Immunotherapy using slow-cycling tumor cells prolonged overall survival of tumor-bearing mice

Qing Sun,Chunxia Zhou,Fan Wu,Wenbo Ma,Yong Zhong,Shuren Zhang,Dongmei Wang,Youhui Zhang

doi:10.1186/1741-7015-10-172

Abstract

BackgroundDespite considerable progress in the development of anticancer therapies, there is still a high mortality rate caused by cancer relapse and metastasis. Dormant or slow-cycling residual tumor cells are thought to be a source of tumor relapse and metastasis, and are therefore an obstacle to therapy. In this study, we assessed the drug resistance of tumor cells in mice, and investigated whether vaccination could promote survival.MethodsThe mouse colon carcinoma cell line CT-26 was treated with 5-fluorouracil to assess its sensitivity to drug treatment. Mice with colon tumors were immunized with inactivated slow-cycling CT-26 cells to estimate the efficacy of this vaccine.ResultsWe identified a small population of slow-cycling tumor cells in the mouse colon carcinoma CT-26 cell line, which was resistant to conventional chemotherapy. To inhibit tumor recurrence and metastasis more effectively, treatments that selectively target the slow-cycling tumor cells should be developed to complement conventional therapies. We found that drug-treated, slow-cycling tumor cells induced a more intense immune response in vitro. Moreover, vaccination with inactivated slow-cycling tumor cells caused a reduction in tumor volume and prolonged the overall survival of tumor-bearing mice.ConclusionsThese findings suggest that targeting of slow-cycling tumor cells application using immunotherapy is a possible treatment to complement traditional antitumor therapy.

Highlights

Despite considerable progress in the development of anticancer therapies, there is still a high mortality rate caused by cancer relapse and metastasis
We investigated the tumorigenicity and drug-resistant potential of slow-cycling tumor cells compared with normal tumor cells, and found evidence supporting the hypothesis that slow-cycling, drug-resistant tumor cells are the source of tumor relapse and metastasis, and are an obstacle to therapy
We found that, the number of tumor cells and the volume of the tumor were reduced by drug treatment, the remnant was composed of drug-resistant, slow-cycling cells. These results provide evidence that slow-cycling tumor cells are resistant to traditional chemotherapy and are responsible for initiating tumor relapse and metastasis

Summary

Introduction

Despite considerable progress in the development of anticancer therapies, there is still a high mortality rate caused by cancer relapse and metastasis. Disseminated tumor cells or residual treatmentresistant tumor cells may persist in a so-called dormant state until they are stimulated into an active cell-cycle and initiate tumor recurrence [2] These dormant or ‘slow-cycling’ residual tumor cells are thought to be a source of tumor relapse and metastasis, and are an obstacle to therapy. The suggested mechanism of the drug resistance of slow-cycling tumor cells is that their minimal activity silences a vast spectrum of metabolic loops targeted by anticancer drugs [3]. This theory is still controversial, and more research is needed

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