Aggressive tumor microenvironment of solid predominant lung adenocarcinoma subtype harboring with epidermal growth factor receptor mutations

Koichi Saruwatari, Shinnosuke Ikemura, Keigo Sekihara, Takeshi Kuwata, Satoshi Fujii, Shigeki Umemura, Keisuke Kirita, Shingo Matsumoto, Kiyotaka Yoh, Seiji Niho, Hironobu Ohmatsu, Atsushi Ochiai, Hirotsugu Kohrogi, Masahiro Tsuboi, Koichi Goto, Genichiro Ishii

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Introduction: Tumor microenvironment critically affects cancer progression. This study aimed to identify differences in microenvironments of lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations by histological subtypes. Methods: The study cohort included 214 lung adenocarcinomas harboring EGFR mutations. We analyzed clinicopathological characteristics of lepidic (LPA), papillary (PPA), acinar (APA), and solid-predominant adenocarcinoma (SPA) subtypes, and examined expression levels of EGFR, E-cadherin, ezrin, laminin-5, ALDH1, and PD-L1 in cancer cells, and of CD34, CD204, podoplanin (PDPN), and FoxP3 in stromal cells in 4 subtypes (n = 20 each). Results: SPA displayed significantly more frequent lymph node metastasis, lymphovascular invasion, and worse prognosis than the other subtypes. Ezrin expression levels in SPA were also significantly higher than in LPA, PPA, or APA (P< 0.05, all). Laminin-5 and PD-L1 expression levels in SPA were significantly higher than in LPA (P< 0.01 for both) and PPA (P< 0.01 for both) and tended to be higher than in APA (laminin-5: P = 0.096, PD-L1: P = 0.081). Furthermore, SPA displayed higher levels of PDPN (+) cancer-associated fibroblasts (P< 0.01) and CD204 (+) tumor-associated macrophages (P< 0.05) than the other subtypes. Conclusion: Compared with other predominant subtypes with EGFR mutations, the microenvironment of SPA with EGFR mutations is characterized by cancer cells with higher invasive and immune evasion potential and more abundant stromal cells with tumor-promoting functions, which would contribute to the more aggressive behavior of SPA.

Original languageEnglish
Pages (from-to)7-14
Number of pages8
JournalLung Cancer
Volume91
DOIs
Publication statusPublished - 2016 Jan 1
Externally publishedYes

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Tumor Microenvironment
Epidermal Growth Factor Receptor
Adenocarcinoma
Mutation
Neoplasms
Stromal Cells
Immune Evasion
Cadherins
Adenocarcinoma of lung
Cohort Studies
Lymph Nodes
Macrophages
Neoplasm Metastasis
kalinin

Keywords

  • Cancer cells
  • Immunohistochemical staining
  • Lung adenocarcinoma with EGFR mutation
  • Microenvironment
  • Solid predominant adenocarcinoma
  • Stromal cells

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

Aggressive tumor microenvironment of solid predominant lung adenocarcinoma subtype harboring with epidermal growth factor receptor mutations. / Saruwatari, Koichi; Ikemura, Shinnosuke; Sekihara, Keigo; Kuwata, Takeshi; Fujii, Satoshi; Umemura, Shigeki; Kirita, Keisuke; Matsumoto, Shingo; Yoh, Kiyotaka; Niho, Seiji; Ohmatsu, Hironobu; Ochiai, Atsushi; Kohrogi, Hirotsugu; Tsuboi, Masahiro; Goto, Koichi; Ishii, Genichiro.

In: Lung Cancer, Vol. 91, 01.01.2016, p. 7-14.

Research output: Contribution to journalArticle

Saruwatari, K, Ikemura, S, Sekihara, K, Kuwata, T, Fujii, S, Umemura, S, Kirita, K, Matsumoto, S, Yoh, K, Niho, S, Ohmatsu, H, Ochiai, A, Kohrogi, H, Tsuboi, M, Goto, K & Ishii, G 2016, 'Aggressive tumor microenvironment of solid predominant lung adenocarcinoma subtype harboring with epidermal growth factor receptor mutations', Lung Cancer, vol. 91, pp. 7-14. https://doi.org/10.1016/j.lungcan.2015.11.012
Saruwatari, Koichi ; Ikemura, Shinnosuke ; Sekihara, Keigo ; Kuwata, Takeshi ; Fujii, Satoshi ; Umemura, Shigeki ; Kirita, Keisuke ; Matsumoto, Shingo ; Yoh, Kiyotaka ; Niho, Seiji ; Ohmatsu, Hironobu ; Ochiai, Atsushi ; Kohrogi, Hirotsugu ; Tsuboi, Masahiro ; Goto, Koichi ; Ishii, Genichiro. / Aggressive tumor microenvironment of solid predominant lung adenocarcinoma subtype harboring with epidermal growth factor receptor mutations. In: Lung Cancer. 2016 ; Vol. 91. pp. 7-14.
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abstract = "Introduction: Tumor microenvironment critically affects cancer progression. This study aimed to identify differences in microenvironments of lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations by histological subtypes. Methods: The study cohort included 214 lung adenocarcinomas harboring EGFR mutations. We analyzed clinicopathological characteristics of lepidic (LPA), papillary (PPA), acinar (APA), and solid-predominant adenocarcinoma (SPA) subtypes, and examined expression levels of EGFR, E-cadherin, ezrin, laminin-5, ALDH1, and PD-L1 in cancer cells, and of CD34, CD204, podoplanin (PDPN), and FoxP3 in stromal cells in 4 subtypes (n = 20 each). Results: SPA displayed significantly more frequent lymph node metastasis, lymphovascular invasion, and worse prognosis than the other subtypes. Ezrin expression levels in SPA were also significantly higher than in LPA, PPA, or APA (P< 0.05, all). Laminin-5 and PD-L1 expression levels in SPA were significantly higher than in LPA (P< 0.01 for both) and PPA (P< 0.01 for both) and tended to be higher than in APA (laminin-5: P = 0.096, PD-L1: P = 0.081). Furthermore, SPA displayed higher levels of PDPN (+) cancer-associated fibroblasts (P< 0.01) and CD204 (+) tumor-associated macrophages (P< 0.05) than the other subtypes. Conclusion: Compared with other predominant subtypes with EGFR mutations, the microenvironment of SPA with EGFR mutations is characterized by cancer cells with higher invasive and immune evasion potential and more abundant stromal cells with tumor-promoting functions, which would contribute to the more aggressive behavior of SPA.",
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AU - Saruwatari, Koichi

