No abstract

Tumor dormancy is a poorly understood stage in cancer progression characterized by mitotic cycle arrest in G0/G1 phase and low metabolism. The cells survive in a quiescent state and wait for appropriate environmental conditions to begin proliferation again giving rise to metastasis. Despite their key role in cancer development and metastasis, the knowledge about their biology and origin is still very limited due to the poorness of established in vitro models that faithfully recapitulated tumor dormancy. Using at least three cycles of 1% O hypoxia and reoxygenation, we establish and characterize the hypoxia-resistant human breast cancer cell line chMDA-MB-231 that can stably survive under 1% O condition by entering into dormant state characterized by arrest in G0/G1 phase and low metabolism. This dormant state is reversible since once replaced in normoxia the cells recover the proliferation rate in 2 weeks. We show that chronic hypoxia induces autophagy that may be the survival mechanism of chMDA-MB-231 cells. Furthermore, the data in this work demonstrate that cycling hypoxic/reoxygenation stress selects MDA-MB-231 population that presents the cancer stem-like phenotype characterized by CD24 /CD44 /ESA expression and spheroid forming capacity. We believe that our study presents a promising approach to select dormant breast cancer cells with stem-like phenotype using the hypoxia/reoxygenation regimen that may represent an area with profound implications for therapeutic developments in oncology. J. Cell. Biochem. 118: 3237-3248, 2017. © 2017 Wiley Periodicals, Inc.

No abstract

The tumor microenvironment is a key factor in disease progression, local resistance, immune-escaping, and metastasis. The rapid proliferation of tumor cells and the aberrant structure of the blood vessels within tumors result in a marked heterogeneity in the perfusion of the tumor tissue with regions of hypoxia. Although most of the tumor cells die in these hypoxic conditions, a part of them can adapt and survive for many days or months in a dormant state. Dormant tumor cells are characterized by cell cycle arrest in G0/G1 phase as well as a low metabolism, and are refractive to common chemotherapy, giving rise to metastasis. Despite these features, the cells retain their ability to proliferate when conditions improve. An understanding of the regulatory machinery of tumor dormancy is essential for identifying early cancer biomarkers and could provide a rationale for the development of novel agents to target dormant tumor cell populations. In this review, we examine the current knowledge of the mechanisms allowing tumor dormancy and discuss the crucial role of the hypoxic microenvironment in this process.