title: Macrophages stimulate gastric and colorectal cancer invasion through EGFR Y(1086), c-Src, Erk1/2 and Akt phosphorylation and smallGTPase activity.
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 Y(1086)), 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.
authors: 1] Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal [2] Faculdade de Engenharia, Universidade do Porto, Porto, Portugal.
authors: A P
authors: AP
authors: Cardoso
authors: 1] Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal [2] Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
authors: M L
authors: ML
authors: Pinto
authors: 1] Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal [2] Faculdade de Engenharia, Universidade do Porto, Porto, Portugal.
authors: A T
authors: AT
authors: Pinto
authors: Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.
authors: M I
authors: MI
authors: Oliveira
authors: Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal.
authors: M T
authors: MT
authors: Pinto
authors: Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.
authors: R
authors: R
authors: Gonçalves
authors: 1] Instituto de Biologia Celular e Molecular, Universidade do Porto, Porto, Portugal [2] Departamento de Biologia Experimental, Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
authors: J B
authors: JB
authors: Relvas
authors: 1] Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal [2] Departmento de Patologia e Oncologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
authors: C
authors: C
authors: Figueiredo
authors: 1] Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal [2] Departmento de Patologia e Oncologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
authors: R
authors: R
authors: Seruca
authors: 1] Humanitas Clinical and Research Center, Rozzano, Italy [2] BIOMETRA Department, University of Milan, Milan, Italy.
authors: A
authors: A
authors: Mantovani
authors: Laboratory of Experimental Cancerology, Ghent University Hospital, Ghent, Belgium.
authors: M
authors: M
authors: Mareel
authors: 1] Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal [2] Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
authors: M A
authors: MA
authors: Barbosa
authors: 1] Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal [2] Departmento de Patologia e Oncologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
authors: M J
authors: MJ
authors: Oliveira
mesh_terms: D015153:Blotting, Western; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059008:Time-Lapse Imaging / Q000379:methods; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D014443:Tyrosine; D066246:ErbB Receptors; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020782:Matrix Metalloproteinases; D020741:rho GTP-Binding Proteins