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Six fundamental properties altered in cancer

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-Self sufficiency in growth signals >Constitutively active RTK, upregulation of Myc, etc -Sustained angiogenesis -Tissue invasion and metastasis -Limitless replicative potential >Up regulation of telomerase, evasion of replicative senescence -Evasion of apoptosis >Down regulation of MHC I receptor, tumor suppressors, etc -Insensitivity to antigrowth signals >Downregulation of inhibitory pathways

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Components of signaling pathways

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Cell surface (extracellular) -Cell surface receptor -Hydrophilic ligand -Plasma membrane >Signal molecules bind to receptor protein, which activates intracellular signal molecules that ALTER target proteins and create a RESPONSE Intracellular -Hydrophobic ligand + carrier protein -Intracellular receptor -Nucleus

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Cell surface receptor signaling pathway

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-Signal molecule (first messenger) -Receptor -Second messengers and intracellular signal proteins -Target protein -Response

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Signal Amplification

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-Small signal produces LARGE response -Presence of enzymes in signal pathway greatly amplifies signal

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Classification of extracellular signaling molecules

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-Endocrine -Paracrine -Autocrine -Signaling by plasma membrane-attached proteins

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Endocrine

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Secreted from cell and travels via ECF to DISTANT sites -HORMONES

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Paracrine

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Molecules which act at sites in CLOSE PROXI MITY, important in development -Ex.) Short range GFs, nerve to nerve, nerve to muscle, etc

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Autocrine

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Cells respond to own secretions, membrane signals, proteolytic cleavage Ex.) Tumors often secrete GFs to stimulate growth and proliferation

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Signaling by plasma membrane-attached proteins

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Membrane bound signaling molecules on one cell bind to receptors on an adjacent cell and trigger its differentiation

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Membrane Receptors and signaling pathways

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-PI3 Kinase pathway -MAP-Kinase pathway -IP3 pathway -cAMP pathway -Jak/Stat Pathway

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RTK (General)

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*Receptor Tyrosine Kinase* -Catalytic receptors with tyrosine kinase activity: *GFRs and InsulinR* -Activated by dimerization: LIGAND induced activation

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Activated RTK

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1.) Activated RTKs can phosphorylate effector proteins -PLC -PI3K 2.) RTK activation reveals docking site for adapter protein GRB2 -GRB2

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Activated RTK (PLC)

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PLC breaks down membrane PIP2 to 2nd messengers: -IP3: Increases calcium and helps with activation of PKC -DAG: Activation of PKC-> Activation of TFs

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Activated RTK (PI3K)

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*Phosphatidyl-inositol 3 kinase* -Phosphorylates membrane phospholipid-> Activation of PKB-> INHIBITS apoptosis

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Activated RTK (GRB2)

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*RTK activation reveals docking site for adaptor protein GRB2* -GRB2 binds to *SOS (RasGEF)* -SOS promotes dissociation of GDP from Ras -GTP binds and SOS dissociates -Activate Ras (GTPase) -MAPK activates TF-> FOS, JUN, MYC >*Stimulate cell proliferation and growth* -Mutant GFR and Ras proteins are associated with many types of cancer

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AKT/PKB

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*Promotes cell survival* -Binding of GF to GFR -Receptor dimerization -Phosphorylation and activation of TK-> Phosphorylation/activation of PI3K -Phosphorylate PIP2-> PIP3 and other proteins activate PKB -PKB phosphorylates and INHIBITS BAD -Activation and accumulation of BCL-2-> Heterodimerization of BAX-> Preventing pore formation= preventing apoptosis= promoting cell survival -Pore formation in the outer membrane of mitochondria, cytochrome C from intermembranous space will leak out, bind to systolic protein, activate caspases, which proteolytically cleave everything in the cell= APOPTOSIS -Akt= PKB

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Overall inhibition (AKT/PKB

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PKB inhibits BAD (BAD inhibits Bcl2) BCL-2 accumulates and inhibits BAX (BAX forms pores)

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RTK: RAS-MAPK Pathway

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*Receptor phosphorylation: Recruitment of adapter proteins* -SOS (RAS GEF) >GEF: Guanine Exchange Factor activates Ras (GTPase) -Mutant GFR and Ras proteins are associated with MANY types of cancer RTK (reveals docking site) -> GRB2 (binds to)-> SOS (will activate via replacing GDP to GTP)-> RAS-> RAF-> MEK-> ERK/MAPK-> Activation of TFs= Fos, Jun, Myc >Myc transcribes Cyclin D and promotes cell cycle *Any of these proteins in pathway are considered proto-oncogenes because if any of these proteins acquires a GOF, it will stimulate cell proliferation*

