Medical Research

Cancer Cells Grow Despite Oxygen Lack

10.12.2014 | Healthy cells reduce their growth when there is a lack of oxygen, called "hypoxia". But hypoxia is a characteristic of malignant tumours like glioblastomas. Researchers from Goethe University Frankfurt and the University of Giessen could show how cancer cells succeed at circumventing the genetic program of growth inhibition.
Prof. Amparo Acker-Palmer
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Prof. Amparo Acker-Palmer
It had already been known that PHD proteins (prolyl-hydroxylase domain proteins) play a key role among the regulators of hypoxia. They control the stability of the hypoxia-induced transcription factors (HIFs) which govern the adaptation of cells to a lack of oxygen. The two teams led by Prof. Amparo Acker-Palmer, Goethe University, and Prof. Till Acker, Justus-Liebig-University, have now discovered that a special PHD protein, PHD3, also controls the epidermal growth factor receptor "EGFR".

In healthy cells, PHD3 responds to stressors such as lack of oxygen by stimulating the uptake of EGF receptors into the cell interior. Growth signals are down-regulated by this internalisation. "We have discovered that PHD3 serves as a scaffolding protein, binding to central adapter proteins such as Eps15 and Epsin1 in order to promote the uptake of EGFR into the cells," Acker-Palmer explains. This process is disrupted in tumour cells due to the loss of PHD3. As a result, the internalisation of EGFR is suppressed, which leads to overactivity of EGFR signals, and thus to uncontrolled cell growth.
In healthy cells
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(© Garvalov et al./Nature Communications)


In healthy cells | PHD3 responds to stressors like oxygen lack by stimulating the uptake of EGF receptors into the cell. Growth signals are down-regulated by this internalization. Tumor cells respond differently due to the loss of PHD3: the internalization of EGFR is suppressed, leading to an overactivity of EGFR signals - the result is uncontrolled cell growth, for instance in glioblastomas.

The research teams were able to show that the loss of PHD3 is a crucial step in the growth of human malignant brain tumours like glioblastomas. The tumour cells thus become refractory to the growth-inhibiting signals under hypoxia. "Clinically, this discovery is highly relevant, because it shows an alternative mechanism for the hyperactivation of the EGF receptor that is independent of its genetic amplification. It can be therapeutically suppressed by EGFR inhibitors," explains Till Acker, a neuropathologist at the University of Giessen.

"Our work shows an unexpected and new function of PHD3 on the interface of two currently red-hot research areas: Oxygen measurement and EGFR signalling," says Acker-Palmer. "This once again proves how significant growth receptor internalisation is to the development of cancer." This connection was already shown by her research team in 2010 for tumour angiogenesis.
  (© Goethe University Frankfurt, AcademiaNet)
Dr. Anne Hardy

More information

Source

  • Anne-Theres Henze, Boyan K. Garvalov, Sascha Seidel, Angel M. Cuesta, Mathias Ritter, Alina Filatova, Franziska Foss, Higinio Dopeso, Clara L. Essmann, Patrick H. Maxwell, Guido Reifenberger, Peter Carmeliet, Amparo Acker-Palmer, Till Acker: Loss of PHD3 allows tumours to overcome hypoxic growth inhibition and sustain proliferation through EGFR, Nature Communications, 25.11.2014, DOI: 10.1038/ncomms6582

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