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Are macrophages interesting targets for anti-cancer therapy?

Are macrophages interesting targets for anti-cancer therapy?. Maria Oliveira. Lisbon, July 4 th , 2010. Invasion : an ideal target for anti-cancer therapy. Adapted from Robbins and Cotran , 7th Edition. The tumour microenvironment.

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Are macrophages interesting targets for anti-cancer therapy?

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  1. Are macrophages interesting targets for anti-cancer therapy? Maria Oliveira Lisbon, July 4th, 2010

  2. Invasion: an ideal target for anti-cancertherapy AdaptedfromRobbinsandCotran, 7th Edition

  3. Thetumourmicroenvironment

  4. Macrophages: obligate partners for cancercellinvasionandmetastasis

  5. Macrophages: central targets for anti-cancertherapy Macrophages: dual role incancer Tumor supression Tumor promotion

  6. Short-term objectives • select candidate molecules suitable for therapeutical approach. • clarify the role of macrophages on gastric cancer cell invasion; • identify the major signalling pathways activated during the molecular crosstalk between invading gastric cancer cells and surrounding macrophages;

  7. Long-term objective: anti-cancertherapy Nanoparticles Specific inhibitors Monocyte / Macrophage

  8. Long-term objective: anti-cancertherapy

  9. M1 and M2 macrophagemodulation Cytokine profile Cell surface receptors Morphology

  10. Monocytes M2 Time Monocytes M1 Altereddifferentiationprogram LPS

  11. Macrophagesstimulategastriccancercellinvasioninto ECM components MatrigelInvasionAssay

  12. MMPs are involved in macrophage-mediated cancer cell invasion LPS-treated macrophages (M1) are less efficient in stimulating cancer cell invasion probably due to their reduced proteolytic activity.

  13. Macrophages stimulate gastric cancer cell motility / migration AGS + RPMI AGS + cmMac AGS + cmMac AGS + RPMI

  14. Inhibition targeting MMPs and EGFR reduced macrophage-mediated invasion Macrophage CSF-1 EGF Breast cancer cell

  15. Macrophages enhance cancer cell EGFR tyrosine phosphorylation (Y1086)

  16. EGFR – silencing related molecules (siRNA)on gastric cancer cells

  17. PLC-, GAB1 and Cbl are required for macrophage-mediated invasion

  18. Macrophage enhance cancer cell EGFR, PLC-, c-Src, Akt and Erkphosphorylation

  19. Monocytes M2 Time Monocytes M1 Altereddifferentiationprogram Silencing LPS M2 Epithelialcell EGFR MMP ROCK PI3K PLC-gama CBLGAB1 SHC Grb2 FAK EGFR MMP ROCK PI3K PLC-gama CBLGAB1 SHC Grb2 FAK Invasion Migration pEGFR pAKT pSrc pPLC-gama pERK = = Signallingpathways Invasion Migration Invasion Migration

  20. Acknowledgments INEB Mário Barbosa Ana Patrícia Cardoso Marta Oliveira Perpétua Pinto do Ó Susana Santos Catarina Almeida Raquel Gonçalves Outdoors Collaborators Marc Mareel (UGhent, Belgium) Alberto Mantovani (ICH, Milan, Italy) Tobias Pukrop Claudia Binder (Georg-August University, Goettingen, Germany) IPATIMUP Raquel Seruca Fátima Carneiro IBMC João Relvas Ana Filipa Gonçalves

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