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

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

Author information

  • 1Pathology 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.
  • 2Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Chiba, Japan.
  • 3Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Chiba, Japan ; Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.
  • 4Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.
  • 5Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
  • 6Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan ; Juntendo University Graduate School of Medicine, Tokyo, Japan.

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.

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