The complexity of cancer is undeniable. We cannot talk about a single disease, but instead of very large group of pathologies, labelled under the concept of “cancer”, characterized by the development of cells that divide and spread without control.
This idea becomes crystal-clear in studies such as the one led by the research group of doctors Xavier Dolcet (IRBLleida, UdL) and David Llobet (IDIBELL). With their last two studies, they have experimentally verified a molecular paradox: the same group of small regulatory molecules, the miR-424(322)s503 cluster, adopts totally opposite roles depending on the type of cancer. While in endometrial cancer it acts as an oncogene, helping the tumor grow, in colorectal cancer it functions as a handbrake against the onset of the tumor.
The study, recently published in the scientific journal Cell Death & Disease, is the result of the close and continuous collaboration between the Gynecological cancer research group of IDIBELL and the Oncogenic and Developmental Signaling group of IRBLleida and the University of Lleida, as well as personnel from CIBERONC (Centro de Investigación Biomédica en Red de Cáncer). Thanks to the results, a new path is opened to better understand the beginning and progression of colorectal cancer, the fourth most common in men and women, and the third most deadly worldwide.
From endometrium to colorectal cancer: linking two investigations
Very often, in the world of biomedical research, an investigation begins almost accidentally or is born directly from previous work. This has been the case of the new study published by IDIBELL and IRBLleida in Cell Death & Disease. While the research team was studying how the miR-424(322)’503 cluster favored endometrial cancer in a context of PTEN gene deficiency (news), they noted that the mice under study that did not have this cluster -and that, therefore, were theoretically more protected against endometrial cancer- presented, instead, abnormally large intestines.
The team developed an independent cohort to investigate the causes of this finding. As far as they could see, mice without the PTEN gene or the miRNA cluster had more precancerous lesions in the colon, more complex and of larger volume than mice with the gene and cluster intact. They corroborated statistical quantifications with histological analysis of colon tissue. According to the results, 10% of mice without PTEN or miRNAs had a normal colon, and 90% developed different types of cancer lesions: low-grade adenomas (50%), high-grade adenomas (20%) or intraepithelial adenocarciomas (20%).
“The double loss of the PTEN gene and the miRNA cluster generates an environment that allows malignant transformation in the colon, accelerating the rapid progression of polyps to invasive adenocarcinomas”, explains Maria Vidal, first author of the study and researcher at IRBLleida and the University of Lleida. “This corroborates that this cluster of miRNAs is crucial to control and stop the development of tumours in the colon, in a context of PTEN loss, even if it does the opposite in endometrial cancer,” she adds.
Oncogene or tumor suppressor depending on the context
One of the most intriguing questions left is why the same molecules behave as oncogenes or tumour suppressors depending on the cellular context. The Dolcet and Llobet team have tested it in two different cancers, using the same experimental model and under the same conditions.
“In the endometrium, if we eliminated this cluster, the tumor grew less. On the other hand, in the colon, it did exactly the opposite: without it, the lesions multiplied and became aggressive”, explains David Llobet, principal investigator of the Gynecological cancer group at IDIBELL. “This duality shows that the function of an miRNA depends entirely on the type of tissue and cellular microenvironment where it is found, especially in cancer,” he continues.
The team hypothesis is that, in the colon, the cluster miR-424(322)’503 acts as part of a compensatory response to tumor suppression. “When PTEN is lost in the colon, the cluster functions as a protective mechanism that helps stop the excessive activation of other potentially oncogenic pathways that are uncontrolled without PTEN”, explains Xavier Dolcet, researcher at IRBLleida and the University of Lleida. “In such a situation, when the cluster loses activity, this compensatory brake is eliminated and excessive signalling is triggered that stimulates colorectal cancer,” he concludes.
Understanding the molecular mechanism by which miR-424(322)’503 works in colorectal, endometrial, or other cancers is essential for the design of future precision medicine therapies. It is crucial to specify them by type of cancer because strategies that could be beneficial for one type of cancer (such as blocking this cluster in endometrial cancer, to slow progression), could be counterproductive in another (if done in colon cancer, a natural protective mechanism would be lost).
The Bellvitge Biomedical Research Institute (IDIBELL) is a research center established in 2004 specialized in cancer, neuroscience, translational medicine, and regenerative medicine. It counts on a team of more than 1.500 professionals who, from 73 research groups, publish more than 1.400 scientific articles per year. IDIBELL is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona, and the City Council of L’Hospitalet de Llobregat.
IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).