Background: Colorectal cancer (CRC) is characterized by a pro-inflammatory microenvironment and features high-energy-supply molecules that assure tumor growth. A still less studied macromolecule is inorganic polyphosphate (iPolyP), a high-energy linear polymer that is ubiquitous in all forms of life. Made up of hundreds of repeated orthophosphate units, iPolyP is essential for a wide variety of functions in mammalian cells, including the regulation of proliferative signaling pathways. Some evidence has suggested its involvement in carcinogenesis, although more studies need to be pursued. Moreover, iPolyP regulates several homeostatic processes in animals, spanning from energy metabolism to blood coagulation and tissue regeneration. Results: In this study, we tested the role of iPolyP on CRC proliferation, using in vitro and ex vivo approaches, in order to evaluate its effect on tumor growth. We found that iPolyP is significantly increased in tumor tissues, derived from affected individuals enrolled in this study, compared to the corresponding peritumoral counterparts. In addition, iPolyP signaling occurs through the TRPM8 receptor, a well-characterized Na+and Ca2+ion channel often overexpressed in CRC and linked with poor prognosis, thus promoting CRC cell proliferation. The pharmacological inhibition of TRPM8 or RNA interference experiments performed in established CRC cell lines, such as Caco-2 and SW620, showed that the involvement of TRPM8 is essential, greater than that of the other two known iPolyP receptors, P2Y1 and RAGE. The presence of iPolyP drives cancer cells towards the mitotic phase of the cell cycle by enhancing the expression ofccnb1, which encodes the Cyclin B protein. In vitro 2D and 3D data reflected the ex vivo results, obtained by the generation of CRC-derived organoids, which increased in size. Conclusions: These results indicate that iPolyP may be considered a novel and unexpected early biomarker supporting colorectal cancer cell proliferation.
背景：结直肠癌（CRC）具有促炎性微环境特征，并富含确保肿瘤生长的高能量供应分子。无机多聚磷酸盐（iPolyP）作为一种高能量线性聚合物，广泛存在于所有生命形式中，但其在肿瘤中的作用研究尚不充分。iPolyP由数百个重复的正磷酸单元构成，对哺乳动物细胞的多种功能至关重要，包括调控增殖信号通路。已有证据表明其参与致癌过程，但尚需进一步研究。此外，iPolyP在动物体内调节多种稳态过程，涵盖能量代谢、凝血机制及组织再生等多个方面。 结果：本研究通过体外和离体实验方法，探讨iPolyP对结直肠癌增殖的影响，以评估其对肿瘤生长的作用。研究发现，与癌旁组织相比，本研究纳入患者来源的肿瘤组织中iPolyP水平显著升高。iPolyP信号传导通过TRPM8受体实现，该受体是特征明确的钠钙离子通道，在结直肠癌中常过度表达且与不良预后相关，从而促进结直肠癌细胞增殖。在已建立的结直肠癌细胞系（如Caco-2和SW620）中进行的TRPM8药理抑制或RNA干扰实验表明，TRPM8的参与至关重要，其作用超过另外两个已知的iPolyP受体（P2Y1和RAGE）。iPolyP通过增强编码细胞周期蛋白B的ccnb1基因表达，驱动癌细胞进入细胞周期的有丝分裂阶段。体外二维和三维实验数据与离体实验结果一致：通过构建结直肠癌来源的类器官模型，观察到iPolyP能促进类器官体积增大。 结论：这些结果表明，iPolyP可能作为一种新型且具有潜在价值的早期生物标志物，支持结直肠癌细胞的增殖过程。
Inorganic Polyphosphate Promotes Colorectal Cancer Growth via TRPM8 Receptor Signaling Pathway
肿瘤(癌症)患者之家