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Macrophages stimulate gastric and colorectal cancer invasion through EGFR Y1086, c-Src, Erk1/2 and Akt phosphorylation and smallGTPase activity

Oncogene volume 33, pages 2123–2133 (2014)Cite this article

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Abstract

The interactions between cancer cells and their microenvironment are crucial for malignant progression, as they modulate invasion-related activities. Tumor-associated macrophages are generally considered allies in the process of tumor progression in several types of cancer, although their role on gastric and colorectal carcinomas is still poorly understood. In this report, we studied the influence of primary human macrophages on gastric and colorectal cancer cells, considering invasion, motility/migration, proteolysis and activated intracellular signaling pathways. We demonstrated that macrophages stimulate cancer cell invasion, motility and migration, and that these effects depend on matrix metalloproteinase (MMP) activity and on the activation of epidermal growth factor receptor (EGFR) (at the residue Y1086), PLC-γ (phospholipase C-gamma) and Gab1 (GRB2-associated binding protein-1), as evidenced by siRNA (small interference RNA) experiments. Epidermal growth factor (EGF)-immunodepletion impaired macrophage-mediated cancer cell invasion and motility, suggesting that EGF is the pro-invasive and pro-motile factor produced by macrophages. Macrophages also induced gastric and colorectal cancer cell phosphorylation of Akt, c-Src and ERK1/2, and led to an increase of RhoA and Cdc42 activity. Interestingly, whereas macrophage-mediated cancer cell c-Src and ERK1/2 phosphorylation occurred downstream EGFR activation, Akt phosphorylation seems to be a parallel event, taking place in an EGFR-independent manner. The involvement of EGF, EGFR-downstream signaling partners and MMPs in macrophage-mediated invasion provides novel insights into the molecular crosstalk established between cancer cells and macrophages, opening new perspectives for the design of new and more efficient therapeutic strategies to counteract cancer cell invasion.

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Acknowledgements

This work was financially supported by FCT (PTDC-SAU-ONC/112511/2009), COMPETE FCOMP-01-0124-FEDER-010915 and Prize L’Oreal for Women Science (Foundation L’Óreal/FCT/UNESCO). AP Cardoso is a PhD Fellow from the International Iberian Nanotechnology Laboratory (INL). AT Pinto and ML Pinto are PhD Fellows (SFRH/BD/74144/2010, SFRH/BD/81103/2011) and MI Oliveira a Postdoc Fellow (SFRH/BPD/37090/2007) from FCT. MJ Oliveira and MT Pinto are granted by Programa Ciência2007–FCT. RGonçalves was funded by the European project DISC Regeneration, NMP3- LA-2008-213904 (FP7). A Mantovani is supported by AIRC, ERC and RF2010 Italian Ministry of Health.

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Authors and Affiliations

  1. Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal

    A P Cardoso, M L Pinto, A T Pinto, M I Oliveira, R Gonçalves, M A Barbosa & M J Oliveira

  2. Faculdade de Engenharia, Universidade do Porto, Porto, Portugal

    A P Cardoso & A T Pinto

  3. Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal

    M L Pinto & M A Barbosa

  4. Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal

    M T Pinto, C Figueiredo & R Seruca

  5. Instituto de Biologia Celular e Molecular, Universidade do Porto, Porto, Portugal

    J B Relvas

  6. Departamento de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, Porto, Portugal

    J B Relvas

  7. Departmento de Patologia e Oncologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal

    C Figueiredo, R Seruca & M J Oliveira

  8. Humanitas Clinical and Research Center, Rozzano, Italy

    A Mantovani

  9. BIOMETRA Department, University of Milan, Milan, Italy

    A Mantovani

  10. Laboratory of Experimental Cancerology, Ghent University Hospital, Ghent, Belgium

    M Mareel

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Correspondence to M J Oliveira.

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Cardoso, A., Pinto, M., Pinto, A. et al. Macrophages stimulate gastric and colorectal cancer invasion through EGFR Y1086, c-Src, Erk1/2 and Akt phosphorylation and smallGTPase activity. Oncogene 33, 2123–2133 (2014). https://doi.org/10.1038/onc.2013.154

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