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BIOLOGIA TUMORAL
� MATERIA ONCOLOGIA MOLECULAR
Dr. José Mordoh. Oncología Molecular, 2013
Orquesta. Bruno Brudovic
LOCURA, de Francis Hammond
ENSAYO DE ORQUESTA. FEDERICO FELLINI
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
Barrio et al. Cancer Biol. Ther. 2012
TRANSICION PROTO-ONCOGENE ONCOGENE
� PROTO-ONCOGENE = GEN NORMAL SUSCEPTIBLE DE TRANSFORMACIÓN
� ONCOGENE = GEN MUTADO
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)
Maestría en Biología Molecular Médica –
Dr. José Mordoh 2013
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)
CHALHOU AND BAKER, (Ann. Rev. Pathol. 2009)
FUNCION DE PTEN
CHALHOU AND BAKER, (Ann. Rev. Pathol.2009)
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
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)
Maestría en Biología Molecular Médica –
Dr. José Mordoh 2013
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)
Maestría en Biología Molecular Médica –
Dr. José Mordoh 2013
Merlin interacciona entre prot. Membrana y actina
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)
Sindrome Peutz-Jeggers
Oncogene. 2007 February 26; 26(9): 1324–1337
Oncogene. 2007 February 26; 26(9): 1324–1337
Baluk et al (2005)
022 OML
Nagy et al, 2012
Barrio et al. Cancer Biol. Ther. 2012
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
ETM
Lee et al, 2005
EL TUMOR ES UNA ASOCIACION ILICITA ENTRE LAS CELULAS TUMORALES Y
EL ESTROMA
TEM MET
TELOMEROS Y TELOMERASA
Artandi and Depinho, 2010
CIRCUITOS INTEGRADOS EN
CANCER
INFLAMACION
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
METABOLISMO ENERGETICO DEREGULADO
IMAGEN DE CEREBRO EN PET SCAN
PET SCAN DE LINFOMA ANTES Y DESPUES TRATAMIENTO (FDG)
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).
MICROAMBIENTE TUMORALCélulas tumorales
Células endoteliales y switch angiogénico
Pericitos
Células inflamatorias Inmunes
Fibroblastos asociados a cáncer (CAF)
Stem cells del estroma tumoral