Page 144 - Read Online

McKenna et al Hypoxia in prostate cancer

Figure 1: Hypoxia impacts upon a number of important pathways which can promote tumor growth and progression

oxygen levels are low, the PHD enzymes become Table 1 shows the reported values from different studies
inactive, thereby reducing the degradation of HIFα. The on various cancers, demonstrating that the oxygen
stabilised HIFα molecules translocate to the nucleus, level in normal tissues can vary from approximately
form dimers with constitutively expressed HIFβ 4%-6% oxygen depending on the tissue; the normal
subunit, and bind to DNA to initiate gene transcription in prostate has one of the lowest reported median
[3]
response to the hypoxic environment . HIF-independent oxygen levels (~4%) . Normal physiological stress
[5]
hypoxia responses have also been described, including responses to a reducing level of oxygen probably
adaptive mechanisms regulated by mTOR signalling , occur between 1% and 3% although the exact level
[6]
p38 MAPK and NF-κB . It is therefore clear that a is difficult to define and may well depend on multiple
[7]
[8]
complex network of cellular and molecular signalling factors including the tissue under investigation. In
tumors, oxygen levels are frequently reported at well
occurs when cells are exposed to hypoxic stress [9,10] .
below 1% indicating that tumor cells are exposed
to severe hypoxic stresses. The proportion of the
This is important during cancer progression, because cells exposed to these extreme hypoxic stresses will
accelerated proliferation of cancer cells can result in vary across the tumor and can also be modified by
abnormal vascularization, unstable blood flow and responses to treatment.
reduced O diffusion within a solid tumor, causing
2
hypoxic regions to develop. This is significant because Untreated prostate tumors are known to be very
tumor hypoxia has been shown to cause numerous hypoxic (~0.3% oxygen) [3,4] , which is > 12 times lower
molecular and genetic changes within cells which than oxygen levels found in the normal prostate [3,11] .
promote cell survival and drive tumor development Prostate tumor hypoxia has been implicated as a
[Figure 1] [9,10] . causative factor in malignant progression [12,13] , genetic

2 Journal of Cancer Metastasis and Treatment ¦ Volume 4 ¦ March 1, 2018