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The iconic “Hallmarks of Cancer” first described by Douglas Hanahan and Robert Weinberg in 2000 continue to develop explosively as efforts to illuminate the “acquired capabilities of cancer” evolve. Hypoxia in the fast-growing, poorly perfused tumor setting is one of the main factors selecting for survival of cancer cells and driving mutagenesis and metastasis. Oxygen in the tumor microenvironment and within the cells is central to metabolism, immunology, epigenetics and therapy resistance of all the cancers.  


In the lab, oxygen levels during cell culture exert effects on metabolism, maintenance, cell yield, and cell survival. Cell culture in the HypOxystation establishes authentic conditions for research into tumor progression, differentiation and self-renewal of cancer stem cells, response to chemotherapeutic drugs, and other events which determine malignancy and outcome of cancer diseases. The HypOxystation enables glove-less access to cultivate and manipulate cells under physiological conditions, in a HEPA-clean environment. 

In this mini-review series, HypOxygen takes a closer look at the way HypOxystation users worldwide are delineating “Hypoxia and the Hallmarks of Cancer”. First up: Avoiding Immune Destruction and Tumor Promoting Inflammation.

1. Avoiding immune destruction

The hypoxic tumor microenvironment has the capacity to create an immune-suppressive network supporting tumor growth.  Hypoxia-mediated activation of HIF-1 and VEGF pathways supports the immune tolerance of tumors through attenuation of the cytotoxic function of immune cells. Migration and homing of immune effector cells into tumors are impaired and multiple elements of immune cell differentiation, tumor angiogenesis, and metabolic changes are impacted by hypoxia in the tumor microenvironment. HIF’s directly and indirectly regulate differentiation and accumulation of myeloid-derived suppressor cells (MDSC’s) in hypoxic regions of tumors, thus suppressing both innate and adaptive immune mechanisms. HIF-regulated TAM localization to hypoxic tumor areas contributes to up-regulation of pro-angiogenic factors and reduced susceptibility to lysis by NK and T cells. T cell-mediated killing of cancer cells is decreased through HIF-1α regulation at hypoxia.

Manipulating the hypoxic tumor microenvironment to overcome immune-suppressive conditions may be crucial to developing successful cancer immunotherapy strategies.


2. Tumor promoting inflammation

Hypoxia and inflammation co-exist in an interactive manner in tumors, primarily connected through HIF-1 mediated mechanisms and induced by various cytokines such as TNF-α and interleukins, transcriptions factors such as NF-κB, and ROS. Increased metabolism in and diminished oxygen supply to the rapidly dividing cancer cells both cause and are caused by intermittent as well as chronic hypoxia in various stages of cancer progression. HIF-1 stabilization in cancer cells increases production of chemotactic factors such as VEGF, which attract monocytes to the tumor where they differentiate into TAM’s. These tumor associated macrophages in areas of low oxygen promote the progression of cancer by producing growth factors, activating angiogenesis, producing immunosuppressive cytokines, and secreting matrix-degrading enzymes to aid in the spreading of the cancer cells. HIF and NF-κB are main drivers of pro-inflammatory responses in T cells, dendritic cells and neutrophils. Hypoxia induces sustained inflammation through preferential homing of neutrophils to hypoxic sites of inflammation in tumors and delayed neutrophil apoptosis via HIF-1α dependent NF-κB activity. Research on the regulation of the chemotactic network in tumors indicates that hypoxia promotes a migratory phenotype in immature DCs and a highly pro-inflammatory state in mature DCs.