Καρκινογένεση Εισαγωγή στις ογκογόνες οδούς σηματοδήτησης του κυττάρου Γιώργος Ρασιδάκης Επ. Καθηγητής Παθολογικής Ανατομικής, Ιατρική Σχολή ΕΚΠΑ Adj. Assistant Professor, M.D. Anderson Cancer Center (USA)

Μεταλλάξεις γονιδίων –ογκογονίδια, ογκοκατασταλτικά γονίδια Δομικές βλάβες χρωμοσωμάτων –διαμεταθέσεις, απώλειες, προσθήκες Διαταραχές αριθμού χρωμοσωμάτων –ανευπλοειδία Καρκίνος  Γονιδιακή νόσος

Table 4.6 The Biology of Cancer (© Garland Science 2007)

Figure 3.23b The Biology of Cancer (© Garland Science 2007)

Table 3.4 The Biology of Cancer (© Garland Science 2007)

Table 4.1 The Biology of Cancer (© Garland Science 2007)

Table 5.1 The Biology of Cancer (© Garland Science 2007)

Figure 5.11 The Biology of Cancer (© Garland Science 2007)

Figure 5.12a The Biology of Cancer (© Garland Science 2007)

Figure 5.12b The Biology of Cancer (© Garland Science 2007)

“ In the survival of favoured individuals and races, during the constantly-recurring struggle for existence, we see a powerful and ever-acting form of selection. ” Charles Darwin, 1859

Interphase (12-24h, RNA and protein synthesis, cell growth) Gap 0 (G0) cell quit dividing temporarily or more permanently Gap 1 (G1) RNA and protein synthesis; G1 checkpoint S (synthesis) DNA replication Gap 2 (G2) protein synthesis and cell growth; G2 checkpoint Mitosis or M Phase (1-2h) division into two similar daughter cells; metaphase checkpoint Cell Cycle and Division

G1 G2 S Cell grows Cell division M DNA replication Cell prepares to divide C C C Metaphase checkpoint G1 checkpoint G2 checkpoint G0 Cells are responsive To mitogenic signals R

G2 S Cell grows Cell division M DNA replication Cell prepares to divide C C C Cyclin D1/2/3 Cdk4/6 RbE2F InactiveInactive P Rb P E2F Active S Phase Genes E2F DP Cyclin E Cdk2 Cyclin A Cdc2 Cyclin A Cdc2 Cyclin B INK4 p15,p16 p18,p19 INK4 p15,p16 p18,p19 CIP/KIP p21, p27 p57 CIP/KIP p21, p27 p57 G1

Apoptosis Pathways Follicular Lymphoma t(14;18)

Σηματοδοτική οδός JAK / STAT

James E. Darnell, Jr., The Rockefeller University

Jaks in hematopoiesis: phenotype of mouse knockouts Jak Type Relevant PhenotypesCytokines Affected Jak1 Impaired lymphoid developmentIL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL- 15, LIF, all interferons Defective responses to class 2 cytokines and those using c or gp130 receptor subunits Jak2 No definitive erythropoiesisEPO, TPO, IL-3, IL-5, GM-CSF, IFN- Jak3 Defective lymphoid developmentIL-4, IL-7, IL-9, IL-15 Dysregulated myelopoiesis EPO, erythropoietin; IFN, interferon; IL, interleukin; TPO, thrombopoietin

Stats in hematopoiesis: phenotypes of mouse knockouts Stat Type Relevant PhenotypesCytokines Affected Stat1 Interferon responses absent: innate immune responses absent highly sensitive to viral/microbial infection IFN- responsive genes not activated IFNs only Stat 2 Type 1 interferon responses impaired IFN- Stat 3 Embryonic lethal Stat 4 IL-12 responses absent production of high IFN-, low IFN- R Th1 cells priming for high level IFN- production lymphocyte proliferation enhancement of NK cell-mediated cytotoxicity Th2 cells IL-12 only Stat5ab Proliferation signaling affected: CFU-Mix, Eos, G, GM, Pre-B peripheral T cells Absence of NK cells IL-2, IL-3, IL-7, GM-CSF, G-CSF Stat6 IL-4 responses absent: -Absence of IL-4 producing Th2 cells -Block in B-cell IgE class switching lymphocyte proliferation (partial) expression of IL-4-induced cell surface markers IL-4 only CFU, colony-forming unit: G-CSF, granulocyte colony-stimulating factor; GM- CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; NK, natural killer.

Σηματοδοτική οδός PI3K / AKT / mTOR

Corradetti and Guan, Oncogene, 2006 Negative feedback loop mTOR-Rictor Activates AKT/PKB

Hay and Sonenberg, Genes Dev mTOR Controls Translation Through Phosphorylation of p70S6K and 4E-BP1 mTOR

Hay and Sonenberg, Genes Dev E-BP1 Ribosome recruitment to mRNA (5’ end) eIF-4E binds the 5’ cap structure of mRNA 4E-BP1 PPPP

Σηματοδοτική οδός RAS / MEK / ERK

Figure 6.12a The Biology of Cancer (© Garland Science 2007)

Figure 6.14 The Biology of Cancer (© Garland Science 2007)

Figure 6.15 The Biology of Cancer (© Garland Science 2007)

AKT PI3K MEKMDM2 p53 RAS ERK mTOR PTEN survival GF- R RAF GF Proliferation BAD

AKT PI3K MEKMDM2 p53 RAS ERK mTOR PTEN Επιβίωση GF- R NF RAF GF Πολλαπλασιασμός Μεταλλάξεις RAS 20-50% Μεταλλάξεις PIK3CA 20% BAD Μεταλλάξεις BRAF Μεταλλάξεις p53 50%

PTEN TSC1/TSC2 Rheb AKT PI3K PDK1 PIP3 p70S6K4E-BP1 eIF4ErpS6 GβL mTOR RAPTOR GβL mTOR RICTOR Protein translation Flt3 GRB2 RAS ERK1/2 RAF1 MEK1/2 SHC SHIP SHP GAB2 GRB2 Cyclins (e.g. D1-3, A) CDK Inhibitors (e.g. p21, p27) JAK SHP1 SOCS SHP2 STAT3 Oncogenic kinases STAT3 Transcription

Σηματοδοτική οδός NFkB

Figure 6.29a The Biology of Cancer (© Garland Science 2007)

CD30 L CD30 TRADD TRAF IKK IKB  FADD FLICE Caspase 3 Anti-apoptosis Survival RIP DNA p52p65 NFkB c-FLIP Bcl-xL c-IAP TRAF1/2 XIAP p52p65 NFkB TNF-R DD apoptosis MAPK P P

Σηματοδοτική οδός Wnt / β-catenin

Σηματοδοτική οδός Notch

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