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Journal of Cancer Research and Clinical Oncology

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01-01-2016 | Original Article – Cancer Research

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

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

Published in: Journal of Cancer Research and Clinical Oncology | Issue 1/2016

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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Aokage K, Ishii G, Ohtaki Y, Yamaguchi Y, Hishida T et al (2011) Dynamic molecular changes associated with epithelial-mesenchymal transition and subsequent mesenchymal-epithelial transition in the early phase of metastatic tumor formation. Int J Cancer 128:1585–1595PubMedCrossRef

Brabletz T, Jung A, Reu S, Porzner M, Hlubek F et al (2001) Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci U S A 98:10356–10361PubMedPubMedCentralCrossRef

Chaffer CL, Brennan JP, Slavin JL, Blick T, Thompson EW et al (2006) Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res 66:11271–11278PubMedCrossRef

Chao YL, Shepard CR, Wells A (2010) Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol Cancer 9:179PubMedPubMedCentralCrossRef

Condeelis J, Segall JE (2003) Intravital imaging of cell movement in tumours. Nat Rev Cancer 3:921–930PubMedCrossRef

Dimou A, Neumeister V, Agarwal S, Anagnostou V, Syrigos K et al (2012) Measurement of aldehyde dehydrogenase 1 expression defines a group with better prognosis in patients with non-small cell lung cancer. Am J Pathol 181:1436–1442PubMedCrossRef

Elzagheid A, Algars A, Bendardaf R, Lamlum H, Ristamaki R et al (2006) E-cadherin expression pattern in primary colorectal carcinomas and their metastases reflects disease outcome. World J Gastroenterol 12:4304–4309PubMedPubMedCentral

Fidler IJ (2003) The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3:453–458PubMedCrossRef

Gao D, Vahdat LT, Wong S, Chang JC, Mittal V (2012) Microenvironmental regulation of epithelial-mesenchymal transitions in cancer. Cancer Res 72:4883–4889PubMedPubMedCentralCrossRef

Goubran HA, Kotb RR, Stakiw J, Emara ME, Burnouf T (2014) Regulation of tumor growth and metastasis: the role of tumor microenvironment. Cancer Growth Metastasis 7:9–18PubMedPubMedCentralCrossRef

Hatanaka Y, Hashizume K, Nitta K, Kato T, Itoh I et al (2003) Cytometrical image analysis for immunohistochemical hormone receptor status in breast carcinomas. Pathol Int 53:693–699PubMedCrossRef

Hudson LG, Zeineldin R, Stack MS (2008) Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression. Clin Exp Metastasis 25:643–655PubMedPubMedCentralCrossRef

Kirita K, Ishii G, Matsuwaki R, Matsumura Y, Umemura S et al (2013) Identification of biological properties of intralymphatic tumor related to the development of lymph node metastasis in lung adenocarcinoma. PLoS ONE 8:e83537PubMedPubMedCentralCrossRef

Kojima M, Higuchi Y, Yokota M, Ishii G, Saito N et al (2014) Human subperitoneal fibroblast and cancer cell interaction creates microenvironment that enhances tumor progression and metastasis. PLoS ONE 9:e88018PubMedPubMedCentralCrossRef

Ksiazkiewicz M, Markiewicz A, Zaczek AJ (2012) Epithelial-mesenchymal transition: a hallmark in metastasis formation linking circulating tumor cells and cancer stem cells. Pathobiology 79:195–208PubMedCrossRef

Luzzi KJ, MacDonald IC, Schmidt EE, Kerkvliet N, Morris VL et al (1998) Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153:865–873PubMedPubMedCentralCrossRef

MacDonald IC, Groom AC, Chambers AF (2002) Cancer spread and micrometastasis development: quantitative approaches for in vivo models. BioEssays 24:885–893PubMedCrossRef

