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Progressive changes in the protein expression profile of alveolar septa in early-stage lung adenocarcinoma

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Abstract

Background

Adenocarcinomas show a stepwise progression from atypical adenomatous hyperplasia (AAH) through adenocarcinoma in situ (AIS) to invasive adenocarcinoma (IA). Immunoglobulin superfamily containing leucine-rich repeat (ISLR) is a marker of tumor-restraining cancer-associated fibroblasts (CAFs), which are distinct from conventional, strongly α-smooth muscle actin (αSMA)-positive CAFs. Fibroblast activation protein (FAP) has been focused on as a potential therapeutic and diagnostic target of CAFs.

Methods

We investigated the changes in protein expression during adenocarcinoma progression in the pre-existing alveolar septa by assessing ISLR, αSMA, and FAP expression in normal lung, AAH, AIS, and IA. Fourteen AAH, seventeen AIS, and twenty IA lesions were identified and randomly sampled. Immunohistochemical analysis was performed to evaluate cancer-associated changes and FAP expression in the pre-existing alveolar structures.

Results

Normal alveolar septa expressed ISLR. The ISLR level in the alveolar septa decreased in AAH and AIS tissues when compared with that in normal lung tissue. The αSMA-positive area gradually increased from the adjacent lung tissue (13.3% ± 15%) to AIS (87.7% ± 14%), through AAH (70.2% ± 21%). Moreover, the FAP-positive area gradually increased from AAH (1.69% ± 1.4%) to IA (11.8% ± 7.1%), through AIS (6.11% ± 5.3%). Protein expression changes are a feature of CAFs in the pre-existing alveolar septa that begin in AAH. These changes gradually progressed from AAH to IA through AIS.

Conclusions

FAP-positive fibroblasts may contribute to tumor stroma formation in early-stage lung adenocarcinoma, and this could influence the development of therapeutic strategies targeting FAP-positive CAFs for disrupting extracellular matrix formation.

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Data availability

All relevant data are presented in the manuscript.

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Acknowledgements

We would like to thank Editage (www.editage.com) for English language editing.

Funding

This research was supported by JSPS KAKENHI [Grant number JP19K09314].

Author information

Authors and Affiliations

  1. Department of General Thoracic Surgery, Osaka International Cancer Institute, 3-1-69, Otemae, Chuo-Ku, Osaka, 541-8567, Japan

    Toru Kimura, Miki Sakaue, Tomohiro Maniwa & Jiro Okami

  2. Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, 2-2-L5, Yamadaoka, , Suita, 565-0871, Japan

    Toru Kimura & Yasushi Shintani

  3. Department of Cancer Drug Discovery and Development, Research Center, Osaka International Cancer Institute, 3-1-69, Otemae, Chuo-Ku, Osaka, 541-8567, Japan

    Takashi Akazawa, Yu Mizote & Hideaki Tahara

  4. Laboratory of Genomic Pathology, Osaka International Cancer Institute, 3-1-69, Otemae, Chuo-Ku, Osaka, 541-8567, Japan

    Harumi Nakamura

  5. Department of Pathology, Osaka International Cancer Institute, 3-1-69, Otemae, Chuo-Ku, Osaka, 541-8567, Japan

    Keiichiro Honma

  6. Project Division of Cancer Biomolecular Therapy, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo, 108-8639, Japan

    Hideaki Tahara

Authors
  1. Toru Kimura
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  2. Takashi Akazawa
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  3. Yu Mizote
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  4. Harumi Nakamura
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  5. Miki Sakaue
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  6. Tomohiro Maniwa
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  7. Yasushi Shintani
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  8. Keiichiro Honma
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  9. Hideaki Tahara
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  10. Jiro Okami
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Contributions

All authors contributed to the study’s conception and design. Toru Kimura, Takashi Akazawa, Yu Mizote, Harumi Nakamura, Miki Sakaue, Tomohiro Maniwa, Yasushi Shintani, Keiichiro Honma, Hideaki Tahara, and Jiro Okami carried out material preparation, and data collection and analysis. Toru Kimura wrote the first draft of the manuscript, and all authors commented on previous versions. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Toru Kimura.

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Conflict of interest

The authors have declared that no competing interest exists.

Ethics approval and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. The study was approved by the Institutional Review Board of the Osaka International Cancer Institute (June 12, 2019. Approval No. 19050). Written informed consent was obtained from all patients.

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Kimura, T., Akazawa, T., Mizote, Y. et al. Progressive changes in the protein expression profile of alveolar septa in early-stage lung adenocarcinoma. Int J Clin Oncol (2024). https://doi.org/10.1007/s10147-024-02507-1

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