DKFZ: or a long time it was considered an established fact that cervical cancer, which is caused by human papillomaviruses (HPV), depends on two specific viral proteins. If they are absent, the cancer cells stop growing permanently. Scientists at the German Cancer Research Center (DKFZ) have now discovered that cancer cells reduce the production of these viral proteins during hypoxia - a condition of oxygen deficiency that is very common in tumors. However, this does not lead to final growth cessation, but instead induces a state of dormancy from which the cancer cells can awaken and start proliferating again and may thus cause the cancer to return.
Human papillomaviruses are considered to be the cause of
approximately five percent of all cancers worldwide. They primarily
cause cervical cancer but are also responsible for many cancers of the
head and neck, the reproductive tract and the anus.
A couple of years ago, researchers were able to uncover the
mechanism that the viruses use to turn cells cancerous. Two viral
proteins, E6 and E7, disable two crucial cancer brakes in infected
cells, thus being responsible for cancer developing.
"E6 and E7 drive cancer growth by preventing senescence, a cell aging
process that is associated with irreversible cessation of cell growth,"
says Felix Hoppe-Seyler of the German Cancer Research (Deutsches
Krebsforschungszentrum, DKFZ) in Heidelberg. When E6 and E7 are blocked,
the cancer cells stop growing. "However, our knowledge about the
functions of E6 and E7 is mostly based on results from cell culture
experiments, where oxygen saturation is high," Hoppe-Seyler explains.
"But many tumors have regions where oxygen is deficient because of
inadequate supply by blood vessels. So we wanted to know what happens in
a state of hypoxia."
When the scientists lowered the oxygen concentration in the Petri
dish to levels commonly found in oxygen-deficient tumor tissue, the
cancer cells reduced the production of E6 and E7 and stopped growing.
However, they did not induce senescence, but instead entered a dormant
state. When oxygen supply was increased again, the dormant cancer cells
awakened and promptly resumed cell division.
The sleeper cells that can form in tumor regions with low oxygen
levels are more resistant to chemotherapy, which preferably targets
dividing cells. Additionally, they escape immune defense because they no
longer produce HPV proteins that could be recognized by immune cells.
Until now, E6 and E7 have been regarded as ideal molecular targets
for targeted treatment of HPV-induced tumors, which currently is a field
of intensive research. However, even these targeted drugs would be
ineffective against the dormant cells because they lack the crucial
Hoppe-Seyler said: "For patients with HPV-induced tumors, the sleeper
cells are a latent danger. If a tumor shrinks, for example in the wake
of successful treatment, and if surviving sleeper cells get reconnected
to blood vessels and oxygen supply, they might cause the disease to
relapse. Assessing the relevance of the findings, he added: "In our
efforts to develop novel therapies, we cannot solely focus on E6 and E7
as targets. We also need to develop strategies for eliminating the
The investigations were supported by the Wilhelm Sander Foundation and German Cancer Aid (Deutsche Krebshilfe).
Karin Hoppe-Seyler, Felicitas Bossler, Claudia Lohrey, Julia
Bulkescher, Frank Rösl, Lars Jansen, Arnulf Mayer, Peter Vaupel,
Matthias Dürst, and Felix Hoppe-Seyler: Induction of Dormancy in Hypoxic
Human Papillomavirus-Positive Cancer Cells.
Proceeding of the National Academy of Science (PNAS) 2017, DOI: 10.1073/pnas.1615758114