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MAP Kinase activates gene transcription

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-Dimeric MAP kinase translocates to nucleus -Activates TFs -MAPK activates expression of genes necessary for cells to progress through cell cycle >Fos, Jun, Myc *Activation of cell proliferation can lead to TUMOR*

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RTK: RAS-MAPK Pathway (Mutation possibilities)

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-Mutation in different genes-> SAME syndrome -Mutations in same gene-> Different syndrome

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Growth factors and their TK receptors associates with tumor formation

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GF binding to GF Receptor= activation of Tyrosine Kinase -GF receptor mutation can cause it to be constitutive in activating RAS/MAPK pathway >Different mutations can affect receptor-> Excessive signaling - Overexpression of GF (even at low levels)= Too MUCH signaling!

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HER Family of Receptors

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*Human Epidermal Growth Factor Receptor* -EGFR1= HER1 -HERs can heterodimerize with HER2 >Causes conformational change and cause dimerization with other receptors >HER 2 always in open confirmation: Ready to dimerize with other HERs

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EGF Receptors in cancer

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-EGF receptor family (Erb/Her) Her1, Her2, Her3, and Her4 -Gene for Her2/EGFR2 is amplified in 30% breast cancer -> HER2 protein overexpression: aggressive and unstable cancers, which can be used as a prognostic marker; proliferation -Signaling pathway is amplified at LOW levels of EGF >Levels that do not stimulate normal cells -*Trastuzumab/Herceptin* is a monoclonal antibody against Her2 used in treatment of breast cancer >-mab-> monoclonal antibody used to block HER2 signaling the treatment of breast cancer

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Targeting HER2

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*Humanized mAb *Trastuzumab (Herceptin)* blocks HER2 signaling* -Drug will bind to ectodermal domain of HER2 and inhibit dimerization -HER2 is always ready to dimerize independent of GF or signals-> so see increase in cancer; target for treatment -Over expressed HER2 splice variant associated with POOR prognosis not blocked >New drugs in trials -Activated EGFR complexes (either bound via ligand or mAb) are endocytosed via clathrin-coated pits -Monoubiquination target receptors to degradation in lysosome via multi-vesicular body -Gene amplification, over-expression or mutations are responsible for transforming potential of oncogenic RTKs.

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EGFR signal transduction (result)

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-Leads to INCREASED cell survival -Cell proliferation -Cell motility (invasion and metastasis)

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TK GF receptors

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*TK GF receptors altered in human tumors* -Different type of GF receptors found over-activated/expressed

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Cetuximab

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Blocks HER1 binding site on HER1-R -Prevents receptor activation -EXTRACELLULAR -Trastuzumab/Herceptin is for HER2!

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Getininib/Erlotinib

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Blocks tyrosine kinase receptor's ability to auto-phosphorylate >Inhibits activation of signal transduction cascades, such as MAPK pathway >INTRACELLULAR

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RAS and mutation

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*RAS is commonly mutated and constitutively activate in MANY cancers* -*Gain of Function mutation* >Point mutations in Ras can lead to ACTIVATION Ex.) Colorectal cancers

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Mutations in RAS-GAP

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*NF1-> Leads to prolonged activation of RAS* -LOSS of function mutation in RAS-GAP gene (NF1) leads to long acting Ras >Nothing to remove the GTP -NF1 gene encodes neurofibromin >Defect= Neurofibromatosis ->Development of benign tumors of cell sheath around peripheral nerves

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Neurofibromatosis

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*AD Genetic disorder: LOF of NF1* -COMPLETE penetrance: show symptoms in some way -Tumors grow along peripheral nerves and NON-nervous tissues (bones, skin, etc) -Small subcutaneous nodules-> Neurofibromas -Light brown cafe au lait spots -Benign lesions of the eye in iris-> Lisch nodules -Predisposition to cancerous tumor formation-> Glioblastoma, pheochromocytoma, juvenile CML, etc

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Targeting Effectors of RTKs

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Small G protein Ras must be directed to plasma membrane to interact with its GEF (SOS) to be activated -Farnesyl group is covalently attached to N-terminus of RAS by farnesyl transferase -Block farnesylation, block RAS function: >Farnesyl transferase inhibitors in clinical trials

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Signal Transduction intermediates (drugs)

