An early function

Although it has concentrated most of its efforts on miR-503, the Molecular Angiogenesis Laboratory has also identified some other microRNAs capable of intervening in the communication between endothelial and tumor cells in breast cancer. The study of some of them has revealed, for example, that the variations in the level of miR-146 exported by the endothelial cells were modelled on those of miR-503. In addition, this interest in the therapeutic action based on miR-146 might be to exclude the fact that, as studied in peripartum cardiomyopathy (2), this microRNA has been shown to be actively involved in immunity (3).

Beyond the research undertaken at the University of Liege (in collaboration with the CHU) in the context of breast cancer, many other studies have shown that the circulating levels of various microRNAs changed in case of tumor development and following chemotherapy treatment(4). “A long-term study (5) monitored smokers”, says Ingrid Struman. “Some of them developed lung cancer. Among those who developed lung cancer, we noticed that the profile of their circulating levels of certain microRNAs were already activated even before we were able to detect the presence of tumor cells in the lungs”.  As the researcher explains, the early modifications of the circulating levels of these microRNAs leads us to the conclusion that they were involved in tumor development at an early stage. In addition, as is the case with miR-503, their presence can be observed in different cancers having higher or lower plasmatic levels according to the type of tumor. It would also seem to be the case that according to their nature but also to the category of cancer, the microRNAs can exert either an antitumor or a protumor action.

Murine models

In the aftermath of work which merited publication in the journal Oncotarget in April 2015(1),Ingrid Struman’s team began a study of patients who had suffered from breast cancer in order to determine whether certain microRNAs, and in particular miR-503, could be predictive of a relapse and, consequently, could serve as biomarkers. Another ambition: during resistance to adjuvant chemotherapy, to determine whether the tumor cells are capable of modifying their ability to respond to miR-503 or other microRNAs or whether in response to the action of cancer cells, the eventual transfer of circulating microRNAs by the endothelial cells dries up.

Another study, on murine models in this case, commenced recently. Its objective is the observation, in vivo, of the effect of miR-503 on tumor progression. One particular test involved the production of exosomes overloaded with this microRNA and their injection into the blood stream. The result has not been conclusive to date. The reason for this is possibly because, in natural conditions, the exchanges which take place between endothelial and cancer cells via the exosomes occur over a short distance, that is to say, in the tumor microenvironment. Also the remote injection of exosomes seems to be problematic. “This is why we are going to try to directly implant into the targeted organ both the tumor and the exosomes”, says Ingrid Struman.

It remains to be established how miR-503 influences tumor progression in the animal.

(2) Halkein, J., Tabruyn, S.P., Ricke-Hoch, M., Haghikia, A., Nguyen, N.Q., Scherr, M., Castermans, K., Malvaux, L., Lambert, V., Thiry, M., Sliwa, K., Noel, A., Martial, J.A., Hilfiker-Kleiner, D., and Struman, I. (2013). MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. The Journal of clinical investigation 123, 2143-2154.
(3) Boldin, M.P., Taganov, K.D., Rao, D.S., Yang, L., Zhao, J.L., Kalwani, M., Garcia-Flores, Y., Luong, M., Devrekanli, A., Xu, J., Sun, G., Tay, J., Linsley, P.S., and Baltimore, D. (2011). miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med 208, 1189-1201.
(4) Freres, P., Josse, C., Bovy, N., Boukerroucha, M., Struman, I., Bours, V., and Jerusalem, G. (2015). Neoadjuvant chemotherapy in breast cancer patients induces miR-34a and miR-122 expression. Journal of cellular physiology 230, 473-481.
(5) Boeri, M., Verri, C., Conte, D., Roz, L., Modena, P., Facchinetti, F., Calabro, E., Croce, C.M., Pastorino, U., and Sozzi, G. (2011). MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci U S A 108, 3713-3718.