Shoko Nakasone1,2, Sachiyo Mimaki3, Tomohiro Ichikawa2, Keiju Aokage2, Tomohiro Miyoshi2, Masato Sugano4, Motohiro Kojima1, Satoshi Fujii1, Takeshi Kuwata4, Atsushi Ochiai5, Masahiro Tsuboi2, Koichi Goto6, Katsuya Tsuchihara3, Genichiro Ishii7. 1. Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. 2. Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan. 3. Division of Translational Research, Research Center for Innovate Oncology, National Cancer Center, Kashiwa, Japan. 4. Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan. 5. Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan. 6. Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. 7. Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. gishii@east.ncc.go.jp.
Abstract
PURPOSE: Podoplanin-positive cancer-associated fibroblasts (CAFs) play an essential role in tumor progression. However, it is still unclear whether specific genomic alterations of cancer cells are required to recruit podoplanin-positive CAFs. The aim of this study was to investigate the relationship between the mutation status of lung adenocarcinoma cells and the presence of podoplanin-positive CAFs. METHODS: Ninety-seven lung adenocarcinomas for which whole exome sequencing data were available were enrolled. First, we analyzed the clinicopathological features of the cases, and then, evaluated the relationship between genetic features of cancer cells (major driver mutations and the number of single nucleotide variants, SNVs) and the presence of podoplanin-positive CAFs. RESULTS: The presence of podoplanin-positive CAFs was associated with smoking history, solid predominant subtype, and lymph node metastasis. We could not find any significant correlations between major genetic mutations (EGFR, KRAS, TP53, MET, ERBB2, BRAF, and PIC3CA) in cancer cells and the presence of podoplanin-positive CAFs. However, cases with podoplanin-positive CAFs had a significantly higher number of SNVs in cancer cells than the podoplanin-negative CAFs cases (median 84 vs 37, respectively; p = 0.001). This was also detected in a non-smoker subgroup (p = 0.037). Multivariate analyses revealed that the number of SNVs in cancer cells was the only statistically significant independent predictor for the presence of podoplanin-positive CAFs (p = 0.044). CONCLUSIONS: In lung adenocarcinoma, the presence of podoplanin-positive CAFs was associated with higher numbers of SNVs in cancer cells, suggesting a relationship between accumulations of SNVs in cancer cells and the generation of a tumor-promoting microenvironment.
PURPOSE:Podoplanin-positive cancer-associated fibroblasts (CAFs) play an essential role in tumor progression. However, it is still unclear whether specific genomic alterations of cancer cells are required to recruit podoplanin-positive CAFs. The aim of this study was to investigate the relationship between the mutation status of lung adenocarcinoma cells and the presence of podoplanin-positive CAFs. METHODS: Ninety-seven lung adenocarcinomas for which whole exome sequencing data were available were enrolled. First, we analyzed the clinicopathological features of the cases, and then, evaluated the relationship between genetic features of cancer cells (major driver mutations and the number of single nucleotide variants, SNVs) and the presence of podoplanin-positive CAFs. RESULTS: The presence of podoplanin-positive CAFs was associated with smoking history, solid predominant subtype, and lymph node metastasis. We could not find any significant correlations between major genetic mutations (EGFR, KRAS, TP53, MET, ERBB2, BRAF, and PIC3CA) in cancer cells and the presence of podoplanin-positive CAFs. However, cases with podoplanin-positive CAFs had a significantly higher number of SNVs in cancer cells than the podoplanin-negative CAFs cases (median 84 vs 37, respectively; p = 0.001). This was also detected in a non-smoker subgroup (p = 0.037). Multivariate analyses revealed that the number of SNVs in cancer cells was the only statistically significant independent predictor for the presence of podoplanin-positive CAFs (p = 0.044). CONCLUSIONS: In lung adenocarcinoma, the presence of podoplanin-positive CAFs was associated with higher numbers of SNVs in cancer cells, suggesting a relationship between accumulations of SNVs in cancer cells and the generation of a tumor-promoting microenvironment.
Entities:
Keywords:
Cancer-associated fibroblasts; Lung adenocarcinoma; Podoplanin; Single nucleotide variants
Authors: Anna Kuchnio; Stijn Moens; Ulrike Bruning; Karol Kuchnio; Bert Cruys; Bernard Thienpont; Michaël Broux; Andreea Alexandra Ungureanu; Rodrigo Leite de Oliveira; Françoise Bruyère; Henar Cuervo; Ann Manderveld; An Carton; Juan Ramon Hernandez-Fernaud; Sara Zanivan; Carmen Bartic; Jean-Michel Foidart; Agnes Noel; Stefan Vinckier; Diether Lambrechts; Mieke Dewerchin; Massimiliano Mazzone; Peter Carmeliet Journal: Cell Rep Date: 2015-07-30 Impact factor: 9.423