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.
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Funding
This study was supported in part by the Advanced Research for Medical Products Mining Programme of the National Institute of Biomedical Innovation (NIBIO), National Cancer Center Research and Development Fund (25-A-6 and 28-A-9).
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This article does not contain any studies with animals performed by any of the authors. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Supplementary Figure 1
. The association between podoplanin expression in CAFs and number of single nucleotide variants (SNVs) in cancer cells in smoking cases. A, Current smoking cases (n = 30). B, Former smoking cases (n = 24). Supplementary Figure 2. The association between the grade of podoplanin-positive CAFs and number of single nucleotide variants (SNVs) in cancer cells. The grade of expression of podoplanin in the CAFs was defined as follows: 0 was defined as when less than 9% of spindle cells within the tumor stroma were stained for podoplanin. Grade1 was defined as when 10 to 49 % of spindle cells within the tumor stroma were stained for podoplanin. Grade2 was defined as when 50% or more of spindle cells within the tumor stroma were stained for podoplanin. (PPTX 174 KB)
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Nakasone, S., Mimaki, S., Ichikawa, T. et al. Podoplanin-positive cancer-associated fibroblast recruitment within cancer stroma is associated with a higher number of single nucleotide variants in cancer cells in lung adenocarcinoma. J Cancer Res Clin Oncol 144, 893–900 (2018). https://doi.org/10.1007/s00432-018-2619-3
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DOI: https://doi.org/10.1007/s00432-018-2619-3