Dailey Kaitlin M, Jacobson Reed I, Johnson Paige R, Woolery Taylor J, Kim Jiha, Jansen Rick J, Mallik Sanku, Brooks Amanda E
Cell and Molecular Biology Program, North Dakota State University, Fargo, ND, United States.
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, United States.
Front Microbiol. 2021 Mar 29;12:624618. doi: 10.3389/fmicb.2021.624618. eCollection 2021.
The tumor microenvironment is characterized by anomalous vascularization, hypoxia, and acidity at the core of solid tumors that culminates in concentrated necrosis and immune system dysregulation among other effects. While this environment presents several challenges for the development of oncotherapeutics that deliver their activity via the enhanced permeability and retention (EPR) effect of the leaky blood vessels around a tumor, oncolytic bacteria, or a class of bacteria with a noted capacity to lyse solid tumors, are attracted to the very environment found at the center of solid tumors that confounds other therapeutics. It is this capacity that allows for a potent, active penetration from the tumor margins into the core, and subsequent colonization to facilitate lysis and immune reactivation. in particular has recently shown great promise in preclinical and clinical trials when administered directly to the tumor. These studies indicate that is uniquely poised to effectively accomplish the long sought after "holy grail" of oncotherapeutics: selective tumor localization via intravenous delivery. This study reports the development of efficient methods that facilitate experimental work and therapeutic translation of including the ability to work with this obligate micro-anaerobe on the benchtop. Additionally, this study seeks to utilize this newfound experimental flexibility to address several gaps in the current knowledge regarding the efficacy of CRIPSR/Cas9-mediated gene insertion in this species to further develop this oncolytic bacteria and the genetic customization of bacteria in general.
肿瘤微环境的特征是实体瘤核心部位血管异常、缺氧和酸性环境，最终导致集中坏死和免疫系统失调等后果。虽然这种环境给通过肿瘤周围渗漏血管的增强渗透和滞留（EPR）效应发挥作用的肿瘤治疗药物的开发带来了诸多挑战，但溶瘤细菌，即一类具有显著溶解实体瘤能力的细菌，却被吸引到实体瘤中心的这种环境中，而这种环境会使其他治疗方法失效。正是这种能力使得溶瘤细菌能够从肿瘤边缘有效且主动地渗透到核心部位，并随后定殖以促进肿瘤溶解和免疫重新激活。特别是在直接给药于肿瘤时，最近在临床前和临床试验中显示出了巨大的前景。这些研究表明，溶瘤细菌独特地具备有效实现肿瘤治疗领域长期追求的“圣杯”目标的能力：通过静脉给药实现选择性肿瘤定位。本研究报告了促进溶瘤细菌实验工作和治疗转化的有效方法的开发，包括在实验台上处理这种专性微需氧菌的能力。此外，本研究旨在利用这种新获得的实验灵活性来填补当前关于CRISPR/Cas9介导的基因插入在该物种中的功效的知识空白，以进一步开发这种溶瘤细菌并总体上对细菌进行基因定制。
