Abstract 2433: The hypoxic tumor microenvironment in vivo selects the tumor cells with cancer stem cell characteristics and increased resistance against genotoxic stresses

Abstract

Abstract Tumor hypoxia has been established as an independent prognostic factor associated with poor patient survival and resistance to conventional therapies. Emerging evidence suggests that hypoxia has the potential to maintain or enhance the stem cell phenotype and confers chemo- or radio-resistance to tumor cells. However, it remains to be determined whether cell fate and acquisition of therapy resistance is regulated in vivo by the hypoxic tumor microenvironment (TME). In this study, we have developed a hypoxia-sensing human breast cancer cell xenograft model using the hypoxia-response element (HRE)-driven enhanced green fluorescence protein (EGFP) as a hypoxia reporter. We have found that the hypoxic tumor cells isolated from xenografts contain increased subpopulations of tumor cells showing the cancer stem cell (CSC) characteristics. Upon re-implantation, the CSC characteristics of the hypoxic tumor cells continue to be further enriched during in vivo growth, whereas secondary xenografts derived from the non-hypoxic tumor cells remain similar to the primary xenografts. Consistent with this finding, the phenotypes exhibited by the hypoxic tumor cells are stably different from those of the non-hypoxic tumor cells isolated from the same tumor mass even when they are maintained under the same ambient culture conditions. Mechanistically, we find that the PI3K/AKT pathway is strongly potentiated in the hypoxic tumor cells and is required to maintain the CSC phenotype. Cell fate differences between hypoxic and non-hypoxic tumor cells are found only in tumor cells isolated from the hypoxic TME in vivo, and are not seen in tumor cells treated by hypoxia in vitro alone. In addition, we have found that naturally hypoxic tumor cells in a breast cancer xenograft model are moderately radio- and chemo-resistant compared to their neighboring non-hypoxic tumor cells in the same tumor. These naturally hypoxic tumor cells are proficient at repairing DNA damages and resist apoptosis induced by genotoxic stresses. The ex vivo hypoxic tumor cells are capable of proficient activation of the DNA damage-sensing pathways, especially the ATM pathway. These previously unrecognized observations suggest that the hypoxic TME may promote malignant progression by coordinating induction, selection and preferential maintenance of the CSC phenotype in tumor cells. This presentation will review our results which strongly suggest that the hypoxic TME may induce adaptive responses, either by clonal evolution or selection, such that hypoxic tumor cells in vivo acquire new functional traits that confer resistance to genotoxic stresses and enhance survival. It can be postulated that previously hypoxic tumor cells may continue to exhibit their aggressive phenotypes long after they have migrated into non-hypoxic regions or after their native niche become normoxic. Citation Format: Hoon Kim, Qun Lin, Zhong Yun. The hypoxic tumor microenvironment in vivo selects the tumor cells with cancer stem cell characteristics and increased resistance against genotoxic stresses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2433.