Drastic morphological and molecular differences between lymph node micrometastatic tumors and macrometastatic tumors of lung adenocarcinoma

Nao Aramaki, Genichiro Ishii, Eiji Yamada, Masahiro Morise, Keiju Aokage, Motohiro Kojima, Tomoyuki Hishida, Junji Yoshida, Norihiko Ikeda, Masahiro Tsuboi, Atsushi Ochiai

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)


Purpose: The expansion of micrometastatic tumors to macrometastatic ones is thought to be tightly regulated by several microenvironmental factors. The aim of this study was to elucidate the morphological and phenotypical differences between micrometastatic and macrometastatic tumors. Method: We first examined the morphological characteristics of 66 lymph node (LN) micrometastatic tumors (less than 2 mm in size) and 51 macrometastatic tumors (more than 10 mm in size) in 42 lung adenocarcinoma cases. Then, we evaluated the expression level of E-cadherin, S100A4, ALDH1, and Geminin in cancer cells and the number of smooth muscle actin (SMA), CD34, and CD204 (+) stromal cells in the primary tumors, matched micrometastatic tumors, and macrometastatic tumors (n = 34, each). Results: Tumor budding reflects the process of EMT, and stromal reactions were observed more frequently in macrometastatic tumors (P < 0.001). E-cadherin staining score for the micrometastatic tumors was significantly higher than that for the primary tumors (P < 0.001). In contrast, the E-cadherin staining score for the macrometastatic tumors was significantly lower than that for the micrometastatic tumors (P = 0.017). As for the stromal cells, the numbers of SMA (+) fibroblasts, CD34 (+) microvessels, and CD204 (+) macrophages were significantly higher for the macrometastatic tumors and primary tumors than for the micrometastatic tumors (P < 0.001, all). Conclusion: The present study clearly showed that dynamic microenvironmental changes (e.g., EMT-related changes in cancer cells and structural changes in stromal cells) occur during the growth of micrometastases into macrometastases.

Original languageEnglish
Pages (from-to)37-46
Number of pages10
JournalJournal of Cancer Research and Clinical Oncology
Issue number1
Publication statusPublished - 2016 Jan 1
Externally publishedYes


  • Cancer microenvironment
  • Lung adenocarcinoma
  • Macrometastasis
  • Micrometastasis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • General Medicine


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