Caffeine Mediates Sustained Inactivation of Breast Cancer-Associated Myofibroblasts via Up-Regulation of Tumor Suppressor Genes
Al-Ansari, Mysoon M. . 2014
Background: Active cancer-associated fibroblasts (CAFs) or myofibroblasts play important roles not only in the development and progression of breast carcinomas, but also in their prognosis and treatment. Therefore, targeting these cells through suppressing their supportive procarcinogenic paracrine effects is mandatory for improving the current therapies that are mainly targeting tumor cells. To this end, we investigated the effect of the natural and pharmacologically safe molecule, caffeine, on CAF cells and their various procarcinogenic effects.
Methodology/Principal Findings: We have shown here that caffeine up-regulates the tumor suppressor proteins p16, p21, p53 and Cav-1, and reduces the expression/secretion of various cytokines (IL-6, TGF-b, SDF-1 and MMP-2), and down- regulates a-SMA. Furthermore, caffeine suppressed the migratory/invasiveness abilities of CAF cells through PTEN- dependent Akt/Erk1/2 inactivation. Moreover, caffeine reduced the paracrine pro-invasion/2migration effects of CAF cells on breast cancer cells. These results indicate that caffeine can inactivate breast stromal myofibroblasts. This has been confirmed by showing that caffeine also suppresses the paracrine pro-angiogenic effect of CAF cells through down- regulating HIF-1aand its downstream effector VEGF-A. Interestingly, these effects were sustained in absence of caffeine.
Conclusion/Significance: The present findings provide a proof of principle that breast cancer myofibroblasts can be inactivated, and thereby caffeine may provide a safe and effective prevention against breast tumor growth/recurrence through inhibition of the procarcinogenic effects of active stromal fibroblasts.
The present work attempts to discover an alternative to conventional medications from organic biomass that can be utilized for various therapeutic applications.
A sol-gel method was used to synthesize the cerium dioxide nanoparticles. The nanoparticles formed were then characterized with UV-visible spectrophotometry, Fourier Transform Infrared…
Breast cancer is the most prevalent form of cancer among women. The microenvironment of a cancer tumor is surrounded by various cells, including the microbiota. An imbalance between microbes and…