Chordoma Foundation

Hypoxia

Hypoxia in Chordoma

Tumor hypoxia occurs when tumor cells are deprived of oxygen and is characteristic of all solid tumors. Hypoxia has numerous effects on tumor development. Tumor cells undergo multiple changes in order to survive and proliferate under low oxygen conditions. In addition to promoting cell survival, the changes can make tumor cells more resistant to cytotoxic therapies.Hypoxia can be exploited in tumor cells through the actions of (1) inhibitors of the pathways through which tumor cells adapt to hypoxia or (2) bioreductive prodrugs, which are activated only in hypoxic tissues.

A common characteristic of solid tumors like chordoma is that their cells are deprived of oxygen and must therefore adapt to the conditions in order to survive and proliferate.1 The series of adaptations not only helps tumor cells to survive but also makes them more resistant to the effects of chemotherapy and radiation.2

Agents that interfere with the pathways involved in a tumor cell’s adaptive response to hypoxia, or agents that directly target hypoxic regions, could have anti-tumor effects and improve patient response to conventional therapies. There is evidence that pathways involved in cellular responses to hypoxia are upregulated in chordoma cells, and those pathways are being explored as targets for systemic therapies. Chordoma patients are currently enrolled in a number of clinical trials evaluating whether treatments can be directed at hypoxic chordoma cells, leaving normal tissues unharmed.

Molecular Evidence


Protein Expression

  • Expression of the proteins VEGF and HIF-1α are shown to increase in response to hypoxia. Levels of these proteins are increased in some chordomas, and both are being explored as promising targets for systemic therapies.3

Preclinical Evidence


In-Vitro Efficacy

  • Evidence suggests that chordoma tumor cells adapt to hypoxic conditions; chordoma cell lines that initially grow in hypoxic conditions are later able to survive in hypoxic or in normal conditions.4
  • Chordoma cells cultured under hypoxic conditions had increased proliferation, VEGF and HIF-1a expression compared to cells in normoxic conditions.5


References

1.
Li X, Ji Z, Ma Y, Qiu X, Fan Q, Ma B. Expression of hypoxia-inducible factor-1α, vascular endothelial growth factor and matrix metalloproteinase-2 in sacral chordomas. Oncol Lett. 2012;3(6):1268-1274. [PubMed]
2.
Wilson W, Hay M. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11(6):393-410. [PubMed]
3.
Horbinski C, Oakley G, Cieply K, et al. The prognostic value of Ki-67, p53, epidermal growth factor receptor, 1p36, 9p21, 10q23, and 17p13 in skull base chordomas. Arch Pathol Lab Med. 2010;134(8):1170-1176. [PubMed]
4.
Yang C, Hornicek F, Wood K, et al. Characterization and analysis of human chordoma cell lines. Spine (Phila Pa 1976). 2010;35(13):1257-1264. [PubMed]
5.
Lee D, Zhang Y, Kassam A, et al. Combined PDGFR and HDAC Inhibition Overcomes PTEN Disruption in Chordoma. PLoS One. 2015;10(8):e0134426. [PubMed]