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.
- Hai et al. (2017) ” TRIM14 is a Putative Tumor Suppressor and Regulator of Innate Immune Response in Non-Small Cell Lung Cancer” Scientific Reports 7, Article number: 39692 (2017)
https://www.nature.com/articles/srep39692 HypOxystation user
- Chouaib et al (2016) “Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer” Oncogene 2016, 1–7
- Labiano et al. (2016) “Hypoxia-induced soluble CD137 in malignant cells blocks CD137L-costimulation as an immune escape mechanism “ Oncoimmunology 2016; 5(1): e1062967
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760326/ HypOxystation user
- Hasmim et al. (2015) “Critical role of tumor microenvironment in shaping NK cell functions: implication of hypoxic stress” Front. Immunol. 6:482.
- Hevia et al. (2015) “Human colon-derived soluble factors modulate gut microbiota composition”
http://journal.frontiersin.org/article/10.3389/fonc.2015.00086/full HypOxystation user
- Labiano et al. (2015) “Immune Response Regulation in the Tumor Microenvironment by Hypoxia”
http://www.seminoncol.org/action/showFullTextImages?pii=S0093-7754%2815%2900025-1 HypOxystation user
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.
- Wadkin et al. (2017) “CD151 supports VCAM-1 mediated lymphocyte adhesion to liver endothelium 2 and is upregulated in chronic liver disease and hepatocellular carcinoma” Am J Physiol Gastrointest Liver Physiol. 2017 May 4
https://www.ncbi.nlm.nih.gov/pubmed/28473332 HypOxystation user
- Wang et al. (2016) “Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling” Journal of Bone and Mineral Research, Vol. 31, No. 9, September 2016, pp 1652–1665
http://onlinelibrary.wiley.com/doi/10.1002/jbmr.2848/epdf HypOxystation user
- Winning & Fandrey (2016) “Dendritic Cells under Hypoxia: How Oxygen Shortage Affects the Linkage between Innate and Adaptive Immunity,” Journal of Immunology Research, vol. 2016, Article ID 5134329
https://www.hindawi.com/journals/jir/2016/5134329/ HypOxystation user
- Jiang et al. (2015) “HIF1α and CEBP's transcriptionally regulate adipogenic diiferentiation of bone marrow-derived MSC's in hypoxia” Stem Cell Research & Therapy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559195/ HypOxystation user
- Tafani et al. (2016) “The Interplay of Reactive Oxygen Species, Hypoxia, Inflammation, and Sirtuins in Cancer Initiation and Progression ” Genome Biology 17:140
- Balamuragan et al. (2016) “HIF-1 at the crossroads of hypoxia, inflammation, and cancer” Int J Cancer. 2016 March 1; 138(5): 1058–1066