Abstract 3751: A mode of treatment resistance of metastatic tumor cells: Propagation exceeds elimination in number
Authors: Kudo-Saito Chie , Ozaki Yukinori , Kinowaki Keiichi , Kawabata Hidetaka , Ogiwara Yamato 
Published: August 2019

Abstract
Purpose: Distant recurrence following metastasis is a major cause of cancer-associated death. Interfering spread and re-growth of the disseminated tumor cells, which could be cancer stem-like cells (CSCs) via EMT, must be greatly helpful for improving prognosis of cancer patients. However, little is known about the molecular mechanisms underlying the refractoriness. In this study, we attempted to elucidate the mechanism how the dormant CSCs would wake up from the sleeping at the metastatic lesions.
Results: C57BL/6 mice were subcutaneously and intravenously implanted with murine melanoma B16-F10 cells or B16-F10 cells transduced with snail gene as an EMT control, and 3 weeks later, the metastasized tumor cells (F10-BM or F10-BM-snail+) were harvested from the bone marrow, a niche for CSCs, or from the subcutaneous tumors as a control (F10-primary). We comprehensively analyzed these clones for EMT-related molecular expressions and biological functions in vitro and in vivo. The F10-primary cells were round and adhesive having high expression of epithelial markers such as E-cadherin, but not mesenchymal markers such as Snail, and the F10-BM-snail+ cells were small and spindle having high expression of mesenchymal markers, but not epithelial markers. In contrast, the F10-BM cells were giant and very adhesive with high expression of epithelial markers, but still keeping high Snail expression in the cytoplasm. Interestingly, these cells were polyploidy having a number of nuclei in a cell, and proliferated significantly slower than the F10-primary cells. However, once receiving stimulation with a low concentration of chemotherapeutics, the F10-BM cells aggressively proliferated through generation of many progeny cells, looking resistant to the treatment. In the in vivo settings, the F10-BM tumor growth was significantly slower after implantation in mice, and the mice survived for a longer term than the F10-primary-implanted mice. As seen in the in vitro culture, the F10-BM tumors quite rapidly grew in response to treatments such as chemotherapeutics and immune checkpoint inhibitors, and the treated mice died significantly earlier than the nontreated F10-BM-implanted or the F10-primary-implanted mice, suggesting hyperprogression that tumor cell propagation might exceed elimination in the mice.
Conclusions: These data suggest that dormant and polyploidy giant cells could be a risk factor of hyperprogression of the metastatic tumors after treatments. We are now identifying a specific molecule regulating this mechanism utilizing cDNA microarray analysis.
Citation Format: Chie Kudo-Saito, Yukinori Ozaki, Keiichi Kinowaki, Hidetaka Kawabata, Yamato Ogiwara. A mode of treatment resistance of metastatic tumor cells: Propagation exceeds elimination in number [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3751.