This image shows the formation of PDE4 in
oxygen-deficient lung tumor cells. Lung cells produce PDE4 (stained green:
left) even if their oxygen content is normal. More PDE4 is produced (right) if
they are oxygen-deficient (hypoxia). The cell nuclei are stained blue. Credit:
MPI for Heart and Lung Research
Lung cancer is the leading cause of cancer
death throughout the world. Standard treatment methods do not usually result in
long-term recovery. In addition to the proliferation of the tumour cells, the
growth of blood vessels controls tumors development. The blood vessel growth is
controlled by several signalling molecules.
Scientists
from the Max Planck Institute for Heart and Lung Research in Bad Nauheim and
Justus Liebig University Giessen have discovered a molecule that plays a key
role in this process. They succeeded in reducing tumour growth in their
experiments by blocking the phosphodiesterase PDE4.
Lung
cancer mainly affects smokers; however the disease can also be caused by
contact with carcinogenic substances like asbestos. Chemotherapy or
radiotherapy often prove insufficient in treating the disease. Hence, scientists
are engaged in an intensive search for ways of halting the growth of lung
tumours. The blood vessels that supply the tumour with nutrients offer a
potential point of attack.
New
blood vessels form to ensure an adequate supply of nutrients to the growing
tumour. The growing tissue is immediately penetrated by blood vessels. The
growth of the blood vessels is regulated by the tumour cells using a complex
signal cascade, which is triggered initially by a low oxygen content (hypoxia) in the tumour tissue.
"This
state, which is known as hypoxia prompts the activation of around 100 genes in
the tumour cells," explains Rajkumar Savai, research group leader at the
Max Planck institute. "In addition to the growth of blood vessels, hypoxia
also stimulates the proliferation of lung cancer cells." Three
molecules play a particularly important role in this process. The activation of
the genes at the beginning of the cascade is triggered by the transcription
factor HIF and a messenger molecule, cAMP, is involved again at the end of the
cascade. The researchers examined the third molecule that acts as a link
between these two molecules in detail.
The
molecule in question is a phosphodiesterase, PDE4. The scientists from Bad
Nauheim and Giessen were able to demonstrate in their study that various
sections of PDE4 have binding sites for HIF.
The
researchers then tested the influence of a PDE4 blockade on the cells from ten
different cell lines, which are characteristic of around 80 percent of lung
cancers, in the laboratory. The rate of cell division in the cells treated with
a PDE4 inhibitor was significantly lower and the HIF level also declined as a
result.
The
effect in the tumour bearing mice was particularly obvious. To observe this,
the Max Planck researchers implanted a human tumour cell line under the skin of
nude mice and treated the animals with the phosphodiesterase 4 inhibitor.
Tumour
growth in these animals declined by around 50 percent. "Our microscopic
analysis revealed that the blood vessel growth in the tumours
of the mice that had been treated with the inhibitor was significantly reduced.
We also observed indicators of decelerated cell division in the tumour cells. Overall, the tumour
growth was strongly curbed."
Werner
Seeger, Director of the MPI and Medical Director of the JLU University Hospital
Giessen, reports:
"We
were able to show that PDE4 plays an important regulation function in cell
division in lung tumours and in the development of blood vessels in cancer.
Therefore, we hope that we have found a starting point for the development of a
treatment here."
In the
view of tumour specialist Friedrich Grimminger, Chairman of the Department of
Medical Oncology in Giessen, it may be possible in future to combine the
inhibition of PDE4 with traditional radiotherapy or chemotherapy.
In this
way, the effect of the traditional treatment measures could be reinforced and
patient prognoses may improve as a result. However, further laboratory studies
are required before clinical tests can be carried out.
More
information: Oncogene (2012). doi:10.1038/onc.2012.136
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