title: Heterogeneous tumor stromal microenvironments of oral squamous cell carcinoma cells in tongue and nodal metastatic lesions in a xenograft mouse model.
abstract: BACKGROUND
  Oral squamous cell carcinoma exhibits a poor prognosis, caused by aggressive progression and early-stage metastasis to cervical lymph nodes. Here, we developed a xenograft mouse model to explore the heterogeneity of the tumor microenvironment that may govern local invasion and nodal metastasis of tumor cells.
  
  
  METHODS
  We transplanted five oral carcinoma cell lines into the tongues of nude mice and determined tongue tumor growth and micrometastatic dissemination by serially sectioning the tongue and lymph node lesions in combination with immunohistochemistry and computer-assisted image analysis. Our morphometric analysis enabled a quantitative assessment of blood and lymphatic endothelial densities in the intratumoral and host stromal regions.
  
  
  RESULTS
  All cell lines tested were tumorigenic in mouse tongue. The metastatic lesion-derived carcinoma cell lines (OSC19, OSC20, and HSC2) yielded a 100% nodal metastasis rate, whereas the primary tumor-derived cell lines (KOSC2 and HO-1-u-1) showed <40% metastatic potential. Immunohistochemistry showed that the individual cell lines gave rise to heterogeneous tumor architecture and phenotypes and that their micrometastatic lesions assimilated the immunophenotypic properties of the corresponding tongue tumors. Notably, OSC19 and OSC20 cells shared similar aggressive tumorigenicity in both the tongue and lymph node environments but displayed markedly diverse immunophenotypes and gene expression profiles.
  
  
  CONCLUSIONS
  Our model facilitated comparing the tumor microenvironments in tongue and lymph node lesions. The results support that tumorigenicity and tumor architecture in the host tongue environment depend on the origin and properties of the carcinoma cell lines and that metastatic progression may take place through heterogeneous tumor-host interactions.
authors.affiliation: Department of Pathology, School of Life Dentistry at Tokyo, The Nippon Dental University, Chiyoda-ku, Tokyo, Japan.
authors.forename: Youichi
authors.initials: Y
authors.lastname: Shirako
authors.affiliation: Department of Pathology, School of Life Dentistry at Tokyo, The Nippon Dental University, Chiyoda-ku, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Taya
authors.affiliation: Department of Pathology, School of Life Dentistry at Tokyo, The Nippon Dental University, Chiyoda-ku, Tokyo, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Biochemistry, School of Life Dentistry at Tokyo, The Nippon Dental University, Chiyoda-ku, Tokyo, Japan.
authors.forename: Tadashige
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Department of Biochemistry, School of Life Dentistry at Tokyo, The Nippon Dental University, Chiyoda-ku, Tokyo, Japan.
authors.forename: Kazushi
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Pathology, School of Life Dentistry at Tokyo, The Nippon Dental University, Chiyoda-ku, Tokyo, Japan.|Department of Food and Life Sciences, School of Life and Environmental Sciences, Azabu University, Chuo-ku, Sagamihara, Kanagawa, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Shimazu
authors.affiliation: Department of Pathology, School of Life Dentistry at Tokyo, The Nippon Dental University, Chiyoda-ku, Tokyo, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Aoba
authors.affiliation: Department of Pathology, School of Life Dentistry at Tokyo, The Nippon Dental University, Chiyoda-ku, Tokyo, Japan.
authors.forename: Yuuichi
authors.identifier: http://orcid.org/0000-0001-8466-6376
authors.initials: Y
authors.lastname: Soeno
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006258:Head and Neck Neoplasms / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D061206:Neoplasm Micrometastasis; D009368:Neoplasm Transplantation; D010641:Phenotype; D000077195:Squamous Cell Carcinoma of Head and Neck; D014062:Tongue Neoplasms / Q000473:pathology*; D059467:Transcriptome; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
keywords: metastasis; oral squamous cell carcinoma; tongue; tumor microenvironment; xenograft