Masahito Naito1, Keiju Aokage2, Kouichi Saruwatari3, Kakeru Hisakane3, Tomohiro Miyoshi4, Tomoyuki Hishida4, Junji Yoshida4, Sugano Masato2, Motohiro Kojima2, Takeshi Kuwata2, Satoshi Fujii2, Atsushi Ochiai2, Yukitoshi Sato5, Masahiro Tsuboi4, Genichiro Ishii6. 1. Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan; Division of Thoracic Surgery, National Cancer Center Hospital, East Kashiwa, Japan; Department of Thoracic Surgery Kitasato University school of Medicine, Japan. 2. Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan. 3. Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan; Division of Thoracic Oncology, National Cancer Center Hospital, East Kashiwa, Japan. 4. Division of Thoracic Surgery, National Cancer Center Hospital, East Kashiwa, Japan. 5. Department of Thoracic Surgery Kitasato University school of Medicine, Japan. 6. Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan. Electronic address: gishii@east.ncc.go.jp.
Abstract
OBJECTIVES: Invasive lepidic predominant adenocarcinoma (LPA) of the lung is thought to progress in a stepwise fashion from adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA). The aim of this study was to investigate the microenvironmental changes during the development from AIS to LPA. MATERIALS AND METHODS: Clinicopathological characteristics of AIS (n=51), MIA (n=59), LPA smaller than 3cm (LPA-S, n=113), and LPA larger than 3cm (LPA-L, n=47) were analyzed. We then evaluated the expression levels of epithelial-mesenchymal transition (EMT)-related molecules (E-cadherin, S100A4), invasion-related molecules (laminin-5, ezrin), stem-cell-related molecules (ALDH-1), and growth factor receptors (c-Met, EGFR) in cancer cells of each group (n=20). The number of tumor-promoting stromal cells, including podoplanin-positive cancer-associated fibroblasts (PDPN+ CAFs), CD204-positive tumor-associated macrophages (CD204+ TAMs), and CD34+ microvessel cells, were also analyzed. RESULTS: No significant difference in these characteristics was found between LPA-S and LPA-L. Laminin-5 expression in the non-invasive carcinoma component of MIA was significantly higher than that of AIS (p<0.001). During the progression from MIA to LPA-S, the expression level of laminin-5 in the invasive carcinoma component was significantly elevated (p<0.01). Moreover, tumor-promoting stromal cells were more frequently recruited in the invasive area of LPA-S (PDPN+ CAFs; p<0.05, CD204+ TAMs; p<0.001, CD34+ microvessel; p<0.05). Ezrin expression in the invasive carcinoma component of LPA-L was significantly increased (p<0.05) compared to LPA-S; however, the number of tumor-promoting stromal cells were not different between these two groups. CONCLUSION: Our current results indicated that microenvironmental molecular changes occur during the progression from MIA to LPA-S and suggested that this process may play an important role in disease progression from AIS to LPA.
OBJECTIVES: Invasive lepidic predominant adenocarcinoma (LPA) of the lung is thought to progress in a stepwise fashion from adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA). The aim of this study was to investigate the microenvironmental changes during the development from AIS to LPA. MATERIALS AND METHODS: Clinicopathological characteristics of AIS (n=51), MIA (n=59), LPA smaller than 3cm (LPA-S, n=113), and LPA larger than 3cm (LPA-L, n=47) were analyzed. We then evaluated the expression levels of epithelial-mesenchymal transition (EMT)-related molecules (E-cadherin, S100A4), invasion-related molecules (laminin-5, ezrin), stem-cell-related molecules (ALDH-1), and growth factor receptors (c-Met, EGFR) in cancer cells of each group (n=20). The number of tumor-promoting stromal cells, including podoplanin-positive cancer-associated fibroblasts (PDPN+ CAFs), CD204-positive tumor-associated macrophages (CD204+ TAMs), and CD34+ microvessel cells, were also analyzed. RESULTS: No significant difference in these characteristics was found between LPA-S and LPA-L. Laminin-5 expression in the non-invasive carcinoma component of MIA was significantly higher than that of AIS (p<0.001). During the progression from MIA to LPA-S, the expression level of laminin-5 in the invasive carcinoma component was significantly elevated (p<0.01). Moreover, tumor-promoting stromal cells were more frequently recruited in the invasive area of LPA-S (PDPN+ CAFs; p<0.05, CD204+ TAMs; p<0.001, CD34+ microvessel; p<0.05). Ezrin expression in the invasive carcinoma component of LPA-L was significantly increased (p<0.05) compared to LPA-S; however, the number of tumor-promoting stromal cells were not different between these two groups. CONCLUSION: Our current results indicated that microenvironmental molecular changes occur during the progression from MIA to LPA-S and suggested that this process may play an important role in disease progression from AIS to LPA.
Authors: David B Nelson; Kyle G Mitchell; Jing Wang; Junya Fujimoto; Myrna Godoy; Carmen Behrens; Xiaofeng Zheng; Jianjun Zhang; Boris Sepesi; Ara A Vaporciyan; Wayne L Hofstetter; Reza J Mehran; David C Rice; Garrett L Walsh; Stephen G Swisher; Cesar A Moran; Neda Kalhor; Annikka Weissferdt; Ignacio I Wistuba; Jack A Roth; Mara B Antonoff Journal: J Thorac Dis Date: 2020-03 Impact factor: 3.005