AU - Ikemura, Shinnosuke

AU - Sekihara, Keigo

AU - Kuwata, Takeshi

AU - Fujii, Satoshi

AU - Umemura, Shigeki

AU - Kirita, Keisuke

AU - Matsumoto, Shingo

AU - Yoh, Kiyotaka

AU - Niho, Seiji

AU - Ohmatsu, Hironobu

AU - Ochiai, Atsushi

AU - Kohrogi, Hirotsugu

AU - Tsuboi, Masahiro

AU - Goto, Koichi

AU - Ishii, Genichiro

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N2 - Introduction: Tumor microenvironment critically affects cancer progression. This study aimed to identify differences in microenvironments of lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations by histological subtypes. Methods: The study cohort included 214 lung adenocarcinomas harboring EGFR mutations. We analyzed clinicopathological characteristics of lepidic (LPA), papillary (PPA), acinar (APA), and solid-predominant adenocarcinoma (SPA) subtypes, and examined expression levels of EGFR, E-cadherin, ezrin, laminin-5, ALDH1, and PD-L1 in cancer cells, and of CD34, CD204, podoplanin (PDPN), and FoxP3 in stromal cells in 4 subtypes (n = 20 each). Results: SPA displayed significantly more frequent lymph node metastasis, lymphovascular invasion, and worse prognosis than the other subtypes. Ezrin expression levels in SPA were also significantly higher than in LPA, PPA, or APA (P< 0.05, all). Laminin-5 and PD-L1 expression levels in SPA were significantly higher than in LPA (P< 0.01 for both) and PPA (P< 0.01 for both) and tended to be higher than in APA (laminin-5: P = 0.096, PD-L1: P = 0.081). Furthermore, SPA displayed higher levels of PDPN (+) cancer-associated fibroblasts (P< 0.01) and CD204 (+) tumor-associated macrophages (P< 0.05) than the other subtypes. Conclusion: Compared with other predominant subtypes with EGFR mutations, the microenvironment of SPA with EGFR mutations is characterized by cancer cells with higher invasive and immune evasion potential and more abundant stromal cells with tumor-promoting functions, which would contribute to the more aggressive behavior of SPA.

AB - Introduction: Tumor microenvironment critically affects cancer progression. This study aimed to identify differences in microenvironments of lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations by histological subtypes. Methods: The study cohort included 214 lung adenocarcinomas harboring EGFR mutations. We analyzed clinicopathological characteristics of lepidic (LPA), papillary (PPA), acinar (APA), and solid-predominant adenocarcinoma (SPA) subtypes, and examined expression levels of EGFR, E-cadherin, ezrin, laminin-5, ALDH1, and PD-L1 in cancer cells, and of CD34, CD204, podoplanin (PDPN), and FoxP3 in stromal cells in 4 subtypes (n = 20 each). Results: SPA displayed significantly more frequent lymph node metastasis, lymphovascular invasion, and worse prognosis than the other subtypes. Ezrin expression levels in SPA were also significantly higher than in LPA, PPA, or APA (P< 0.05, all). Laminin-5 and PD-L1 expression levels in SPA were significantly higher than in LPA (P< 0.01 for both) and PPA (P< 0.01 for both) and tended to be higher than in APA (laminin-5: P = 0.096, PD-L1: P = 0.081). Furthermore, SPA displayed higher levels of PDPN (+) cancer-associated fibroblasts (P< 0.01) and CD204 (+) tumor-associated macrophages (P< 0.05) than the other subtypes. Conclusion: Compared with other predominant subtypes with EGFR mutations, the microenvironment of SPA with EGFR mutations is characterized by cancer cells with higher invasive and immune evasion potential and more abundant stromal cells with tumor-promoting functions, which would contribute to the more aggressive behavior of SPA.

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KW - Immunohistochemical staining

KW - Lung adenocarcinoma with EGFR mutation

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KW - Solid predominant adenocarcinoma

KW - Stromal cells

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