Acute vs. chronic vs. intermittent hypoxia in breast Cancer: a review on its application in in vitro research

Abstract

Hypoxia has been linked to elevated instances of therapeutic resistance in breast cancer. The exposure of proliferating cancer cells to hypoxia has been shown to induce an aggressive phenotype conducive to invasion and metastasis. Regions of the primary tumors in the breast may be exposed to different types of hypoxia including acute, chronic or intermittent. Intermittent hypoxia (IH), also called cyclic hypoxia, is caused by exposure to cycles of hypoxia and reoxygenation (H-R cycles). Importantly, there is currently no consensus amongst the scientific community on the total duration of hypoxia, the oxygen level, and the possible presence of H-R cycles. In this review, we discuss current methods of hypoxia research, to explore how exposure regimes used in experiments are connected to signaling by different hypoxia inducible factors (HIFs) and to distinct cellular responses in the context of the hallmarks of cancer. We highlight discrepancies in the existing literature on hypoxia research within the field of breast cancer in particular and propose a clear definition of acute, chronic, and intermittent hypoxia based on HIF activation and cellular responses: (i) acute hypoxia is when the cells are exposed for no more than 24 h to an environment with 1% O2 or less; (ii) chronic hypoxia is when the cells are exposed for more than 48 h to an environment with 1% O2 or less and (iii) intermittent hypoxia is when the cells are exposed to at least two rounds of hypoxia (1% O2 or less) separated by at least one period of reoxygenation by exposure to normoxia (8.5% O2 or higher). Our review provides for the first time a guideline for definition of hypoxia related terms and a clear foundation for hypoxia related in vitro (breast) cancer research.

Ruthenium-Based Photoactivated Chemotherapy

“…Hypoxia occurs whenever the number of cells around a blood vessel becomes too large for available O 2 delivery (Figure a). Cells might develop too quickly for the available blood supply, such as in an embryo or in a tumor, but in other cases, the blood supply may become suddenly or chronically impaired because of a wound, of PDT treatment, of ischemia, of high altitudes, or of apnea . As hypoxia is a natural phenomenon, cells have evolved different mechanisms to cope with it, which are primarily controlled by the transcription factors HIF1α and HIF2α .…”

“…Cells might develop too quickly for the available blood supply, such as in an embryo or in a tumor, but in other cases, the blood supply may become suddenly or chronically impaired because of a wound, of PDT treatment, of ischemia, of high altitudes, or of apnea. 118 As hypoxia is a natural phenomenon, cells have evolved different mechanisms to cope with it, which are primarily controlled by the transcription factors HIF1α and HIF2α. 119 These mechanisms are highjacked in cancer cells, 120 which must always face an abnormally low state of oxygenation during early tumor development.…”

Chitosan-g-estrone Nanoparticles of Palbociclib Vanished Hypoxic Breast Tumor after Targeted Delivery: Development and Ultrasound/Photoacoustic Imaging

“…It has been reported that hypoxic tumors are three times more resistant to therapy compared with normoxic tumors . Additionally, the limited vascularization in the hypoxic tumor acts as a barrier to the tumor permeability of the anticancer drug …”

“…31 Additionally, the limited vascularization in the hypoxic tumor acts as a barrier to the tumor permeability of the anticancer drug. 32 Therefore, considering the therapeutic requirement for treating advanced-stage breast cancers, a targeted drug delivery system may be a solution that allows the targeted delivery of the loaded drug to tumors. So, here we proposed ER targeted NPs loaded with PLB for the targeted therapy of advancedstage breast cancers.…”

Differential response of luminal and basal breast cancer cells to acute and chronic hypoxia

“…The tissue microenvironment of breast cancer is highly heterogenous and, depending on the local extent of newly formed blood vessels, it can contain regions of acute, intermittent and chronic hypoxia [10]. This is relevant as cancer cells show different cellular responses depending on the duration and frequency of hypoxia exposure [9,11,12]. Acute hypoxia is associated with reversible changes, chronic hypoxia is associated with long-term cellular changes potentially developing into mutagenesis and genetic instability [9].…”