Di Pompo Gemma, Cortini Margherita, Baldini Nicola, Avnet Sofia
Biomedical Science and Technologies Lab, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.
Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy.
Cancers (Basel). 2021 Jul 30;13(15):3848. doi: 10.3390/cancers13153848.
In bone sarcomas, extracellular proton accumulation is an intrinsic driver of malignancy. Extracellular acidosis increases stemness, invasion, angiogenesis, metastasis, and resistance to therapy of cancer cells. It reprograms tumour-associated stroma into a protumour phenotype through the release of inflammatory cytokines. It affects bone homeostasis, as extracellular proton accumulation is perceived by acid-sensing ion channels located at the cell membrane of normal bone cells. In bone, acidosis results from the altered glycolytic metabolism of bone cancer cells and the resorption activity of tumour-induced osteoclasts that share the same ecosystem. Proton extrusion activity is mediated by extruders and transporters located at the cell membrane of normal and transformed cells, including vacuolar ATPase and carbonic anhydrase IX, or by the release of highly acidic lysosomes by exocytosis. To date, a number of investigations have focused on the effects of acidosis and its inhibition in bone sarcomas, including studies evaluating the use of photodynamic therapy. In this review, we will discuss the current status of all findings on extracellular acidosis in bone sarcomas, with a specific focus on the characteristics of the bone microenvironment and the acid-targeting therapeutic approaches that are currently being evaluated.
在骨肉瘤中，细胞外质子积累是恶性肿瘤的内在驱动因素。细胞外酸中毒会增加癌细胞的干性、侵袭性、血管生成、转移能力以及对治疗的抗性。它通过释放炎性细胞因子将肿瘤相关基质重编程为促肿瘤表型。它影响骨稳态，因为位于正常骨细胞细胞膜上的酸敏感离子通道能感知细胞外质子积累。在骨骼中，酸中毒源于骨癌细胞糖酵解代谢的改变以及与肿瘤共享同一生态系统的肿瘤诱导破骨细胞的吸收活性。质子外排活性由位于正常细胞和转化细胞细胞膜上的外排器和转运体介导，包括液泡型ATP酶和碳酸酐酶IX，或者通过胞吐作用释放高酸性溶酶体来实现。迄今为止，许多研究都聚焦于酸中毒及其在骨肉瘤中的抑制作用，包括评估光动力疗法应用的研究。在这篇综述中，我们将讨论骨肉瘤细胞外酸中毒所有研究结果的现状，特别关注骨微环境的特征以及目前正在评估的针对酸的治疗方法。
