title: Identification of biological properties of intralymphatic tumor related to the development of lymph node metastasis in lung adenocarcinoma.
abstract: BACKGROUND
  Intralymphatic tumors in the extratumoral area are considered to represent the preceding phase of lymph node metastasis. The aim of this study was to clarify the biological properties of intralymphatic tumors susceptible to the development of lymph node metastasis, with special reference to the expression of cancer initiating/stem cell (CIC/CSC) related markers in cancer cells and the number of infiltrating stromal cells.
  
  
  METHODS
  Primary lung adenocarcinomas with lymphatic permeation in the extratumoral area were retrospectively examined (n = 107). We examined the expression levels of CIC/CSC related markers including ALDH1, OCT4, NANOG, SOX2 and Caveolin-1 in the intralymphatic cancer cells to evaluate their relationship to lymph node metastasis. Moreover, the number of infiltrating stromal cells expressing CD34, α-smooth muscle actin, and CD204 were also evaluated.
  
  
  RESULTS
  Among the intralymphatic tissues, low ALDH1 expression in cancer cells, high SOX2 expression in cancer cells, and a high number of CD204(+) macrophages were independent predictive factors for lymph node metastasis (P = 0.004, P = 0.008, and P = 0.028, respectively). Among these factors, only low ALDH1 expression in cancer cells was significantly correlated with the farther spreading of lymph node metastasis (mediastinal lymph node, pathological N2) (P = 0.046) and the metastatic lymph node ratio (metastatic/resected) (P = 0.028). On the other hand, in the primary tumors, ALDH1 expression in the cancer cells was not associated with lymph node metastasis. Intralymphatic cancer cells expressing low ALDH1 levels exhibited lower E-cadherin expression levels than cancer cells with high levels of ALDH1 expression (P = 0.015).
  
  
  CONCLUSIONS
  Intralymphatic cancer cells expressing low levels of ALDH1 and infiltrating macrophages expressing CD204 have a critical impact on lymph node metastasis. Our study also highlighted the significance of evaluating the biological properties of intralymphatic tumors for tumor metastasis.
authors.affiliation: Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Chiba, Japan ; Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan ; Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kirita
authors.affiliation: Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Genichiro
authors.initials: G
authors.lastname: Ishii
authors.affiliation: Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Chiba, Japan ; Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Matsuwaki
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Matsumura
authors.affiliation: Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Umemura
authors.affiliation: Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Yoh
authors.affiliation: Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Niho
authors.affiliation: Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Goto
authors.affiliation: Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ohmatsu
authors.affiliation: Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan ; Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ohe
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Kanji
authors.initials: K
authors.lastname: Nagai
authors.affiliation: Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000080924:Aldehyde Dehydrogenase 1 Family; D015820:Cadherins / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D008207:Lymphatic Metastasis; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D050697:Retinal Dehydrogenase / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000378:metabolism
chemical_list: D015820:Cadherins; D007527:Isoenzymes; C495139:MSR1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D051117:Scavenger Receptors, Class A; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase