Identification of biological properties of intralymphatic tumor related to the development of lymph node metastasis in lung adenocarcinoma

PLoS One. 2013 Dec 23;8(12):e83537. doi: 10.1371/journal.pone.0083537. eCollection 2013.

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.

Material and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology*
  • Adenocarcinoma of Lung
  • Adult
  • Aged
  • Aged, 80 and over
  • Aldehyde Dehydrogenase 1 Family
  • Cadherins / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Isoenzymes / metabolism
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology*
  • Lymphatic Metastasis
  • Macrophages / metabolism
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Retinal Dehydrogenase / metabolism
  • SOXB1 Transcription Factors / metabolism
  • Scavenger Receptors, Class A / metabolism

Substances

  • Cadherins
  • Isoenzymes
  • MSR1 protein, human
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Scavenger Receptors, Class A
  • Aldehyde Dehydrogenase 1 Family
  • ALDH1A1 protein, human
  • Retinal Dehydrogenase

Grants and funding

This work was supported by the National Cancer Center Research and Development Fund (23-A-12 and 23-K-18), the Foundation for the Promotion of Cancer Research, 3rd-Term Comprehensive 10-Year Strategy for Cancer Control, the Advanced research for medical products Mining Programme of the National Institute of Biomedical Innovation (NIBIO), and JSPS KAKENHI (24659185). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.