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

Simple Summary To date, there has been no definite experimental evidence for the significance of circulating tumor cells (CTCs) as an indicator to estimate the chemotherapeutic effect in cancer patients. We previously reported a transient increase in CTC number 1 week after single-dose chemotherapy in human breast, lung, and gastric cancer xenograft mouse models. In the present study, we extensively examined the dynamics of both CTCs and tumor tissues after single and repetitive doses of chemotherapy in two human pancreatic cancer xenograft models to understand the mechanistic aspect of CTC mobilization after chemotherapy. We confirmed the transient increase in CTC number 1-2 weeks after chemotherapy and proposed a hypothesis that transient CTC mobilization after chemotherapy occurs by the shedding of growth-arrested tumor cells into disrupted tumor blood vessels in the primary tumor tissues 1-2 weeks after chemotherapy, which corresponds to the maximal destructive phase of primary tumor tissues before tissue repair and regeneration.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.