Department of Mechanical & Aerospace Engineering (MAE), Herbert Wertheim College of Engineering (HWCOE), University of Florida (UF), Gainesville, FL 32611, USA; UF Health Cancer Center (UFHCC), University of Florida (UF), Gainesville, FL 32611, USA.
Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, PR China.
Biomaterials. 2022 Nov;290:121823. doi: 10.1016/j.biomaterials.2022.121823. Epub 2022 Oct 5.
Electrically excitable cells such as neurons transmit long-distance calcium or electrical signals to regulate their physiological functions. While the molecular underpinnings and down-stream effects of these intercellular communications in excitable cells have been well appreciated, little is known about whether and how non-excitable cancer cells spontaneously initiate and transmit long-distance intercellular signals. Here we report that non-excitable human colon and prostate cancer cells spontaneously initiate and spread intercellular calcium waves, in vitro and ex vivo. Xenograft model studies suggest that these calcium signals promote the growth rate of tumors in mice. Pharmacological studies elucidated that the inositol-trisphosphate-receptor (IPR)-regulated calcium release from endoplasmic reticulum (ER), which is activated by the G-PLC-IPR pathway, is a major cause for the initiation of spontaneous calcium transients. Further, the spatial-temporal characteristics of calcium dynamics can be tuned by the culture substrates of different mechanical stiffnesses. Our results provide evidence that calcium dynamics enables long-distance functional communication in non-excitable cancer cells and offer the potential to modulate calcium signaling for new cancer therapies.
电兴奋细胞，如神经元，通过传递远距离钙或电信号来调节其生理功能。虽然兴奋性细胞中这些细胞间通讯的分子基础和下游效应已得到很好的理解，但对于非兴奋癌细胞是否以及如何自发启动和传递远距离细胞间信号知之甚少。在这里，我们报告非兴奋的人结肠和前列腺癌细胞在体外和体内自发启动和传播细胞间钙波。异种移植模型研究表明，这些钙信号促进了小鼠肿瘤的生长速度。药理学研究阐明，内质网（ER）中肌醇三磷酸受体（IPR）调节的钙释放，其由 G-PLC-IPR 途径激活，是自发钙瞬变启动的主要原因。此外，钙动力学的时空特征可以通过不同机械硬度的培养底物进行调节。我们的结果提供了证据，表明钙动力学使非兴奋癌细胞中的远距离功能通讯成为可能，并为新的癌症治疗方法调节钙信号提供了潜力。
