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When there is a lack of oxygen, cancerous diseases tend to spread
In their current investigations, scientists from the Ludwig Maximillians University (LMU) in Munich were able to decipher the mechanism that causes tumors to spread to other tissues at low oxygen concentrations. The researchers observed that when there is a lack of oxygen, a small molecule that normally triggers a protective mechanism is slowed down.
The research team led by Professor Heiko Hermeking was able to determine for the first time the mechanisms that are responsible for the fact that tumors tend to increase metastasis at low oxygen concentrations, reports the LMU. The effect is important for many cancer patients, since tumors are often poorly supplied with blood and therefore often have a poor oxygen supply, the scientists report. Due to this lack of oxygen, the tumors respond poorly to radiation and chemotherapy and tend to metastasize, the experts explain the connection. The scientists have published the results of their current study in the journal "Gastroenterology".
Special RNA molecule increasingly deactivated
In their studies on colon carcinomas, the scientists found that the so-called "tumor suppressor gene p53" was inactivated in more than half of the tumors. In previous studies, Prof. Hermeking had already proven that this gene encoded a protein, which in turn directly induced an extremely short RNA molecule - the so-called micro-RNA-34a (miR-34a). This in turn plays a central role in tumor suppression. "In intestinal carcinomas, we have observed that miR-34a is particularly often inactivated in metastatic tumors in which oxygen is often lacking," reports Prof. Hermeking of the test results.
Relationship between metastasis and lack of oxygen deciphered
The inactivation of miR-34a could now for the first time be directly linked to the lack of oxygen. "At low oxygen levels, the tumor cells produce the so-called hypoxia-induced factor HIF1a, which directly inhibits the protective RNA molecule," reports the LMU. In addition, a reaction chain is set in motion, which up-regulates further proteins and ultimately triggers a process in which locally growing, non-invasive surface cells are transformed into aggressive cells. These penetrate other tissues and the tumor metastasizes. The process is referred to as epithial-mesenchymal transition (EMT) and also plays an important role in the migration of cells during embryonic development.
Special protein with far-reaching effects
According to the researchers, the protein PPP1R11 is involved in the fateful reaction chain. The production of this protein was particularly high on the invasion front of tumors that are poorly supplied with oxygen. Normally, the production of PPP1R11 in the cells is suppressed directly by miR-34a and thus indirectly by the tumor suppressor p53. In this way, the reaction chain could be reversed and a protective mechanism triggered, which causes the cells to remain in place. This inhibits metastasis.
New approaches to therapies
According to the researchers, the new study results also indicate that metastatic intestinal tumors could possibly be treated if important proteins of the shown reaction chain could be inhibited and miR-34a could be activated in parallel. “In particular, molecules that could substitute miR-34a and take over their function are already being investigated in clinical studies,” explains Prof. Hermeking. The authors of the study concluded that these could be of great relevance for future treatment options, especially for tumors with poor oxygen supply.