Of all the “Hallmarks of Cancer” defined by Hanahan and Weinberg, the ability to proliferate indefinitely is often considered to be the most central to cancer’s core features. Sustaining Growth and Resisting Cell Death enable cancer cells to override signaling that ensures normal tissues’ homeostasis of numbers and size. Previous chapters in our mini-series on “Hypoxia and the Hallmarks of Cancer” have showcased Avoiding Immune Destruction and Tumor Promoting Inflammation and Genome Instability and Mutation and Enabling Replicative Immortality as well as Inducing Angiogenesis and Activating Invasion and Metastasis.
In part four of our mini-series describing “Hypoxia and the Hallmarks of Cancer”, we look more closely at how researchers are using the HypOxystation to delineate the Hallmarks Sustaining Growth and Resisting Cell Death.
The HypOxystation creates a cell culture environment that mimics authentic conditions for cancer research with regard to oxygen, CO2, temperature, and humidity. Glove-less access to culture and manipulate cells under physiological conditions, in a HEPA-clean environment, allows cancer researchers to re-create the hypoxic tumor microenvironment.
Find out more about hypoxia in your specific field by searching our new Publications List; current publications by HypOxystation users provide a resource for researchers interested in investigating their cells under truly authentic, physiological culture conditions. We hope the science community will find these papers, which are searchable and linked to the original papers, to be useful in elucidating the importance of hypoxic cell culture in their own labs.
1. Resisting Cell Death
The ability of cells to resist cell death under hypoxic conditions is central to the progression of cancer and the acquisition of resistance to chemotherapy so frequently encountered in tumors. Hypoxia in the tumor microenvironment exerts selective pressure favoring cells that have lost the functionality of apoptosis genes and can expand uncontrollably. Hypoxia also contributes to survival by inducing autophagy, in a pathway involving HIF-1, beclin, BNIP3 and BNIP3L, in which cellular autophagy acts to recycle cellular organelles, satisfy metabolic demand and improve hypoxic tolerance. HIF-1 mediates cell-cycle retardation and arrest, causing hypoxic tumor cells to become resistant to radiotherapies. NF-κB, through its effects on myriad transcription factors, for example through inhibition of cell death signaling, is activated by hypoxia and reactive oxygen species, and also promotes cell survival.
- Chen et al. (2017) “Autophagy enhanced the radioresistance of non-small cell lung cancer by regulating ROS level under hypoxia condition” International Journal of Radiation Biology, 2017 DOI: 10.1080/09553002.2017.1325025
www.tandfonline.com/doi/ref/10.1080/09553002.2017.1325025?scroll=top HypOxystation user
- Audas et al. (2016) “Adaptation to Stressors by Systemic Protein Amyloidogenesis” Developmental Cell 39, 155–168, October 24, 2016
www.cell.com/developmental-cell/fulltext/S1534-5807(16)30598-6?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1534580716305986%3Fshowall%3Dtrue HypOxystation user
- Knoll et al. (2016) “Hypoxia regulates TRAIL sensitivity of colorectal cancer cells through mitochondrial autophagy” Oncotarget. 2016 Jul 5;7(27):41488-41504
www.ncbi.nlm.nih.gov/pubmed/27166192 HypOxystation user
- Mysore et al. (2016) “A DNA binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma has Potent Anti tumor Activity” Mol Cancer Res March 2016 14:253-266
www.ncbi.nlm.nih.gov/pmc/articles/PMC4794370/ HypOxystation user
- Rey et al. (2016) “Molecular targeting of hypoxia in radiotherapy” Advanced Drug Delivery Reviews 2016
www.sciencedirect.com/science/article/pii/S0169409X16302769 HypOxystation user
- Tan et al. (2016) “Role of Autophagy as a Survival Mechanism for Hypoxic Cells in Tumors” Neoplasia (2016) 18, 347–355
www.ncbi.nlm.nih.gov/pubmed/27292024 HypOxystation user
- Poillet-Perez et al. (2015) “Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy“ Redox Biology 4, 184–192
2. Sustaining Growth
Cancer is essentially based on the cells’ inability to “stop” when suppressors signal an end to growth, and the compunction to “go” despite a lack of bonafide growth signals. Hypoxia in the context of cancer, in precipitating genomic instability and mutation, results in numerous inactive tumor suppressor genes and activated growth factor genes, such that the combination of constitutive proliferative signaling and mutated cancer genes leads to sustained growth. HIF and NF-κB regulated pathways involving Notch, mTOR, WNT11, CAIX, and IGF-1, among many others, contribute to sustained growth in cancer as regulation of proliferation derails. Induced by hypoxia-regulated proteins, anabolic pathways for nucleotide and lipid synthesis are ramped up and enable the rapid proliferation typical of cancer.
- Thienpont et al (2016) “Tumor hypoxia causes DNA hypermethylation by reducing TET activity” Nature 2016 September 01; 537(7618): 63–68.
www.nature.com/nature/journal/v537/n7618/abs/nature19081.html?foxtrotcallback=true HypOxystation user
- Humtsoe et al. (2016) “ErbB3 upregulation by the HNSCC 3D microenvironment modulates cell survival and growth” Oncogene 35, 1554-1564 (24 March 2016)
www.nature.com/onc/journal/v35/n12/full/onc2015220a.html HypOxystation user
- Alam et al. (2016) “HIF2α contributes to antiestrogen resistance via positive bilateral crosstalk with EGFR in breast cancer cells” Oncotarget, Vol. 7, No. 10 2016
www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=7167&pubmed-linkout=1 HypOxystation user
- Adriaens et al. (2016) “Quantitative analysis of ChIP‑seq data uncovers dynamic and sustained H3K4me3 and H3K27me3 modulation in cancer cells” Epigenetics & Chromatin (2016) 9:48
epigeneticsandchromatin.biomedcentral.com/articles/10.1186/s13072-016-0090-4 HypOxystation user
- Hansson et al. (2016) “Overexpression of functional SLC6A3 in clear cell renal cell carcinoma” Clin Cancer Res. 2016 Sep 23
clincancerres.aacrjournals.org/content/23/8/2105.full-text.pdf HypOxystation user
- Mori et al. (2016) “Induction of WNT11 by hypoxia and hypoxia-inducible factor-1α regulates cell proliferation, migration and invasion” Scientific Reports 6:21520