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BIOLOGIA TUMORAL MATERIA ONCOLOGIA MOLECULAR Dr. José Mordoh. Oncología Molecular, 2013

Biol Cel Tumoral 2013 [Modo de compatibilidad] · Jeghers (poliposis intestinal) Sindrome Peutz-Jeggers. Oncogene. 2007 February 26; 26(9): 1324–1337. Oncogene. 2007 February 26;

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Page 1: Biol Cel Tumoral 2013 [Modo de compatibilidad] · Jeghers (poliposis intestinal) Sindrome Peutz-Jeggers. Oncogene. 2007 February 26; 26(9): 1324–1337. Oncogene. 2007 February 26;

BIOLOGIA TUMORAL

� MATERIA ONCOLOGIA MOLECULAR

Dr. José Mordoh. Oncología Molecular, 2013

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Orquesta. Bruno Brudovic

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LOCURA, de Francis Hammond

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ENSAYO DE ORQUESTA. FEDERICO FELLINI

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BIOLOGIA DE LA CELULA TUMORAL

CELULA NORMAL CLINICA

(1) Mutaciones -

CELULA TUMORAL

(2) Crecimiento tumor + Interaccion -con el estroma

-

TUMOR(3) Efecto de los tratamientos ++

Crecimiento tumoralInteraccion con el organismo

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Barrio et al. Cancer Biol. Ther. 2012

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TRANSICION PROTO-ONCOGENE ONCOGENE

� PROTO-ONCOGENE = GEN NORMAL SUSCEPTIBLE DE TRANSFORMACIÓN

� ONCOGENE = GEN MUTADO

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MANTENIMIENTO DE SEÑALIZACION PROLIFERATIVA� 1) Mutaciones somáticas activan vías

río abajo (BRAF activa señalización MAP kinasa)

� 2) Disrupción circuitos negativos (mutaciones en ras; PTEN fosfatasa)

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Maestría en Biología Molecular Médica –

Dr. José Mordoh 2013

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MANTENIMIENTO DE SEÑALIZACION PROLIFERATIVA� 1) Mutaciones somáticas activan vías río

abajo (BRAF activa señalización MAP kinasa)

� 2) Disrupción circuitos negativos (mutaciones en ras; PTEN fosfatasa)

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CHALHOU AND BAKER, (Ann. Rev. Pathol. 2009)

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FUNCION DE PTEN

CHALHOU AND BAKER, (Ann. Rev. Pathol.2009)

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Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is an antagonist of class I phosphatidylinositol 3—kinase (PI3K) signaling. In response to extracellular stimuli (e.g., insulin, growth factors, chemokines), the catalytic subunit of PI3K (p110) is recruited to receptor tyrosine kinases (RTKs) or G protein—coupled receptors (GPCRs) at the membrane through its regulatory subunit (p85 or p101), where it phosphorylates phosphatidylinositol-4,5 bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5 trisphosphate (PIP3). PTEN is a lipid phosphatase that antagonizes the action of PI3K by dephosphorylating PIP3 at position D3 to generate PIP2

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EVADIENDO SUPRESORES TUMORALES

� 1) La proteína Rb detecta señales stress extracelulares

� 2) La proteína p53 detecta stress intracelular

� 3) Sin embargo,son mecanismos redundantes. Ratones quiméricos para Rb mutados ó ratones KO para p53 se desarrollan normalmente

Hanahan and Weinberg, 2011)

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Maestría en Biología Molecular Médica –

Dr. José Mordoh 2013

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EVADIENDO INHIBICION POR CONTACTO

� 1) Merlin (producto gen NF2) une receptores tirosina kinasa a moléculas adhesión, como las E-caderinas

� 2) La proteína LKB1 (AMP kinasa) organiza la estructura epitelial y mantiene la integridad tisular. Está mutada en el sindrome Peutz-Jeghers (poliposis intestinal)

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Maestría en Biología Molecular Médica –

