title: Tumour-associated macrophages are recruited and differentiated in the neoplastic stroma of oral squamous cell carcinoma.
abstract: To confirm our hypothesis that macrophages recruited to fight against oral squamous cell carcinoma (SCC) invasion are functionally differentiated within neoplastic stromata, we analysed arrangements of macrophage subtypes and cancer-associated fibroblasts (CAFs) in their association with blood vasculatures in the neoplastic stroma. Surgical specimens of oral SCC were immunohistochemically examined for macrophage phenotypes (CD68, CD163, and CD204) and stromal environments (perlecan, connexin 43, and CD31). Human monocytes were co-cultured with ZK-1 cells of oral SCC origin in different culture conditions. SCC stromata were divided into two types: fascicular (fibroblast-rich) and reticular (perlecan-rich). Regardless of stromal types, CD68 positive (+)/CD163+/CD204+ macrophages were recruited when blood vessels were abundant. Connexin 43+ fibroblasts were enriched in the fascicular stroma, where blood vessels were depleted. In co-culture experiments, monocytes, in the presence of ZK-1 cells, showed TNF-α(low)/IL-12(low) and IL-10(high)/VEGF(high)/MMP-9(high) with increased expression levels for fibronectin and perlecan. With direct contact with monocytes, SCC cells also expressed CD68 and CD163. SCC stromata were characterised by CD163+/CD204+ tumour-associated macrophages (TAMs) and connexin 43+ CAFs. TAMs are differentiated from monocytes by the physical contact with oral SCC cells in the perlecan-rich neoplastic stroma, which is also induced by the cross-talk between SCC cells and stromal cells including TAMs.
authors.affiliation: Division of Oral Pathology, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Department of Oral Pathology, Faculty of Dentistry, Tanta University, Tanta, Egypt.
authors.forename: Ahmed Abdelaziz Mohamed
authors.initials: AA
authors.lastname: Essa
authors.affiliation: Division of Oral Pathology, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Oral Pathology Section, Department of Surgical Pathology, Niigata University Hospital, Niigata, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Maruyama
authors.affiliation: Division of Oral Pathology, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Oral Pathology Section, Department of Surgical Pathology, Niigata University Hospital, Niigata, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Abé
authors.affiliation: Division of Oral Pathology, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Hamzah
authors.initials: H
authors.lastname: Babkair
authors.affiliation: Department of Oral Pathology, Faculty of Dentistry, Tanta University, Tanta, Egypt.
authors.forename: Adel Mohamed
authors.initials: AM
authors.lastname: Raghib
authors.affiliation: Department of Oral Pathology, Faculty of Dentistry, Tanta University, Tanta, Egypt.
authors.forename: Eman Mohey El-Din
authors.initials: EM
authors.lastname: Megahed
authors.affiliation: Division of Oral Pathology, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Division of Oral Pathology, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Oral Pathology Section, Department of Surgical Pathology, Niigata University Hospital, Niigata, Japan. Electronic address: tsaku@dent.niigata-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Saku
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D002454:Cell Differentiation; D018920:Coculture Techniques; D018031:Connexin 43 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D055806:Microvessels / Q000473:pathology; D009000:Monocytes; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D000098902:CD163 Antigen; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018031:Connexin 43; D005353:Fibronectins; D019812:Heparan Sulfate Proteoglycans; D011956:Receptors, Cell Surface; D051117:Scavenger Receptors, Class A; D000098902:CD163 Antigen; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C500216:GJA1 protein, human; C495139:MSR1 protein, human; C071927:perlecan
keywords: CD163; CD204; Tumour-associated macrophages; cancer stroma; connexin 43; oral squamous cell carcinoma