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

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

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.

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Abbreviations

LN:

Lymph node

EMT:

Epithelial-mesenchymal transition

MET:

Mesenchymal-epithelial transition

PT:

Primary tumor

Mic:

Micrometastatic tumor

Mac:

Macrometastatic tumor

CAF:

Cancer-associated fibroblast

TAM:

Tumor-associated macrophage

NSCLC:

Non-small cell lung cancer

ALDH1:

Aldehyde dehydrogenase 1

SMA:

Smooth muscle actin

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Acknowledgments

All work reported herein was performed at the National Cancer Center Hospital East, Kashiwa, Chiba, Japan. The research was approved by the Internal Review Board of the institution. No patient consent was required as the research is a retrospective chart review, and no personally identifiable information was included in the manuscript.

Conflict of interest

The authors have no conflict of interest to disclose.

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Authors and Affiliations

  1. Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan

    Nao Aramaki, Genichiro Ishii, Masahiro Morise, Motohiro Kojima & Atsushi Ochiai

  2. Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan

    Nao Aramaki, Eiji Yamada, Keiju Aokage, Tomoyuki Hishida, Junji Yoshida & Masahiro Tsuboi

  3. Division of General Thoracic Surgery, Department of Surgery, Tokyo Medical University School of Medicine, Tokyo, Japan

    Nao Aramaki & Norihiko Ikeda

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  1. Nao Aramaki
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  2. Genichiro Ishii
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  3. Eiji Yamada
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Correspondence to Genichiro Ishii.

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Aramaki, N., Ishii, G., Yamada, E. et al. Drastic morphological and molecular differences between lymph node micrometastatic tumors and macrometastatic tumors of lung adenocarcinoma. J Cancer Res Clin Oncol 142, 37–46 (2016). https://doi.org/10.1007/s00432-015-1996-0

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  • DOI: https://doi.org/10.1007/s00432-015-1996-0

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