体外冲击波调控肿瘤反应性基质控制前列腺癌进展。
Modulating tumor reactive stroma by extracorporeal shock waves to control prostate cancer progression.
机构信息
Department of Medical Sciences, University of Turin, Turin, Italy.
Department of Oncology, Pathology Unit, A.O.U., Città della Salute e della Scienza Hospital, Turin, Italy.
出版信息
Prostate. 2020 Sep;80(13):1087-1096. doi: 10.1002/pros.24037. Epub 2020 Jul 1.
BACKGROUND
Prostate 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.
METHODS
Primary 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/mm , 1000 pulses; 0.59 mJ/mm , 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.
RESULTS
ESWs 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.
CONCLUSIONS
This 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.
背景
前列腺癌是全球第二大常见癌症。肿瘤微环境由激活的成纤维细胞组成，即所谓的癌相关成纤维细胞（CAFs）。它们高表达α-平滑肌肌动蛋白（α-SMA）和 I 型胶原（COL1），并支持肿瘤上皮细胞的增殖和迁移。体外冲击波（ESW），即声波，在治疗肥厚性瘢痕方面非常有效，因为它们能够调节纤维化。基于这一原理，本研究评估了 ESW 对 CAF 激活的影响，以及 ESW 处理后的 CAF 对前列腺上皮癌上皮细胞生长和迁移的影响。
方法
从因高危前列腺癌而行手术的患者的肿瘤中制备了 10 例原发性 CAF 培养物。用 ESW 处理 CAF（能量水平：0.32mJ/mm ，1000 个脉冲；0.59mJ/mm ，250 个脉冲）。治疗后，测定基质激活标志物 α-SMA 和 COL1 的信使 RNA 和蛋白水平。随后，用 ESW 处理后的 CAF 产生的条件培养基处理两种不同的雄激素抵抗型前列腺癌细胞系（PC3 和 DU145）。在不同时间点，评估 PC3 和 DU145 细胞的活力和迁移。通过 CAF 和 PC3 或 DU145 细胞共培养系统评估细胞活力。
结果
ESW 降低了 CAF 中 α-SMA 和 COL1 的基因表达和蛋白水平。用 ESW 处理后的 CAF 产生的条件培养基处理 PC3 和 DU145，导致其生长和侵袭能力降低。ESW 处理后的 CAF 与 PC3 或 DU145 细胞共培养系统证实了上皮细胞数量的减少。
结论
这项体外研究首次证明，ESW 能够调节前列腺 CAF 的激活，使其向更“不活跃”的基质转变，从而减缓前列腺癌上皮细胞的生长和迁移。然而，只有进一步在体内进行的研究才能证实将这种新疗法应用于前列腺癌患者的可能性。
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