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*Signal transduction intermediates can be targets for anti-cancer drugs* Cancers are proliferating rapidly so they are acquiring mutations RAPIDLY -Best treatment would be treating with drugs that target different pathways and different stages of the pathway

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Drugs that inhibit RAF Kinase (BRAF)

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Sorafenib: Hepatic and renal cancer Vemurafenib: Late stage melanoma

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Gleevec

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Specific inhibitor of a SMALL family of TK -Include Bcl-Abl, Kit, and PDGFR (platelet derived growth factor receptor) -Used to treat CML

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Transcription Factors as proto-Oncogenes

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-Transcription of c-Fos and C-Myc enhanced upon growth factor receptor activation -c-Fos, c-Myc stimulate TF of genes, like *Cyclin D* >Promotes progression through G1 and G1->S -In tumors: oncogenic forms of these or other TFs are frequently expressed at high and unregulated levels -Ex.) Burkitt's lymphoma t(8:14) -> c-Myc translocation moves c-Myc gene next to strong Ig promoter.

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Oncogenic transformation

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*Results in changes in mRNA/Protein Expression* -Alterations in signal transduction pathways resulting in cancer cause changes in gene expression -Different amounts of varying types of mRNAs in normal growing cells vs. tumor cells -Most direct effects on gene expression is exerted by activation of transcription factors -mRNA microarray examines hundreds of genes within a cell >Higher than average expression (tumor cell overexression) = RED >Lower than average expression (loss of expression =GREEN

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C-abl

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*Tyrosine Kinase activation by translocation* -Intracellular TK >NOT A RECEPTOR KINASE -Fused with BCR-> Can form Philadelphia chromosome (9:22) >Overexpression >CML

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Stages of cancer

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− Stage I: localized tumor, in situ − Stage II: local invasion/spread − Stage III: invasion of surrounding structures − Stage IV: mets into lymph nodes >From there cancer can travel throughout the body

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Steroid hormones

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-Lipid soluble -Simple, kinase-free signaling -Steroid can diffuse through the membrane and enter cytoplasm where it will bind to its INTRACELLULAR receptor. -Binding to intracellular receptor will induce conformation change releasing the chaperone and exposing a site that allows the receptor to enter the nucleus.

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Estrogen mediated transcriptional activation

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Some breast tumors rely on estrogen-mediated transcriptional activation for growth -After entering the cell, estrogen/estradiol attaches to its receptor >estrogen receptor (ER)-> Transcription factor -Complex enters nucleus, binds to *estrogen response element (ERE)* >Enhances transcription-> Particularly *Cyclin D*

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Estrogen antagonist

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Binds to receptors but do NOT activate estrogen receptor -Estrogen receptor antagonist-> *tamoxifen* >Binds to some site as estradiol >Inhibits activation of gene expression *Inhibits expression of Cyclin D*

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Prostate Cancer (Diagnosis)

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Diagnosis -PSA (prostate specific antigen) + Digital rectal exam -Biopsy -CT bone scan >If masses are found in biopsy

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Prostate cancer (occurrence)

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-Prostate cancer= Primarily in the peripheral zone (outside) -BPH (Benign prostatic hyperplasia) occurs primarily in transition zone (inside)

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Prostate cancer (stages)

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1.) Carcinoma 2.) Invasion 3.) Further invasion to epididymis 4.) Lymph nodes affected and spread in lymph nodes

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Androgen action (Testosterone)

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*Cell proliferation and PSA (prostate specific antigen) production* -Testosterone binds to androgen receptors and activates the target genes (like estrogen). -Target genes for active testosterone receptor is Cyclin D -Excess of receptor-> Excess of Cyclin D-> Excess cell proliferation -PSA is a marker for *excessive androgen receptor signaling* -Androgen receptor is INDEPENDENT of GF receptor signaling >PSA only tells if over-active ANDROGEN receptor signaling -Cyclin D is a marker for excessive cell proliferation/growth

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Prostate cancer (signs and symptoms)

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-Early stages: Often none unless do PSA/PR exam to screen >Frequent urination, nocturia, hemturia, dysuria, impotence -Advanced: Bone pain >Spine, pelvis, ribs, femur >Spinal cord compression: urinary and fecal incontinence

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Androgen treatment

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-Androgen ablation: Androgen receptor antagonists (*flutamide, bicalutamide*)-> Main therapeutic intervention for the treatment of hormone sensitive prostate cancer >BUT: These cancers eventually become androgen independent, and go on to progress and metastasize.

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