Editors' ChoiceCancer

Winter is coming: Tumor cells go into hibernation

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Science Translational Medicine  15 Feb 2017:
Vol. 9, Issue 377, eaam6063
DOI: 10.1126/scitranslmed.aam6063

Abstract

In response to hypoxia in the primary tumor microenvironment, tumor cells induce a state of dormancy enabling their persistence at metastatic sites and resistance to therapy.

Bears hibernate to preserve energy during the long winter. Similarly, tumor cells may induce a state of hibernation, termed dormancy, in order to survive in patients, resist therapy, and contribute to clinical relapse. In nature, entry into a dormant state is often synchronized with the environment—for example, seasonal changes. Fluegen et al. demonstrate that reduced oxygenation in the primary tumor acts as the environmental signal activating tumor cell expression of dormancy-associated genes and hibernation.

Using a triple negative breast cancer (TNBC) cell line engineered to express a fluorescent protein in response to hypoxia, the authors demonstrate that pockets of primary tumor cells experience hypoxia resulting in coincident induction of hypoxia-dependent (GLUT1 and HIF1α) and dormancy-inducing (NR2F1 and DEC2) genes. Similarly, in human primary head and neck squamous cell carcinoma, regions of high GLUT1 expression were enriched for expression of NR2F1, indicating coregulation of hypoxia and dormancy programs in both mice and humans. To interrogate the role of hypoxia in vivo, the authors utilized microfabricated devices that generate hypoxia gradients, defined by expression of GLUT1, when loaded with a hypoxia-mimetic. Induction of hypoxia generated overlapping expression of DEC2 and NR2F1, and growth-arrested, hypoxic cells induced a NR2F1-dependent, repressive chromatin state. Histone H2B labeling was used to track cells in vivo and determine the fate of hypoxia-imprinted cells that disseminate from primary tumors (DTC). Those cells that retain label demonstrate significantly reduced proliferation and are termed quiescent. Increased numbers of label-retaining, quiescent DTCs were induced by hypoxia, and these DTCs demonstrated enhanced persistence in lung. Furthermore, in both experimental and spontaneous metastasis models, hypoxia-imprinted DTCs showed preferential survival and resistance to treatment with the chemotherapeutic agent cisplatin over hypoxia-naïve DTCs.

Estrogen receptor positive (ER+) luminal breast cancer is characterized by late metastatic relapse as compared with TNBC. Consistent with their model, the authors demonstrate that ER+ breast cancer cells are more sensitive to hypoxia-induced, NR2F1-dependent dormancy. Taken together, these results indicate that both cell-intrinsic and cell-extrinsic environmental factors may induce tumor cell hibernation, even while on therapy, leading to clinical delays in metastatic relapse.

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