A group of researchers led by the Complutense University of Madrid (UCM) and the Research Institute of Hospital 12 de Octubre (i+12) has designed a therapeutic strategy aimed at the endocannabinoid system and, specifically, at the cannabinoid receptor CB2, with which they manage to stabilize breast cancer cells and reduce their plasticity.
The work, published in the journal "Communications Biology," demonstrates that a transient modulation and low doses of CB2 long-term limits the ability of breast tumor cells to change state and acquire traits associated with self-renewal, invasion, treatment resistance, and the generation of new tumors.
"Tumor cells did not transform into normal cells, but they lost their ability to return to progenitor states associated with self-renewal, invasion, therapeutic resistance, and the formation of new tumors," specified the director of the Cancer STEM Lab of the Department of Biochemistry and Molecular Biology of the Faculty of Biological Sciences of the UCM, María Salazar Roa.
In contrast to conventional approaches that focus on destroying malignant cells or blocking their proliferation, this approach, framed within the so-called differentiation therapies, seeks to modify or fix the state of tumor cells to restrict possible transitions to more aggressive forms.
"Cancer is not just a sum of isolated molecular alterations, but a dynamic and self-organized system, capable of responding to environmental pressures and treatments. That is why we need to complement approaches aimed at specific targets with a more global view of cellular states and their transitions," explained Salazar-Roa, emphasizing the relevance of the study.
Brief exposure and low doses
Cannabinoids have been analyzed for decades in the oncological field, generally at high concentrations and seeking a direct cytotoxic effect. On this occasion, scientists have inverted the traditional logic to explore what happens with short exposures to very low amounts, without relying on direct damage to tumor cells.
For this, they resorted to three-dimensional organoids of breast cancer obtained from patient samples and murine models. These organoids reproduce key characteristics of tumor tissue, such as three-dimensional architecture, cellular diversity, and certain collective behaviors, which allows for the analysis of phenomena that go unnoticed in classic two-dimensional cultures.
The organoids, organized into separate experimental groups, were treated for four days with low doses of THC, the main psychoactive component of cannabis that acts on cannabinoid receptors, or with SR144528, a selective synthetic ligand of CB2 with a distinct pharmacological profile. Compared to the controls, both interventions generated converging effects.
Persistent effect over time
After this period, the compounds were removed and the cultures were maintained for several weeks to check whether the changes were temporary or if the cells retained the new state achieved. Additionally, the organoids were exposed to signals capable of promoting dedifferentiation and increasing tumor aggressiveness in order to test the stability of the intervention.
In another series of assays, the cells from the organoids were transplanted into the mammary gland of mice to verify whether the effects were maintained "in vivo" once the exposure to the compounds was finished.
Despite the treatment being limited to four days, the observations showed that the consequences lasted for several weeks "in vitro" and more than 100 days "in vivo" after transplantation in the animal models.
Salazar Roa has emphasized that the results highlight the need to rigorously analyze cannabinoids as pharmacological active principles, "distancing them from both stigmatization and the generation of therapeutic expectations without evidence."
The scientist has also pointed out that the possible oncological application explored in this work is not included in Royal Decree 903/2025, which regulates the preparation and hospital dispensing of magistral formulas based on standardized cannabis preparations.
"This regulation does not contemplate the oncological application studied here nor does it imply that our preclinical results can be directly transferred to patients. It also does not include experimental synthetic ligands like SR2," she detailed.
In the project have also collaborated the La Paz University Hospital, the National Center for Cancer Research, the Severo Ochoa Molecular Biology Center, and the Massachusetts Institute of Technology (MIT), among other entities.