Biological Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup 56212, Republic of Korea.
Department of Microbiology, School of Medicine, Kyungpook National University, 680 gukchaebosang-Ro, Jung-gu, Daegu 41944, Republic of Korea.
J Control Release. 2023 Mar;355:199-210. doi: 10.1016/j.jconrel.2023.02.001. Epub 2023 Feb 7.
Bacterial cancer therapies aim to manipulate bacteria to effectively deploy therapeutic payloads to tumors. Attenuated bacteria alone often cannot eradicate solid tumors. Attenuated Salmonella can be engineered to deliver cytotoxic drugs to either trigger an immune response or increase antitumor efficacy when combined with chemotherapeutic drugs. However, the extracellular matrix (ECM) surrounding cancer cells forms a barrier that often limits the ability of chemotherapeutic and cytotoxic drugs to penetrate and eliminate tumors. To overcome this limitation, we developed a strategy to combine chemotherapy with an attenuated Salmonella typhimurium strain engineered to secrete HysA protein (from Staphylococcus aureus; Hyaluronidase, HAase) in tumors. The engineered Salmonella effectively degraded hyaluronan (HA), which is a major ECM constituent in tumors, and suppressed tumor growth in mouse models of pancreatic adenocarcinoma (ASPC-1) and breast cancer (4T1). Furthermore, it prolonged survival when combined with chemotherapeutic drugs (doxorubicin or gemcitabine). Upon bacterial colonization, the HAase-mediated ECM degradation decreased interstitial fluid pressure (IFP) in the tumor microenvironment. Additionally, HA degradation using HAase-expressing bacteria in vivo led to decreased binding to the receptor, CD44, expressed in tumors. This may modulate proliferation- and apoptosis-related signal pathways. Therefore, ECM-targeting bacteria can be used as a synergistic anticancer therapeutic agent to maximize chemotherapeutic drug delivery into highly invasive tumors.
细菌癌症疗法旨在操纵细菌，将治疗有效载荷有效递送至肿瘤。单独使用减毒细菌通常无法根除实体瘤。减毒沙门氏菌可被工程化以递送细胞毒性药物，以在与化疗药物联合使用时引发免疫反应或增加抗肿瘤功效。然而，癌细胞周围的细胞外基质（ECM）形成了一道屏障，通常限制了化疗药物和细胞毒性药物穿透和消除肿瘤的能力。为了克服这一限制，我们开发了一种策略，将化疗与工程化减毒鼠伤寒沙门氏菌菌株与分泌 HysA 蛋白（来自金黄色葡萄球菌；透明质酸酶，HAase）相结合，以在肿瘤中使用。工程化的沙门氏菌有效地降解了透明质酸（HA），HA 是肿瘤中主要的 ECM 成分，并抑制了胰腺腺癌（ASPC-1）和乳腺癌（4T1）小鼠模型中的肿瘤生长。此外，当与化疗药物（阿霉素或吉西他滨）联合使用时，它延长了生存时间。在细菌定植后，HAase 介导的 ECM 降解降低了肿瘤微环境中的间质液压力（IFP）。此外，体内使用表达 HAase 的细菌降解 HA 导致与肿瘤中表达的受体 CD44 的结合减少。这可能调节与增殖和凋亡相关的信号通路。因此，靶向 ECM 的细菌可用作协同抗癌治疗剂，以最大限度地将化疗药物递送至高度侵袭性肿瘤中。