Markiewicz A, Ahrends T, Welnicka-Jaskiewicz M, Seroczynska B, Skokowski J et al (2012) Expression of epithelial to mesenchymal transition-related markers in lymph node metastases as a surrogate for primary tumor metastatic potential in breast cancer. J Transl Med 10:226PubMedPubMedCentralCrossRef

Mehlen P, Puisieux A (2006) Metastasis: a question of life or death. Nat Rev Cancer 6:449–458PubMedCrossRef

Okudela K, Woo T, Mitsui H, Suzuki T, Tajiri M et al (2013) Downregulation of ALDH1A1 expression in non-small cell lung carcinomas–its clinicopathologic and biological significance. Int J Clin Exp Pathol 6:1–12PubMedPubMedCentral

Otranto M, Sarrazy V, Bonte F, Hinz B, Gabbiani G et al (2012) The role of the myofibroblast in tumor stroma remodeling. Cell Adh Migr 6:203–219PubMedPubMedCentralCrossRef

Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78PubMedCrossRef

Ronnov-Jessen L, Petersen OW, Bissell MJ (1996) Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol Rev 76:69–125PubMed

Samatov TR, Tonevitsky AG, Schumacher U (2013) Epithelial-mesenchymal transition: focus on metastatic cascade, alternative splicing, non-coding RNAs and modulating compounds. Mol Cancer 12:107PubMedPubMedCentralCrossRef

Shibue T, Weinberg RA (2009) Integrin beta1-focal adhesion kinase signaling directs the proliferation of metastatic cancer cells disseminated in the lungs. Proc Natl Acad Sci U S A 106:10290–10295PubMedPubMedCentralCrossRef

Shibue T, Brooks MW, Inan MF, Reinhardt F, Weinberg RA (2012) The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer Discov 2:706–721PubMedPubMedCentralCrossRef

Shibue T, Brooks MW, Weinberg RA (2013) An integrin-linked machinery of cytoskeletal regulation that enables experimental tumor initiation and metastatic colonization. Cancer Cell 24:481–498PubMedCrossRef

Taddei ML, Giannoni E, Comito G, Chiarugi P (2013) Microenvironment and tumor cell plasticity: an easy way out. Cancer Lett 341:80–96PubMedCrossRef

Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454PubMedCrossRef

Troester MA, Lee MH, Carter M, Fan C, Cowan DW et al (2009) Activation of host wound responses in breast cancer microenvironment. Clin Cancer Res 15:7020–7028PubMedPubMedCentralCrossRef

Tsai JH, Yang J (2013) Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev 27:2192–2206PubMedPubMedCentralCrossRef

Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J (2012) Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22:725–736PubMedPubMedCentralCrossRef

Wan L, Pantel K, Kang Y (2013) Tumor metastasis: moving new biological insights into the clinic. Nat Med 19:1450–1464PubMedCrossRef

Wong CW, Lee A, Shientag L, Yu J, Dong Y et al (2001) Apoptosis: an early event in metastatic inefficiency. Cancer Res 61:333–338PubMed

Yamaguchi Y, Ishii G, Kojima M, Yoh K, Otsuka H et al (2010) Histopathologic features of the tumor budding in adenocarcinoma of the lung: tumor budding as an index to predict the potential aggressiveness. J Thorac Oncol 5:1361–1368PubMedCrossRef

Yao D, Dai C, Peng S (2011) Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res 9:1608–1620PubMedCrossRef

Title: Drastic morphological and molecular differences between lymph node micrometastatic tumors and macrometastatic tumors of lung adenocarcinoma
Authors: Nao Aramaki
Genichiro Ishii
Eiji Yamada
Masahiro Morise
Keiju Aokage
Motohiro Kojima
Tomoyuki Hishida
Junji Yoshida
Norihiko Ikeda
Masahiro Tsuboi
Atsushi Ochiai
Publication date: 01-01-2016
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 1/2016
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-015-1996-0

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

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Purpose

Method

Results

Conclusion

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