors
        
        different adhesion molecules, some are more susceptible for the specific cancer cells
        
        premetastatic niche
        
        suitable conditions for tumor cells to grow
        
        seeds can influence the soil before tumor cells actually arrive
      - survive and grow (difficult)
    - - characteristic for only some tumor cell types
      - another study
        
        can be identified by bulk tumor samples
        
        RNA purification
- - - - group of enzymes required
      - DNA is uncoiled
        
        enzyme complex
        
        cuts the DNA
        
        polymerase synthesizes and ligates
    - - PARP1
    - - corrects replication errors
        
        made by polymerases
      - specificity based
    - - homologous
        
        S or G2
      - non-homologous
        
        G1 because its simple and DNA can be properly repaired in G2
  - - - block DNA synthesis
    - - alkylating agents
      - platinum based
        
        form covalent bonds with DNA
        
        damage of DNA
        
        apoptosis
        
        binds amino group within DNA
        
        covalent bounds
        
        tolerance in few months
      - antimetabolites
        
        S phase
        
        stops synthesis
        
        antimetabolites interfere
      - organic drugs
        
        inhibits topoisomerase II
        
        not used anymore because of side effects
        
        bind to tubulin and prevent microtubule assembly
    - - targeting and penetration into the tumor
    - - intrinsic resistance
      - extrinsic
      - cancer stem cells are intrinsically resistant
        
        cancer stem cells
        
        undifferentiated cells
        
        can undergo differentiation to specialize
        
        somatic stem cells
        
        characteristics
        
        induced to be organ specific
        
        renew themselves
        
        small fraction of tumor cells
        
        self renewal
        
        not proliferation
        
        give rise to progenitor cells
        
        enhanced resistance to drugs
        
        terminology :no_entry:
        
        cancer-initiating cells
        
        tumor-initiating cells
        
        cells giving rise to tumor, but not cancerous stem cell!
        
        in carcinogenesis
        
        self renewal provides increased opportunities for carcinogenesis
        
        via mutations
        
        polycomb proteins
        
        epigenetic modification=binds histones
        
        2 more items...
        
        stops stemness and starts lineage differentiation
        
        targeting
        
        1 more item...
        
        alteration in cell self-renewal process
        
        Wnt pathway=self renewal responsible mechanism
        
        deletion of Wnt regulated transcription factors results in stem cells mulching in intestines
        
        canonical
        
        1 more item...
        
        non-canonical
        
        1 more item...
        
        ligand type decides
        
        in cancer
        
        3 more items...
        
        hedgehog=self renewal responsible mechanism
        
        ligands
        
        3 more items...
        
        receptors
        
        2 more items...
        
        GLI1
        
        inhibitors
        
        1 more item...
        
        therapeutic strategies
        
        targeting ABC cassette
        
        tarpeting tumor microenvrinment
        
        regulating molecular mechanisms
        
        regulatory mechanisms involved
      - mechanisms
        
        increasing the efflux
        
        decreasing the intake of the drug
        
        increasing the number of targeted molecules within the cells
        
        altering drug metabolism
        
        altering DNA repairing process
      - targeting DNA repair pathway
        
        combination
        
        trying to target different processes
        
        2-3 strategies
        
        synthetic lethal
        
        PARP and DNA repair mechanism
        
        reqruits enzymatic complex
        
        DNA is repaired
        
        PARP inhibitors
        
        with BRCA knock out
        
        cell dies