Menghini Stefano, Vizovisek Matej, Enders Jonathas, Schuerle Simone
Department of Health Sciences and Technology, Institute for Translational Medicine, ETH Zurich, CH-8092, Zurich, Switzerland.
Cancer Metab. 2023 Aug 9;11(1):12. doi: 10.1186/s40170-023-00313-3.
The use of bacteria in cancer immunotherapy has the potential to bypass many shortcomings of conventional treatments. The ability of anaerobic bacteria to preferentially accumulate and replicate in hypoxic regions of solid tumors, as a consequence of bacterial metabolic needs, is particularly advantageous and key to boosting their immunostimulatory therapeutic actions in situ. While several of these bacterial traits are well-studied, little is known about their competition for nutrients and its effect on cancer cells which could serve as another potent and innate antineoplastic action. Here, we explored the consequences of the iron-scavenging abilities of a particular species of bacteria, Magnetospirillum magneticum, which has been studied as a potential new class of bacteria for magnetically targeted bacterial cancer therapy. We investigated their influence in hypoxic regions of solid tumors by studying the consequential metabolic effects exerted on cancer cells. To do so, we established an in vitro co-culture system consisting of the bacterial strain AMB-1 incubated under hypoxic conditions with human breast cancer cells MDA-MB-231. We first quantified the number of viable cells after incubation with magnetotactic bacteria demonstrating a lower rate of cellular proliferation that correlated with increasing bacteria-to-cancer cells ratio. Further experiments showed increasing populations of apoptotic cells when cancer cells were incubated with AMB-1 over a period of 24 h. Analysis of the metabolic effects induced by bacteria suggest an increase in the activation of executioner caspases as well as changes in levels of apoptosis-related proteins. Finally, the level of several human apoptosis-related proteins was investigated, confirming a bacteria-dependent triggering of apoptotic pathways in breast cancer cells. Overall, our findings support that magnetotactic bacteria could act as self-replicating iron-chelating agents and indicate that they interfere with proliferation and lead to increased apoptosis of cancer cells. This bacterial feature could serve as an additional antineoplastic mechanism to reinforce current bacterial cancer therapies.
在癌症免疫治疗中使用细菌有可能克服传统治疗方法的许多缺点。由于细菌的代谢需求，厌氧菌能够优先在实体瘤的缺氧区域积聚和复制，这一特性特别有利，也是增强其原位免疫刺激治疗作用的关键。虽然对这些细菌的一些特性已经进行了深入研究，但对于它们对营养物质的竞争及其对癌细胞的影响却知之甚少，而这可能是另一种强大的天然抗肿瘤作用。在这里，我们探讨了一种特定细菌——趋磁螺菌的铁清除能力的影响，该细菌已被研究作为一种潜在的新型细菌用于磁靶向细菌癌症治疗。我们通过研究对癌细胞产生的代谢影响，来调查它们在实体瘤缺氧区域的作用。为此，我们建立了一个体外共培养系统，由在缺氧条件下与人乳腺癌细胞MDA-MB-231一起孵育的AMB-1菌株组成。我们首先对与趋磁细菌孵育后的活细胞数量进行了定量，结果表明细胞增殖率较低，且与细菌与癌细胞比例的增加相关。进一步的实验表明，当癌细胞与AMB-1一起孵育24小时后，凋亡细胞的数量增加。对细菌诱导的代谢影响的分析表明，执行蛋白酶的激活增加以及凋亡相关蛋白水平发生变化。最后，对几种人类凋亡相关蛋白的水平进行了研究，证实了乳腺癌细胞中凋亡途径的细菌依赖性触发。总体而言，我们的研究结果支持趋磁细菌可以作为自我复制的铁螯合剂，并表明它们会干扰癌细胞的增殖并导致其凋亡增加。这种细菌特性可以作为一种额外的抗肿瘤机制，以加强当前的细菌癌症治疗。
