THC and CB2R Could Make Cancer Cells Less Aggressive

Cancer cells are turning out to be more adaptable than once thought, prompting scientists to devise equally ingenious ways of improving the odds of survival.

Recent medical research has drawn attention to a major challenge: cancer cells possess plasticity.

Certain cancer cells can spontaneously return from a differentiated state to an ‘immature’, stem-cell-like form. By changing identity in this way, they can produce tumours that are more varied, aggressive and proliferative.

This adaptability helps them evade conventional treatments, including chemotherapy and radiotherapy, which are intended to halt cell division and destroy cancerous cells, along with other cells.

Regrettably, such therapies can also impose evolutionary pressure that selects for more aggressive, treatment-resistant cancers able to spread more effectively through the body.

THC treatment and cancer cell plasticity

In a new experiment, medical researchers used the cannabis compound THC to encourage cancer cells to ‘lock in’, potentially making tumours less aggressive.

Published in Communications Biology, the study examined how an ultra-low-dose, 4-day cannabinoid treatment affected organoids: laboratory-grown, three-dimensional mammary tumour models made from breast cancer cells obtained from people and from mouse models.

The experiment focused on the endocannabinoid system (ECS), which, the researchers note, can control developmental pathways that are mirrored in cancer evolution and embryonic development.

The ECS contains two principal cannabinoid receptors, CB1R and CB2R. The team adjusted these using two kinds of ligands, molecules that either enhance or inhibit receptor activity to produce a biological response.

Following a low-dose, 4-day pulse of THC, an agonist, the organoids showed lower cell invasiveness, reduced capacity for self-renewal and less tumour initiation.

Notably, the effect appears to be driven mainly by CB2R, which is linked to inflammatory responses, rather than CB1R, which is connected with cannabis’s psychoactive effects.

CB2R modulation in breast cancer organoids

The researchers then used a biomolecular ‘good cop, bad cop’ approach. They exposed CB1R and CB2R separately to inverse agonists named SR1 and SR2, respectively, which lower the receptors’ baseline activity.

Even with this reversal, the organoids still appeared to become less, in essence, cancerous. Remarkably, the CB2R inverse agonist SR2 replicated THC’s cancer-moderating effects, whereas the CB1R inverse agonist SR1 did not.

There was, however, an unexpected finding: organoids from mice genetically engineered without CB2R displayed similar changes.

Taken together, the findings may indicate that CB2R’s baseline activity is key to cancer-cell differentiation, and that altering it can affect the plasticity of cancer cells.

Of equal practical significance, the team found indications that these tumour-suppressing effects remain stable in vivo.

When THC-treated organoids were transplanted into living, cancer-prone mice, the effects lasted for as long as 100 days. Those mice developed tumours later, with slower tumour growth and less aggressive lesions, than mice given control organoids.

In another experiment, THC-treated cells generated fewer clusters of cancer cells in the lungs four weeks after injection.

The modulated organoids also proved resilient when researchers deliberately attempted to increase their tumour-forming activity.

Potential therapeutic effects of CB2R modulation

These results create a range of potential therapeutic paths. Controlling this process could mean that “differentiated cells [to] occupy space and resources that would otherwise be used for tumor expansion”, the researchers explain.

CB2R modulation also appears to raise oestrogen receptor activity, making breast cancer cells more responsive to endocrine therapy using the widely prescribed drug tamoxifen.

As well as demonstrating the value of exploring complementary treatment approaches, the research indicates that subtle CB2R modulation could reprogramme tumour-cell behaviour, producing genome-wide effects that endure long after cannabinoid withdrawal.

“This view is consistent with the concept that tumor cell populations occupy continuous and dynamic state landscapes, where relatively small perturbations can trigger large-scale and self-reinforcing transitions in collective behavior,” the researchers conclude.

The research was published in Communications Biology.

This article was fact-checked by Peter Dockrill and edited by Peter Dockrill. Although we take pride in our process, we are only human. If you notice an error, please let us know.