Neoplasia 3

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What are the Three E's

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elimination, equilibrium, escape

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explain elimination

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transformed cells escaping intrinsic control are subjected to etrinsic tumor supressor mechanisms that detect and eliminate developing tumors before they become clinically apparent

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go on

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this is also known as immunoediting, which takes into account the observation that te immune system both protects the host against tumor development and promotes tumor growth.

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equilibrium

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a phoase of tumor dormancy where tumor cells and immunitiy enter a dynamic equilibrium that keeps tumor expansion in check

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escape

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where tumor cells emerge that either display reduced immunogenicities or engage a large number of possible immunosupressive mechanisms to attenuate antitumor responses leading to the appearance of progressivley growing tumors,

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tumor specific antigens

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unique to tumor cells, difficult to be identified on naturally occuring tumors

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tumor associated antigens

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highly expressed in tumor cells found in neuroblastoma, malignant melanoma, sarcoma, carcinomas of the colon breast cervix ovary testis kidney. Include onco fetal antigens

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tumor specific antigens

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unique to tumor cells and not expressed on normal cells, responsible for rejection of the tumor

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tumor associated antigens

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expressed by tumor cells and normal cells

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tsa

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neo antigens, weakly immunogenic or non immunogenic, can be membrane bound or secreted.

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TAA

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include alpha fetoprotein and carcino embryonic antigen

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AFP

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found in patients with hepatocellular carcinoma

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CEA

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found in colon cancer

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AFP

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secreted protein

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CEA

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cell membranes and secreted fluids

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shared tumor antigens

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differentiation antigens

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espressed in the normal tissue, may not be strongly immunogenic, may result in autoimmunity when used in therapy

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antigens found in normal cells but overexpressed in tumors

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may be tolerated by the immune system

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cancer testis genes

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expressed in many tumor types but not in normal tissues except reproductive cells, immune privileged, may be useful as a cance vaccine

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origin of new tumor antigens

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introduction of new genetic informaiton from a virus, alteration of oncogenes or tumor supressor genes by carcinogens, abnormally highlevels of proteins that are normally present at a substantially lowe level, uncovering of antigens normally buried in a cell membrane because of defectiv emembrane homeostasis in tumor cells, release of antigens normally seequestered within the cell or tis organelles when tumor cells die

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examples

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new genetic information from a virus

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HPV E6 and E7

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alteration of oncogenes or tumor supressor genes

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ras, p53

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high levels of normally low proteins

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PSA, melanoma associated antigens

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expressed only during embryonic development

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CEA

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tumor antigens

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antigen

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function and expressed on

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cyclin dependent kinase 4 CDK4

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cell cycle regulator, melanoma

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beta-catenin

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signal transduction, melanoma

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caspase-8

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apoptosis regulator, squamous cell carcinoma

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mage1 mage3 )melanoma antigen encoding gene)

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normal testicular proteins, melanoma, breast, glioma tumors

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tyrosinase

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melanin synthesis, melanoma

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surface Ig idiotype

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b cell receptor, lymphoma

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erb2, her2, neu

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receptor tyrosine kinase, breast and ovarian cancer

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muc1

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underglycosylated mucin, breast and pancreatic tumors

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hpv E6 and E7

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viral gene products, cervical carcinoma

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cytotoxic t lymphocytes

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major immune cells responsibe ofr the killing of cancer cells

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ctls recognize

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antigen MHC I comples through TCR and CD8

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lyse target cells through

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perforin granzyme and Fas/FasL mechanism

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NK cells activated by

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IL-2

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recognize tumor cells with

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low mhc I expression

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kill tumor cells through

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perforin granzyme

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macrophages activeted by

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lymphokins and interferon secreted by th1 cells

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kill tumor cells through

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secretion of tnf and ROS

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acts as

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APC to present TAA to Tcells

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dendritic cells

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major apc presenting taas to t cells

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central in the initaiation of

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tumor specific immune response

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cytokins

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produced by immune cells, stimulate activity of other immune cells

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produced by dendritic cells and induces ctls

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IL 12

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Treg

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sub set of t cells that prevent autoimmune reactions

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activated by

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TGF beta

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express

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cd4 and cd25

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accumulation of treg cells in cancers

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inhibits anti tumor immune responses

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mechanism of humoral immunity

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complement fixation, antibody dependent cell mediated cytotoxiicity

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activeated by

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TH2 cells

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immune tolerance to tumor antigens

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lack of co stimulatory molecule B7, low expression of MHC I

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other failures of immune defense

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immunse suppression by chemical physical or viral pathogens, cytotoxic drugs or radiation, or Tregs

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overexpression of FasL on tumor cells triggers

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Fas mediated apoptosis in T cells

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cachexia

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loss of body fat lean mass weakness anemia anorexia

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potential cause

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cytokines produced by tumor cells such as tnf a ifn gamma, IL 6

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what may cause breakdown of muscle proteins

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proteolysis inducing factor

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human t cell leukemia virus 1

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singgle stranded Rna retrovirus, associated with adult t cell leukemia lymphoma

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transmission mediated by

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infected t cells

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major target

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cd4+ t cells

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known viral oncoproteins

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TAX, contributes to the ability of the virus to cause ATL by altering the cell cycle and causing centrosome abnormality

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hep b patients are at an increased risk for

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liver and hepatocellular carcinoma

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hbx

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viral transcription factor essential for hbv infection

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stimulates

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cell dna synthesis through the Ras map kinase signaling pathway

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can induce

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liver cancer

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known HPV oncogenes

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e6 and e7

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e6

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binds to and promotes degradation of p53

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e7

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binds to and inactivates Rb

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epstein barr

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member of herpesvirus, associated with mononucleosis

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associated with

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malignancies

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known oncoprotein

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LMP1

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kaposis sarcoma

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k1 protein, activates akt cell survival pathway and blocks fas mediated apoptosis

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helicobacter pylori

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gram negative, cause of peptic ulcer, gastric adenocarcinoma and lymphoma

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passive cellular immunotherapy

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effector cells are isolated from the host exposed to IL2 and put back into the host

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passive humoral immunotherapy

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admin of exogenous antibodies and complements for b lymphomas

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active specific immunotherapy

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cellular immunity can be induced to specific well defined antigens

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these are

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peptide based vaccines, dna vaccines, tumor cells

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cytokines

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regulate innate and adaptive immune systems, usually ineffective when used individually

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major cytokines used are

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ifn a, il2, gmcsf, and il12

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2 cytokines approved for treatment of cancer

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il2, ifna 2b

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ifn alpha

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glycoproteins with antitumor and anti viral activity, increase expression of mhcI and II, augment NK cell activity, significant adverse effects

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IL2

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t cell growth factor, severe adverse effects

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gm csf

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transplantation to reconstitute myeloid cells

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iL 12

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promote nk and t cell activity

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bacterial adjuvants

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BCG, tumoricidal activity