Modulating tumor reactive stroma by extracorporeal shock waves to control prostate cancer progression

Abstract

BackgroundProstate cancer is the second most common cancer worldwide. Tumor microenvironment is composed of activated fibroblasts, the so called carcinoma‐associated fibroblasts (CAFs). They express high levels of α‐smooth muscle actin (α‐SMA) and type I collagen (COL1), and support proliferation and migration of tumor epithelial cells. Extracorporeal shock waves (ESWs), acoustic waves, are effective in the treatment of hypertrophic scars, due to their ability to modulate fibrosis. Based on this rationale, the study evaluated the effects of ESWs on CAF activation and the influence of ESW‐treated CAFs on the growth and migration of epithelial prostatic carcinoma cells.MethodsPrimary cultures of CAFs (n = 10) were prepared from tumors of patients undergoing surgery for high‐risk prostate carcinoma. CAFs were treated with ESWs (energy levels: 0.32 mJ/mm2, 1000 pulses; 0.59 mJ/mm2, 250 pulses). After treatment, the messenger RNA and protein levels of the stromal activation markers α‐SMA and COL1 were determined. Subsequently, two different stabilized cell lines (PC3 and DU145) of androgen‐resistant prostate cancer were treated with the conditioned media produced by ESW‐treated CAFs. At different times, viability and migration of PC3 and DU145 cells were evaluated. Viability was also assessed by coculture system using CAFs and PC3 or DU145 cells.ResultsESWs reduced gene expression and protein level of α‐SMA and COL1 in CAFs. The treatment of PC3 and DU145 with conditioned media of ESW‐treated CAFs determined a reduction of their growth and invasive potential. Coculture systems between ESW‐treated CAFs and PC3 or DU145 cells confirmed the epithelial cell number reduction.ConclusionsThis in vitro study demonstrates for the first time that ESWs are able to modulate the activation of prostate CAFs in favor of a less “reactive” stroma, with consequent slowing of the growth and migration of prostate cancer epithelial cells. However, only further studies to be performed in vivo will confirm the possibility of using this new therapy in patients with prostate cancer.

Correlation of Intravoxel Incoherent Motion and Diffusion Kurtosis MR Imaging Models With Reactive Stromal Grade in Prostate Cancer

“…9,23 The main cells in the reactive stroma of PCa are CAF, which are responsible for the synthesis, deposition, and remodeling of extracellular matrix (ECM), leading to an increase in the stroma and the continued production of pro-cancer growth factors. 24 Rinella et al 25 showed that CAF levels could be regulated by extracorporeal shock wave (ESW) to control PCa progression. PCa patients may have multiple tumor lesions with varying RSG scores between each lesion; therefore, MRI/TRUS fusion biopsy technique was used in this study to allow correspondence between biopsy sites and tumor lesions.…”

Multimodality Characterization of Cancer-Associated Fibroblasts in Tumor Microenvironment and Its Correlation With Ultrasound Shear Wave-Measured Tissue Stiffness in Localized Prostate Cancer

“…A positive correlation between CAF heterogeneity and stiffness on USWE provides us a non-invasive way to image the cancer microenvironment. This opens us to a new area that has prognostic and therapy monitoring prospects in novel treatments such as extracorporeal shock waves ( 41 ). PCa is a clinically and molecularly heterogeneous disease and we need better prognostic biomarkers for risk stratification of patients for various treatment options.…”

Mechanobiological Strategies to Augment Cancer Treatment

“…90 For example, it has been shown that MMP-14, involved in pancreatic cancer metastasis, is mechanically regulated to further induce other MMPs to act in action. Hence, particular 65,79 (b) mechanical stretch, 151,152,160 (c) high-intensity ultrasound frequency, 45,75,136,138,139 (d) and low-intensity pulsed ultrasound. 55,68,70,71 .…”

“…Lower levels of these markers consequently reduced the growth of prostate cancer epithelial cells. 159 Thus, targeting CAFs may improve treatment outcomes given the prevalence of CAFs and pro-tumorigenic role.…”

“…Schematic representation of mechanobiology-based therapies. Targeting cancer cells by mechanical perturbations like (a) shock wave,65,79 (b) mechanical stretch,151,152,160 (c) high-intensity ultrasound frequency,45,75,136,138,139 (d) and low-intensity pulsed ultrasound 55,68,70,71. .…”