Mobilization of Circulating Tumor Cells after Short- and Long-Term FOLFIRINOX and GEM/nab-PTX Chemotherapy in Xenograft Mouse Models of Human Pancreatic Cancer

Author:

Ito Yukako1,Kobuchi Shinji1ORCID,Kawakita Amiri1,Tosaka Kazuki1,Matsunaga Yume1,Yoshioka Shoma1,Jonan Shizuka2,Amagase Kikuko2,Hashimoto Katsunori3,Kanda Mitsuro4,Saito Takuya5,Nakanishi Hayao56

Affiliation:

1. Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan

2. Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga 603-8577, Japan

3. Department of Medical Technology, Faculty of Medical Sciences, Shubun University, Ichinomiya City 491-0938, Japan

4. Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan

5. Department of Gastroenterological Surgery, Aichi Medical University, Nagakute City 480-1195, Japan

6. Laboratory of Pathology, Okazaki City Hospital, Okazaki 444-0002, Japan

Abstract

Mobilization of CTCs after various types of therapy, such as radiation therapy, has been reported, but systematic study of CTCs after chemotherapy remained quite limited. In this study, we sequentially examined CTC numbers after single-dose and repetitive-dose chemotherapy, including FORFIRINOX (FFX) and Gemcitabine and nab-Paclitaxel (GnP) using two pancreatic cancer xenograft models. CTC was detected by the immunocytology-based microfluidic platform. We further examined the dynamic change in the histology of primary tumor tissues during chemotherapy. We confirmed a transient increase in CTCs 1–2 weeks after single-dose and repetitive-dose of FFX/GnP chemotherapy. Histological examination of the primary tumors revealed that the peak period of CTC at 1–2 weeks after chemotherapy corresponded to the maximal destructive phase consisting of cell cycle arrest, apoptosis of tumor cells, and blood vessel destruction without secondary reparative tissue reactions and regeneration of tumor cells. These findings indicate that mobilization of CTCs early after chemotherapy is mediated by the shedding of degenerated tumor cells into the disrupted blood vessels driven by the pure destructive histological changes in primary tumor tissues. These results suggest that sequential CTC monitoring during chemotherapy can be a useful liquid biopsy diagnostic tool to predict tumor chemosensitivity and resistance in preclinical and clinical settings.

Funder

Ministry of Education, Science, Sports, Culture, and Technology, Japan

Grant-in-Aid for a Priority Research Project from the Knowledge Hub Aichi, Japan

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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