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01.12.2018 | Letter to the Editor | Ausgabe 1/2018 Open Access

Journal of Hematology & Oncology 1/2018

Selective killing of circulating tumor cells prevents metastasis and extends survival

Zeitschrift:
Journal of Hematology & Oncology > Ausgabe 1/2018
Autoren:
Yi Rang Kim, Jung Ki Yoo, Chang Wook Jeong, Jin Woo Choi
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13045-018-0658-5) contains supplementary material, which is available to authorized users.
A correction to this article is available online at https://​doi.​org/​10.​1186/​s13045-018-0688-z.
Abbreviations
CTCs
Circulating tumor cells
GFP
Green fluorescent protein
PDT
Photodynamic therapy
RB
Rose bengal

Circulating tumor cells (CTCs) present in the vascular system are tumor cells that will metastasize from primary or disseminated tumors [ 1]. Rapid advancements in detection and isolation techniques have led to the remarkable discoveries on the role of CTCs and their association with cancer prognosis [ 27]. Since an increased number of CTCs are associated with poor prognosis, CTC-targeted therapies may provide a promising new approach which could improve cancer prognosis [ 8, 9]. However, the unpredictable nature and dynamics of CTCs and the lack of adequate treatment modalities hamper the selective targeting of CTCs.
In the present study, we demonstrate the clinical benefit of selective CTC elimination by using a technique that we developed previously [ 10]. We used the original photodynamic therapy (PDT) methodology with stepwise modification to selectively kill CTCs using energy transfer between the green fluorescent protein (GFP) expressed by CTCs and the rose bengal (RB) accumulated in the CTCs (Fig.  1a). To mimic the circulation within the blood vessels in vitro, a piece of tubing was connected to a peristaltic pump. GFP + and GFP NCI-H460 cells were incubated with RB and were passed through the tubing (Fig.  1b). A greater number of propidium iodide-positive cells (which indicates cell death) was observed among the GFP + NCI-H460 cells than the GFP NCI-H460 cells. Furthermore, GFP cells showed lower damage than GFP + cells (Fig.  1c). Moreover, the number of dead cells was significantly higher among GFP + NCI-H460 cells than GFP NCI-H460 cells (Fig.  1d).
Then, to test the CTC-targeting PDT in vivo, GFP + NCI-H460 cells were incubated with RB and injected into mice via the tail vein. Immediately after, a blue laser was illuminated onto the mouse‘s femoral vein, underneath the skin flap (treated group; Fig.  2a). Because the numbers of CTCs were drastically decreased in the intravenous tumor cell injection model (Additional file  1), whole mouse blood was extracted by cardiac puncture about 15 min after tumor cell injection. In the treated group, the number of CTC colonies were significantly decreased in the clonogenic assay (Fig.  2b and Additional file  2a), and GFP expression from the clones was observed (Additional file  2b); hence, each colony had originated from exogenously injected GFP-expressing cancer cells.
CTC-targeting PDT was also performed in mice with GFP+ metastatic 4T1 cells transplanted into their flanks (Fig.  2c). No changes in primary tumor size (Additional file  3) were observed between treated (irradiated) mice and untreated mice, implying limited effects on GFP normal cells; however, the numbers of CTCs observed in the fluorescent images were significantly decreased in the treated mice compared to those the untreated mice (Fig.  2d and Additional file  4). In the treated group, the number of lung metastatic nodules in the treated mice was significantly lower compared to that in the untreated group (Fig.  2e). Mice receiving treatment for 1 week showed survival gain compared with untreated mice ( P = 0.0325) (Fig.  2f). However, the difference was more significant in the mice treated for 2 weeks ( P = 0.0026). There was no hematologic difference between the untreated group and the 2 weeks treatment group (Additional file  5). Materials and methods are described in Additional file 6.
To prove the benefits of CTC elimination, we developed an energy transfer-based PDT that targets GFP-expressing CTCs. Using this technique, we attempted to eliminate CTCs and optimize conditions to specifically target CTCs, with minimum damage to normal cells. To our knowledge, this is the first experimental study to demonstrate that the direct killing of CTCs extends survival in vivo . The present study highlights the concept of energy distinction between normal and cancer cells by using a new factor, i.e., cancer cell-specific fluorescence.
Although this is a preliminary study using the externally fluorescence-labeled cancer cells and the injected mouse models, thus, this strategy is not suitable for in vivo targeting therapeutics of CTC; we reveal that clearance of CTC is associated with the reduction of metastasis and extension of survival. In addition, this experiment directly suggests CTCs are a core seed to be metastasized into secondary organs. Advancements in the field of molecular diagnostics have made it possible to use combinations of fluorescence proteins and photosensitizers or molecular-targeted photosensitizers in diverse biological fields, including cancer stem cell-targeted therapy.

Funding

This work was supported by the grants from Kyung Hee University (KHU-20170844 for JW Choi) and the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (HA17C0039 for YR Kim and CW Jeong).

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Ethics approval and consent to participate

All animal experiments were approved by the Institutional Animal Care and Use Committee at Kyung Hee University (KHSIRB 18-014) and were performed in compliance with the institutional guidelines.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.

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