Identified the cells responsible for relapse in colon cancer

Colon cancer is the third most common in the world, with about 2 million new cases each year. Most patients are diagnosed when the tumor is still located in the colon or rectum. These tumors are removed by surgery, and in many cases, treated with chemotherapy with the intention of preventing recurrence of the disease. Even so, in a percentage of patients between 20% and 35%, the cancer reappears in other vital organs as metastases. These originate from residual tumor cells that remain hidden at the time of surgery, mainly in the liver or lung. Metastases are the leading cause of death for almost all types of cancer, including colon cancer.

Most of the research in colorectal cancer has focused on understanding the primary disease. In recent years there have also been important advances in the characterization of metastatic disease once it manifests. But until now it had not been possible to address the investigation of this small population of tumor cells that is disseminated and that is invisible to the diagnostic techniques used in the clinical setting. This ignorance has resulted in a lack of effective therapies to eliminate residual disease and prevent metastatic recurrence, which has a poor prognosis.

Scientists from the Institute for Research in Biomedicine of Barcelona (IRB Barcelona), led by Dr. Eduard Batlle, ICREA researcher and group leader at the Cancer Network Biomedical Research Center (CIBERONC) in Spain, have identified for the first time hidden residual tumor cells in the liver and lung, and have characterized how they evolve to give rise to the appearance of metastases in these organs.

“Understanding and avoiding the phenomenon of relapses after surgery is an unresolved medical need. After many years researching colon cancer, we have taken a first step to prevent metastases in patients who present with a localized disease”, explains Dr. Eduard Batlle, head of the Colorectal Cancer laboratory at IRB Barcelona.

Extravasation of residual colorectal cancer tumor cell in a hepatic portal vein. (Image: IRB Barcelona. CC BY-NC-ND)

The authors of the study have generated a new experimental mouse model that recreates the process followed by patients who suffer relapses, and which typically goes through the stages of diagnosis, curative surgery, and subsequent relapse. In parallel, they have developed a methodology that makes it possible to isolate a tiny fraction of hidden disseminated tumor cells in the body.

“Our model, very similar to the progression of the disease in patients, has allowed us to characterize the primary tumor and the dynamics of the residual disease. We have studied from micrometastases of 3 or 4 cells, to medium-sized metastases, or even larger ones, characterizing how each of them evolves during the progression of the disease”, comments Dr. Adrià Cañellas-Socias, a researcher at the same laboratory and first author of the study.

Scientists have known for years that colon cancer is made up of different types of tumor cells, which perform different functions during the progression of the disease. Within the amalgamation of cell types that make up colon cancers, researchers led by Dr. Batlle have identified a population, which they have called HRCs (High Relapse Cells). . These cells show little proliferative activity and do not contribute to the growth of the primary tumor. However, groups of HRCs are able to break away from cancer in the colon, migrate to reach the bloodstream, reach the liver and remain hidden for a time after surgery. In samples from patients with colon cancer, researchers have been able to verify the presence of these same cells in patients who have a higher risk of recurrence of the disease after treatment.

The researchers have also confirmed that eliminating these cells through genetic techniques is sufficient to prevent the formation of metastases; that is, the mice that develop colon cancer remain free of disease after surgery of the primary tumor, without suffering subsequent relapses. Dr. Batlle’s team has also developed a therapeutic strategy to specifically eradicate residual disease and prevent recurrence; show that incipient metastases, when they are not yet visible, can be eliminated by treatment with immunotherapy, prior to surgery.

“Our discovery reveals for the first time how the group of tumor cells responsible for relapses behaves, and also the genes that define them. In addition, it represents a proof of concept that opens the way for the development of new therapies, specifically aimed at eliminating residual disease, as well as new diagnostic tools to identify those patients with a higher risk of relapse. Lastly, our study suggests a review of the clinical guidelines for the treatment of this type of cancer because, in many cases, it would be advisable to apply immunotherapy before surgery”, concludes Dr. Batlle.

These discoveries open up the possibility of developing new lines of research. Dr. Batlle’s laboratory is now focused on studying when the HRCs that have reached the liver are “activated” to regenerate a tumor, with the intention of interfering in this process and preventing the formation of metastases. They are also doing research to understand what factors influence the appearance of these cells and why the number of these cells varies from one patient to another.

Scientists from the Biostatistics and Bioinformatics platform, led by Dr. Camile Stephan-Otto, and from the Advanced Digital Microscopy platform, directed by Julien Colombelli, both at IRB Barcelona, ​​have participated in this work. Researchers from the laboratories of Dr. Simon Leedham, at the University of Oxford (United Kingdom); Dr. Sabine Tejpar, at the Catholic University of Leuven (Belgium); Dr. Holger Heyn, at the National Center for Genomic Analysis (CNAG-CRG) and Dr. Xavier Trepat at the Institute of Bioengineering of Catalonia.

The study is titled “Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells”. And it has been published in the academic journal Nature. (Source: IRB Barcelona)