title: Macrophages modulate migration and invasion of human tongue squamous cell carcinoma.
abstract: Oral tongue squamous cell carcinoma (OTSCC) has a high mortality rate and the incidence is rising worldwide. Despite advances in treatment, the disease lacks specific prognostic markers and treatment modality. The spreading of OTSCC is dependent on the tumor microenvironment and involves tumor-associated macrophages (TAMs). Although the presence of TAMs is associated with poor prognosis in OTSCC, the specific mechanisms underlying this are still unknown. The aim here was to investigate the effect of macrophages (Mfs) on HSC-3 tongue carcinoma cells and NF-kappaB activity. We polarized THP-1 cells to M1 (inflammatory), M2 (TAM-like) and R848 (imidazoquinoline-treated) type Mfs. We then investigated the effect of Mfs on HSC-3 cell migration and NF-kappaB activity, cytokine production and invasion using several different in vitro migration models, a human 3D tissue invasion model, antibody arrays, confocal microscopy, immunohistochemistry and a mouse invasion model. We found that in co-culture studies all types of Mfs fused with HSC-3 cells, a process which was partially due to efferocytosis. HSC-3 cells induced expression of epidermal growth factor and transforming growth factor-beta in co-cultures with M2 Mfs. Direct cell-cell contact between M2 Mfs and HSC-3 cells induced migration and invasion of HSC-3 cells while M1 Mfs reduced HSC-3 cell invasion. M2 Mfs had an excess of NF-kappaB p50 subunit and a lack of p65 subunits both in the presence and absence of HSC-3 cells, indicating dysregulation and pro-tumorigenic NF-kappaB activation. TAM-like cells were abundantly present in close vicinity to carcinoma cells in OTSCC patient samples. We conclude that M2 Mfs/TAMs have an important role in OTSCC regulating adhesion, migration, invasion and cytokine production of carcinoma cells favouring tumor growth. These results demonstrate that OTSCC patients could benefit from therapies targeting TAMs, polarizing TAM-like M2 Mfs to inflammatory macrophages and modulating NF-kappaB activity.
authors: Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland; Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, Oulu, Finland; Oulu Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland.
authors: Emma
authors: E
authors: Pirilä
authors: Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland; Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, Oulu, Finland; Oulu Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland.
authors: Otto
authors: O
authors: Väyrynen
authors: Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland; Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, Oulu, Finland; Oulu Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland.
authors: Elias
authors: E
authors: Sundquist
authors: Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland; Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, Oulu, Finland; Oulu Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland.
authors: Kaisa
authors: K
authors: Päkkilä
authors: Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland; Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, Oulu, Finland; Oulu Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland.
authors: Pia
authors: P
authors: Nyberg
authors: Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland; Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, Oulu, Finland; Oulu Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland.
authors: Sini
authors: S
authors: Nurmenniemi
authors: Department of Pedodontics, Cariology and Endodontology, University of Oulu, Oulu, Finland.
authors: Virve
authors: V
authors: Pääkkönen
authors: Department of Community Dentistry, Institute of Dentistry, University of Oulu, Oulu, Finland.
authors: Paula
authors: P
authors: Pesonen
authors: Department of Oral Pathology and Oral Medicine, School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Dan
authors: D
authors: Dayan
authors: Department of Oral Pathology and Oral Medicine, School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel; Institute of Pathology, The Chaim Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel.
authors: Marilena
authors: M
authors: Vered
authors: Institute of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway; Department of Pathology, University Hospital of Northern Norway, Tromsø, Tromsø, Norway.
authors: Lars
authors: L
authors: Uhlin-Hansen
authors: Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland; Department of Diagnostics and Oral Medicine, Institute of Dentistry, University of Oulu, Oulu, Finland; Oulu Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland; Oulu University Hospital, Oulu, Finland.
authors: Tuula
authors: T
authors: Salo
mesh_terms: D000818:Animals; D015415:Biomarkers; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004705:Endocytosis / Q000276:immunology; D064593:Heterografts; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D051381:Rats; D014062:Tongue Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D016328:NF-kappa B