Taking statins, commonly used cholesterol-lowering drugs, is thought to slow the progress of prostate cancer—at least in some cases. But how? If that question could be answered, scientists might find ways to enhance the effect of statins and, possibly, even prevent prostate cancer from advancing to difficult-to-treat stages, such as the development of bone metastases.
Scientists have already observed that prostate cancer cells can be made to migrate more or less aggressively in models of metastatic processes. For example, scientists have amassed a growing body of evidence that arachidonic acid (AA), an omega-6 polyunsaturated fatty acid, is strongly chemotactic. AA, which occurs in high concentrations in bone marrow, attracts prostate cancer cells. Then, when prostate cancer cells take up AA, they shift to an aggressive, migratory phenotype.
Scientists at the University of Manchester have shown that when prostate cancer cells are exposed to AA, they change shape, becoming rounder and also sprouting projections that that help them to squeeze through the gaps in surrounding tissues and become established in the bone marrow. These scientists also observed that they were able to stop the cells developing these characteristics by treating them with statins, which disrupted their ability to manufacture cholesterol.
These scientists, who have been working to understand the basis of these phenotypic changes, are particularly interested in teasing out the signaling pathways that may lead to increased or decreased transendothelial migration (TEM).
Their most recent work appeared April 16 in the British Journal of Cancer, in an article entitled “Arachidonic acid induction of Rho mediated transendothelial migration in prostate cancer.” As the title indicates, the researchers established that AA enhances TEM. Moreover, they determined that AA “stimulates amoeboid characteristics” and that TEM is “driven by Rho signaling.”
In their article, the authors described how they used selective knockdown of components of the Rho pathway (RhoA, RhoC, ROCK1, and ROCK2) to show that Rho signaling is crucial to TEM: “Functions of these components were analyzed, regarding adhesion to bone marrow endothelial cells, migration in two dimensions, and the induction of the amoeboid phenotype by AA. TEM was reduced by simvastatin treatment of [cells of the] PC3-GFP and DU-145 [prostate cancer cell lines], which inhibited Rho pathway signaling.”
The authors concluded that AA-induced TEM is mediated by the induction of a Rho-driven amoeboid phenotype. “Inhibition of this cell migratory process,” they noted, “may be an important therapeutic target in high-risk prostate cancer.”
Professor Noel Clarke, who jointly led the study with Mick Brown, Ph.D., and Thomas Tawadros, M.D., Ph.D., said, “Our study shows how naturally occurring fatty acids in the bone marrow directly interact with the body’s system of manufacturing cholesterol to enhance prostate cancer cells’ ability to spread around the body. Understanding this process will provide vital clues as to how drugs like statins might benefit certain groups of prostate cancer patients who are more at risk of their cancer spreading.”
By focusing on a single chemotactic agent in their study, explained the University of Manchester researchers, they were able to observe its individual effects, thereby facilitating specific analysis of the consequent downstream pathway activation: “This has yielded new information, but further work is required to find other factors influencing RhoA, RhoC, ROCK1, and ROCK activity in prostate cancer in order to understand their individual role in early implantation of circulating tumor cells in bone marrow stroma.”
The researchers speculate that the observed statin effect may be related, at least in part, to their effect on the G-proteins: “The Rho and Rac subfamilies of small GTPase are mostly geranylgeranylated, which could explain the mechanism of amoeboid regulation by simvastatin seen in our study. It may also explain the effects of statins on prostate and other cancers in large population studies, where they are known to decrease prostate cancer progression and mortality but not its incidence.”
The researchers advocate additional work to clarify the role of fatty acid metabolism, the better to position TEM as a therapeutic target for limiting prostate cancer progression and metastasis.