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

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Abstract

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.

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Funding

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

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Authors and Affiliations

  1. Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan

    Shoshi Hisamitsu, Tomoyuki Miyashita, Shota Yamazaki, Atsushi Ochiai & Genichiro Ishii

  2. Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, 277-8577, Chiba, Japan

    Shoshi Hisamitsu, Tomoyuki Miyashita, Hiroko Hashimoto, Hiroshi Nakamura, Shota Yamazaki & Genichiro Ishii

  3. Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Shinya Neri

  4. Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan

    Masato Sugano

  5. Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan

    Atsushi Ochiai

  6. Department of Thoracic Oncology, National Cancer Center Hospital, Kashiwa, Chiba, Japan

    Koichi Goto

  7. Department of Thoracic Surgery, National Cancer Center Hospital, Kashiwa, Chiba, Japan

    Masahiro Tsuboi

Authors
  1. Shoshi Hisamitsu
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  2. Tomoyuki Miyashita
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  4. Shinya Neri
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  5. Masato Sugano
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  6. Hiroshi Nakamura
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  7. Shota Yamazaki
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  8. Atsushi Ochiai
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  9. Koichi Goto
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  10. Masahiro Tsuboi
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  11. Genichiro Ishii
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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.

Corresponding author

Correspondence to Genichiro Ishii.

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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.

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

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Figure S1. Schematic of the main experiment. A) The experimental schematic of the effect of CM derived from CAFs treated with cisplatin on the growth of cisplatin-pretreated A549 cells. B) Experimental schematic of the effect of CM derived from naïve CAFs on the growth of naïve A549 cells.

Figure S2. Expression levels of 9 EMT related factors in cisplatin-pretreated A549 cells for 4 d following cisplatin removal. Values are means ± S.D. from three independent experiments. *p< 0.05

Figure S3. Expression levels of IL-6, HGF, VEGF-A, FGF-2, and IGF-1mRNA in naïve CAFs and cisplatin-treated CAFs. A) Expression levels of IL-6, HGF, VEGF-A, FGF-2, and IGF-1mRNA in naïve CAFs. Naïve and cisplatin-treated CAF1 and CAF3 don’t have promoting effect on A549 cell regrowth, while CAF2 and CAF4 have promoting effect. (Figure 3). First we examined expression levels of IL-6, HGF, VEGF-A, FGF-2, and IGF-1mRNA in naïve CAFs1,2,3, and 4 by RT-PCR method. The expression of HGF was obviously lower in naïve CAF2 and CAF4 compared to CAF1 and CAF3. B) Expression levels of IL-6, HGF, VEGF-A, FGF-2, and IGF-1mRNA in cisplatin-treated CAFs. HGF expression level in cisplatin-treated CAF2 was obviously higher than cisplatin-treated CAF1, which was the reverse result using naïve CAF1 and CAF2.

Figure S4. Summary of this study. A: In TME without cisplatin, CAFs did not increase the proliferation of A549 cells. B: In the TME following cisplatin treatment, cisplatin-exposed CAFs stimulated the growth of cisplatin-exposed A549 cells.

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Hisamitsu, S., Miyashita, T., Hashimoto, H. et al. Interaction between cancer cells and cancer-associated fibroblasts after cisplatin treatment promotes cancer cell regrowth. Human Cell 32, 453–464 (2019). https://doi.org/10.1007/s13577-019-00275-z

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