Treatment with Cannabinoids as a Promising Approach for Impairing Fibroblast Activation and Prostate Cancer Progression

Abstract

Endo-, phyto- and synthetic cannabinoids have been proposed as promising anti-cancer agents able to impair cancer cells’ behavior without affecting their non-transformed counterparts. However, cancer outcome depends not only on cancer cells’ activity, but also on the stromal cells, which coevolve with cancer cells to sustain tumor progression. Here, we show for the first time that cannabinoid treatment impairs the activation and the reactivity of cancer-associated fibroblasts (CAFs), the most represented stromal component of prostate tumor microenvironment. Using prostate cancer-derived CAFs, we demonstrated that WIN 55-212.2 mesylate, a synthetic full agonist of cannabinoid receptors (CBs) 1 and 2, downregulates α-smooth muscle actin and matrix metalloprotease-2 expression, and it inhibits CAF migration, essential features to ensure the activated and reactive CAF phenotype. Furthermore, by impairing stromal reactivity, WIN 55-212.2 mesylate also negatively affects CAF-mediated cancer cells’ invasiveness. Using selective antagonists of CBs, we proved that CAFs response to WIN 55-212.2 mesylate is mainly mediated by CB2. Finally, we suggest that endocannabinoids self-sustain both prostate tumor cells migration and CAFs phenotype by an autocrine loop. Overall, our data strongly support the use of cannabinoids as anti-tumor agents in prostate cancer, since they are able to simultaneously strike both cancer and stromal cells.

Cannabinoid WIN 55,212-2 Inhibits Human Glioma Cell Growth by Triggering ROS-Mediated Signal Pathways

“…It was found that WIN could relieve breast cancer [ 7 ], prostate cancer [ 15 ], and gastric cancer [ 19 ] in mice and prolong their survival by 50%. In vitro experiments showed that WIN could induce death of prostate cancer cells, liver cancer cells, and other tumor cells [ 20 , 21 ]. WIN inhibited DNA synthesis in T3 lymphocytes of human blastocysts and rodents, as well as in the Lewis lung cancer cells [ 22 ].…”

Cannabinoids and Prostate Cancer: A Systematic Review of Animal Studies

“…In particular, emerging evidence suggests that cannabinoids have a dual role in counteracting prostate cancer progression, as well as the proliferation of stromal cells in the prostate tumor microenvironment. In a recent study, Pietrovito et al [ 36 ] reported that the cannabinoid treatment of prostate cancer cells (LNCaP, PC3, and DU145) selectively impaired cell-survival, while at the same time regulating prostrate stromal fibroblast phenotypes under in vitro conditions. The authors further showed that the activity of the synthetic cannabinoid WIN 55-212-2 was mediated by the increased expression of CB2 receptors, which are normally downregulated in healthy prostate fibroblast cells.…”

“…The authors further showed that the activity of the synthetic cannabinoid WIN 55-212-2 was mediated by the increased expression of CB2 receptors, which are normally downregulated in healthy prostate fibroblast cells. The expression of both CB1 and CB2 receptors was elevated in LNCaP cells compared to PC3 and DU145 cells [ 36 ]. Similar results were also found by Roberto et al [ 46 ], who demonstrated that WIN55,212-2 substantially reduced cell proliferation, invasion, and migration, as well as inducing G0/G1 cell cycle arrest apoptosis, in a dose-dependent manner in cultured PC3, DU145, and LNCaP prostate cancer cells.…”

“…The expression of cannabinoid receptors on the surface of prostate cancer cells is greater than that seen in non-cancerous cells, which suggests that the endocannabinoid system may play a crucial role in the growth of these cancer cells [ 33 ]. Other have also suggested that CB1 and CB2 play a role in the development of prostate cancers [ 29 , 34 , 35 , 36 ].…”

Molecular Mechanism of Cannabinoids in Cancer Progression

“…WIN 55,212-2 inhibited tumor proliferation in prostate cancer via CB2R [ 65 , 66 ] and in human BEL7402 hepatocellular carcinoma cells [ 67 ]. WIN 55,212-2 and CP 55-940 induced cell death in C6 (rat) and U373 (human) glioma tumour lines [ 68 ].…”