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Hallmarks of Cancer: Sustaining Growth and Resisting Cell Death

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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.

 

 

 

 

 

 

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 signalling, is activated by hypoxia and reactive oxygen species, and also promotes cell survival.

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.

SustainingGrowthSliceLITERATURE:

 

 

 

 

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