title: CD163-Positive Macrophages Within the Tumor Stroma Are Associated With Lymphangiogenesis and Lymph Node Metastasis in Oral Squamous Cell Carcinoma.
abstract: OBJECTIVE
  Increasing evidence shows that tumor stromal components, particularly tumor-associated macrophages (TAMs), play an important role in the tumor progression of various solid malignant tumor types. However, their roles in oral squamous cell carcinoma (OSCC) have not been fully elucidated.
  
  
  METHODS
  Seventy human tongue OSCC samples were analyzed in the present study. Immunohistochemistry was used to investigate the correlations between the densities of CD68-, CD163-, and CD204-positive TAMs and clinicopathologic parameters. Lymphatic vessel density (LVD) was estimated using the D2-40 antibody. In vitro studies also were conducted to investigate the effect of conditioned medium (CM) derived from OSCC cell lines on cytokine and chemokine expression in RAW264.7 mouse monocytic leukemia cells.
  
  
  RESULTS
  Increased densities of CD68-, CD163-, and CD204-positive TAMs were significantly correlated with lymph node metastasis (P = .035, .0082, and .038, respectively). Higher LVD occurred considerably more frequently in patients with nodal metastasis than in those without such metastasis. Moreover, LVD was considerably increased in patients with higher CD163-positive TAM densities. Studies using immunofluorescence showed that vascular endothelial growth factor (VEGF)-C was expressed in 52 of 70 patients with CD163-positive TAMs (74.2%). Moreover, CM derived from OSCC cell lines stimulated the expression of Il-10, Ccl22, Vegf-a, and Vegf-c in RAW264.7 cells; however, Il-12p35 expression levels were not changed.
  
  
  CONCLUSIONS
  CD163-positive TAMs promote lymphangiogenesis through VEGF-C expression, which contributes to regional lymph node metastasis in OSCC.
authors.affiliation: Graduate School Student, Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamagata
authors.affiliation: Assistant Professor, Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tomioka
authors.affiliation: Junior Associate Professor, Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Resident, Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sato
authors.affiliation: Professor, Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Harada
authors.affiliation: Professor, Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Assistant Professor, Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: kayamori.mpa@tmd.ac.jp.
authors.forename: Kou
authors.initials: K
authors.lastname: Kayamori
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D005260:Female; D006801:Humans; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000473:pathology; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D014062:Tongue Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D011956:Receptors, Cell Surface