Microenvironmental changes in the progression from adenocarcinoma in situ to minimally invasive adenocarcinoma and invasive lepidic predominant adenocarcinoma of the lung.
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.



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.



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.



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.
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.
Masahito
M
Naito
Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan.
Keiju
K
Aokage
Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan; Division of Thoracic Oncology, National Cancer Center Hospital, East Kashiwa, Japan.
Kouichi
K
Saruwatari
Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan; Division of Thoracic Oncology, National Cancer Center Hospital, East Kashiwa, Japan.
Kakeru
K
Hisakane
Division of Thoracic Surgery, National Cancer Center Hospital, East Kashiwa, Japan.
Tomohiro
T
Miyoshi
Division of Thoracic Surgery, National Cancer Center Hospital, East Kashiwa, Japan.
Tomoyuki
T
Hishida
Division of Thoracic Surgery, National Cancer Center Hospital, East Kashiwa, Japan.
Junji
J
Yoshida
Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan.
Sugano
S
Masato
Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan.
Motohiro
M
Kojima
Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan.
Takeshi
T
Kuwata
Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan.
Satoshi
S
Fujii
Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan.
Atsushi
A
Ochiai
Department of Thoracic Surgery Kitasato University school of Medicine, Japan.
Yukitoshi
Y
Sato
Division of Thoracic Surgery, National Cancer Center Hospital, East Kashiwa, Japan.
Masahiro
M
Tsuboi
Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Japan. Electronic address: gishii@east.ncc.go.jp.
Genichiro
G
Ishii
D065311:Adenocarcinoma in Situ / Q000378:metabolism / Q000473:pathology* / Q000601:surgery / Q000648:ultrastructure; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000080924:Aldehyde Dehydrogenase 1 Family; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007564:Japan; D008168:Lung / Q000378:metabolism / Q000473:pathology* / Q000601:surgery / Q000648:ultrastructure; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology*; D050697:Retinal Dehydrogenase / Q000378:metabolism; D000097794:Kalinin; D000099149:Ezrin
D000080924:Aldehyde Dehydrogenase 1 Family; D015703:Antigens, CD; D015820:Cadherins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D007527:Isoenzymes; D050697:Retinal Dehydrogenase; D000097794:Kalinin; D000099149:Ezrin; C513384:CDH1 protein, human; C510223:ALDH1A1 protein, human
Adenocarcinoma in situ; Lepidic predominant lung adenocarcinoma; Minimally invasive adenocarcinoma; Stepwise progression; Tumor microenvironment