MiR-503: antitumor microRNA

At GIGA-Cancer, Ingrid Struman's group focusses on the transfer of the microRNA from endothelial cells into cancer cells during tumor angiogenesis. Before this work, no information was available on the role of endothelial exosomes and the microRNAs they contain for tumor growth. The Molecular Angiogenesis Laboratory was the first to shed light on the existence of a transfer of the microRNAs of the endothelial cells to tumor cells by means of the exosomes (1). The researchers then showed that if endothelial cells were grown in culture in a pro-tumor environment, the content of the exosomes they exported became modified. Among the microRNAs whose presence became reduced, the biologists at GIGA-Cancer identified miR-503 in particular. Functional studies led them to conclude that this microRNA show antitumor properties: when transfected into human breast cancer cells, it caused a phenotypic change that had the consequence of reducing the proliferative and invasive potential of these cells.

“Our theory was that the tumor cells, when implanted in the host, send a signal leading to a reduced export of miR-503 by the endothelial cells thus reducing the antitumor response of the host, explains Ingrid Struman. In order to assess the relevance of this observation in humans, we wanted to determine whether the plasmatic level of microRNAs was modulated in patients affected by breast cancer. The measurement we carried out revealed an increase in the plasmatic RNA level in the blood of patients following treatment by an adjuvant chemotherapy treatment”.

This led to the inevitable conclusion that the chemotherapy prescribed for these patients could have an impact that goes beyond a mere direct action on the cancer cells. In fact, the observed increase in the plasmatic level of Mir-503 could be partly due to an increase in the secretion of antitumor microRNAs by the endothelial cells. At this stage, the researchers did not know if this was indeed the case or whether other cell types were involved.

But this is not the whole story: it also seems that the phenotypic change induced by miR-503 in the tumor cells modifies their production of angiogenic factors. This results in an inhibition of angiogenesis.

All the available data reveals for the first time the involvement of endothelium in the modulation of tumor development through the export of the miR-503 microRNA in response to chemotherapy. “This process could be complementary to the direct effects generated by the miR-503 microRNA on the tumor and enhance the response of the host during treatment of the disease”, explains Ingrid Struman.

Therapeutic prospects

Communication (the term is used reservedly) between endothelial cells and tumor cells was established in vitro. But up to the present, the researchers in the Molecular Angiogenesis Laboratory have not been able to show the origin of miR-503 in vivo. They would specifically like to isolate endothelial exosomes in patients suffering from breast cancer and demonstrate an eventual modification of the expression of microRNA. Unfortunately, this objective is faces an obstacle in terms of the absence of techniques in relation to research into specific types of exosomes by means of antibodies.

What therapeutic possibilities can be anticipated based on the work of the GIGA-Cancer team? According to Ingrid Struman, two avenues can be explored. The first would involve the injection of the antitumor microRNA into the blood stream in order to increase the level beyond the increase brought about by chemotherapy. Applied to other microRNAs, this technique is at the heart of clinical trials for several pathologies. Ingrid Struman cites the example of miR-122, in phase two of the treatment for hepatitis C. The second approach would be centred on the increase of the miR-503 load in the secreted exosomes. “For the moment, we do not know how to increase the export of microRNAs in these vesicles”, comments the researcher. “It is an objective of our future studies. If we succeed in identifying the proteins involved, we will be able to act on them.”

(1) Bovy N., Blomme B., Frères P., Dederen S., Nivelles O., Lion M., Carnet O., Martial J.A., Noël A., Thiry M., Jérusalem G., Josse C., Bours V., Tabruyn S.P., Struman I., Endothelial exosomes contribute to the antitumor response during breast cancer neoadjuvant chemotherapy via microRNA transfer, Oncotarget, 2015 Apr 30;6(12):10253-66.