Human Cell

, Volume 32, Issue 4, pp 453–464 | Cite as

Interaction between cancer cells and cancer-associated fibroblasts after cisplatin treatment promotes cancer cell regrowth

  • Shoshi Hisamitsu
  • Tomoyuki Miyashita
  • Hiroko Hashimoto
  • Shinya Neri
  • Masato Sugano
  • Hiroshi Nakamura
  • Shota Yamazaki
  • Atsushi Ochiai
  • Koichi Goto
  • Masahiro Tsuboi
  • Genichiro IshiiEmail author
Research Article


Regrowth of cancer cells following chemotherapy is a significant problem for cancer patients. This study examined whether cancer-associated fibroblasts (CAFs), a major component of a tumor microenvironment, promote cancer cell regrowth after chemotherapy. First, we treated human lung adenocarcinoma cell line A549 and CAFs from four patients with cisplatin. Cisplatin treatment inhibited the viable cell number of A549 cells and induced epithelial–mesenchymal transition. After cisplatin was removed, A549 cells continued to manifest the mesenchymal phenotype and proliferated 2.2-fold in 4 days (regrowth of A549 cells). Cisplatin treatment inhibited the viable cell number of CAFs from four patients also. The CM (derived from cisplatin-pretreated CAFs from two patients) significantly enhanced the regrowth of cisplatin-pretreated A549 cells, and the CM derived from cisplatin-naïve CAFs marginally enhanced A549 regrowth. By contrast, the CM derived from either cisplatin-pretreated CAFs or cisplatin-naïve CAFs failed to enhance the growth of cisplatin-naïve A549 cells. The CM derived from cisplatin-pretreated CAFs did not enhance the proliferation of A549 cells in which epithelial–mesenchymal transition was induced by TGFβ-1. Our findings indicate the possibility that humoral factors from cisplatin-pretreated CAFs promote the regrowth of cisplatin-pretreated A549 cells. These results suggest that interactions between cancer cells and CAFs may significantly enhance cancer cell regrowth within the tumor microenvironment after cisplatin treatment.


Cancer-associated fibroblasts Tumor microenvironment Cisplatin Regrowth of cancer cells Lung adenocarcinoma cells 


Author contributions

SH contributed to the design and coordination of the study, performed experiment, and prepared the manuscript. TM and HH performed the experiment, and read and approved the final manuscript. SN, MS, HN, SY, AO, KG and MT contributed to preparing the manuscript, and read and approved the final manuscript. GI contributed to the design and coordination of the study, revised the article for important intellectual content, and read and approved the final manuscript.


This work was supported in part by JSPS KAKENHI (16H05311).

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

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.

Informed consent

Comprehensive informed consent was obtained from all individual participants included in the study.

Supplementary material

13577_2019_275_MOESM1_ESM.pptx (272 kb)
Supplementary material 1 (PPTX 271 kb)


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Copyright information

© Japan Human Cell Society and Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  • Shoshi Hisamitsu
    • 1
    • 2
  • Tomoyuki Miyashita
    • 1
    • 2
  • Hiroko Hashimoto
    • 2
  • Shinya Neri
    • 3
  • Masato Sugano
    • 4
  • Hiroshi Nakamura
    • 2
  • Shota Yamazaki
    • 1
    • 2
  • Atsushi Ochiai
    • 1
    • 5
  • Koichi Goto
    • 6
  • Masahiro Tsuboi
    • 7
  • Genichiro Ishii
    • 1
    • 2
    Email author
  1. 1.Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier SciencesThe University of TokyoKashiwaJapan
  2. 2.Division of Pathology, Exploratory Oncology Research and Clinical Trial CenterNational Cancer CenterKashiwaJapan
  3. 3.Department of Thoracic SurgeryKyoto University Graduate School of MedicineKyotoJapan
  4. 4.Department of Pathology and Clinical LaboratoriesNational Cancer Center Hospital EastKashiwaJapan
  5. 5.Exploratory Oncology Research and Clinical Trial CenterNational Cancer CenterKashiwaJapan
  6. 6.Department of Thoracic OncologyNational Cancer Center HospitalKashiwaJapan
  7. 7.Department of Thoracic SurgeryNational Cancer Center HospitalKashiwaJapan

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