Abstract
Prostate cancer is diagnosed late in life, when co-morbidities are frequent. Among them, hypertension, hypercholesterolemia, diabetes or metabolic syndrome exhibit an elevated incidence. In turn, prostate cancer patients frequently undergo chronic pharmacological treatments that could alter disease initiation, progression and therapy response. Here we show that treatment with anti-cholesterolemic drugs, statins, at doses achieved in patients, enhance the pro-tumorigenic activity of obesogenic diets. In addition, the use of a mouse model of prostate cancer and human prostate cancer xenografts revealed that in vivo simvastatin administration alone increases prostate cancer aggressiveness. In vitro cell line systems supported the notion that this phenomenon occurs, at least in part, through the direct action on cancer cells of low doses of statins, in range of what is observed in human plasma. In sum, our results reveal a prostate cancer experimental system where statins exhibit an undesirable effect, and warrant further research to address the relevance and implications of this observation in human prostate cancer.
Highlights
The initiation, progression and therapeutic eradication of cancer is largely associated to the evolving mutational landscape of the tumor [1]
In order to evaluate the impact of statins in Prostate cancer (PCa) biology, we first evaluated the effect of statin exposure in the context of obesity in Pten prostate-specific heterozygous mice (Ptenpc+/-), which exhibit a weak, non-cancerous phenotype [10, 17]
Simvastatin treatment administered after the onset of obesity (Figure 1a) led to invasive cancerous lesions with an incidence of 45%, a phenotype only achieved in this mouse model when both copies of Pten are lost in the prostate epithelium [10, 13] (Figure 1c, 1d)
Summary
The initiation, progression and therapeutic eradication of cancer is largely associated to the evolving mutational landscape of the tumor [1]. Due to its predominant diagnosis in men above 60 years old, comorbidities are frequent. These include obesity, metabolic syndrome, arterial hypertension and diabetes [8]. Anti-hypercholesterolemic treatment is prescribed to millions of individuals around the globe in the form of statins, and their benefits and harms have been studied [9]. Due to their extensive and chronic use, it is of the utmost importance to carefully evaluate the impact of this long-term therapy on the biology of cancer, at doses and administration modes achieved in human subjects. Through the use of PCa mouse models, cellular systems and observational studies in patients we demonstrate that treatment with these compounds is associated to increased aggressive features in this disease
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