Dr. José Mordoh 2013

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Merlin interacciona entre prot. Membrana y actina

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EVADIENDO INHIBICION POR CONTACTO

� 1) Merlin (producto gen NF2) une receptores tirosina kinasa a moléculas adhesión, como las E-caderinas

� 2) La proteína LKB1 (AMP kinasa) organiza la estructura epitelial y mantiene la integridad tisular. Está mutada en el sindrome Peutz-Jeghers (poliposis intestinal)

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Sindrome Peutz-Jeggers

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Oncogene. 2007 February 26; 26(9): 1324–1337

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Oncogene. 2007 February 26; 26(9): 1324–1337

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Baluk et al (2005)

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022 OML

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Nagy et al, 2012

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Barrio et al. Cancer Biol. Ther. 2012

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TRANSICION EITELIO-MESENQUIMAL (ETM)

Mecanismo mediante el cual las células transformadas adquieren la capacidad de invadir, resistir

apoptosis y diseminar

En tejidos no tumorales, pueden producir fibrosis

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ETM

Lee et al, 2005

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EL TUMOR ES UNA ASOCIACION ILICITA ENTRE LAS CELULAS TUMORALES Y

EL ESTROMA

TEM MET

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TELOMEROS Y TELOMERASA

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Artandi and Depinho, 2010

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CIRCUITOS INTEGRADOS EN

CANCER

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INFLAMACION

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Adaptive immune responses control tumor-associated myeloid cell bioactivity and tumor progression. Polarized responses by adaptive immune cells alter the balance between pro- and anti-tumor myeloid cell bioactivities. When the host’s response to neoplastic cell growth results in the production of TH1 cytokines by CD4+ T lymphocytes and NK cells, myeloid cells in turn induce programs promoting tumor regression and/or dormant disease. However, when these adaptive immune responses include chronic B lymphocyte activation and IgG production in combination with TH2 and TREG lymphocyte activation, programs of immune suppression, angiogenesis, tissue remodeling, and invasion are favored in myeloid cells and contribute to tumor progression and metastasis

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METABOLISMO ENERGETICO DEREGULADO

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IMAGEN DE CEREBRO EN PET SCAN

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PET SCAN DE LINFOMA ANTES Y DESPUES TRATAMIENTO (FDG)

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Figure 1. The Altered Metabolism of Cancer Cells Drivers (A and B). The metabolic derangements in cancer cells may arise either from the selection of cells that have adapted to the tumor microenvironment or from aberrant signaling due to oncogene activation. The tumor microenvironment is spatially and temporally heterogeneous, containing regions of low oxygen and low pH (purple). Moreover, many canonical cancer-associated signaling pathways induce metabolic reprogramming. Target genes activated by hypoxia-inducible factor (HIF) decrease the dependence of the cell on oxygen, whereas Ras, Myc, and Akt can also upregulate glucose consumption and glycolysis. Loss of p53 may also recapitulate the features of the Warburg effect, that is, the uncoupling of glycolysis from oxygen levels.Advantages (C–E). The altered metabolism of cancer cells is likely to imbue them with several proliferative and survival advantages, such as enabling cancer cells to execute the biosynthesis of macromolecules (C), to avoid apoptosis (D), and to engage in local metabolite-based paracrine and autocrine signaling (E).Potential Liabilities (F and G). This altered metabolism, however, may also confer several vulnerabilities on cancer cells. For example, an upregulated metabolism may result in the build up of toxic metabolites, including lactate and noncanonical nucleotides, which must be disposed of (F). Moreover, cancer cells may also exhibit a high energetic demand, for which they must either increase flux through normal ATP-generating processes, or else rely on an increased diversity of fuel sources (G).

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MICROAMBIENTE TUMORALCélulas tumorales

Células endoteliales y switch angiogénico

Pericitos

Células inflamatorias Inmunes

Fibroblastos asociados a cáncer (CAF)

Stem cells del estroma tumoral

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