Hyaluronidase-Expressing Salmonella Effectively Targets Tumor-Associated Hyaluronic Acid in Pancreatic Ductal Adenocarcinoma
Hyaluronidase-Expressing Salmonella Effectively Targets Tumor-Associated Hyaluronic Acid in Pancreatic Ductal Adenocarcinoma
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DOI：
10.1158/1535-7163.mct-19-0556
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发表时间：
2020-02-01
影响因子：
5.7
通讯作者：
Manuel, Edwin R.
中科院分区：
文献类型：
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作者：
Ebelt, Nancy D.;Zuniga, Edith;Manuel, Edwin R.
在胰腺导管腺癌(PDAC)中，癌细胞周围的细胞外基质(ECM)形成屏障，常常限制化疗药物和细胞毒免疫亚群穿透和清除肿瘤的能力。致密的基质基质保护癌细胞，也称为结缔组织增生，是主要的细胞外基质成分，如胶原蛋白和透明质酸(HA)过度产生的结果。尽管针对ECM成分的候选药物在增加化疗药物的渗透率方面表现出了希望，但与周围健康组织中ECM全身性耗尽相关的严重不良反应限制了它们在更高、更有效的剂量下的使用。目前，很少有策略优先降解肿瘤组织中的ECM而不是健康组织。有鉴于此，我们开发了一种减毒的、肿瘤靶向的表达功能性细菌透明质酸酶(BHS-ST)的鼠伤寒沙门氏菌(ST)，能够降解沉积在PDAC肿瘤中的人HA。我们的数据显示，BHS-ST(I)在全身给药后靶向和定植原位人类PDAC肿瘤，(Ii)在体内被有效诱导以耗尽肿瘤来源的HA，这反过来(Iii)显著增加鼠伤寒沙门氏菌在促结缔组织增生性肿瘤中的扩散。BHS-ST代表了一种有前景的新的肿瘤ECM靶向策略，该策略可能有助于将肿瘤外毒性降至最低，同时最大限度地将药物输送到高度促结缔组织增生性肿瘤中。
In pancreatic ductal adenocarcinoma (PDAC), the extracellular matrix (ECM) surrounding cancer cells forms a barrier that often limits the ability of chemotherapeutic drugs and cytotoxic immune subsets to penetrate and eliminate tumors. The dense stromal matrix protecting cancer cells, also known as desmoplasia, results from the overproduction of major ECM components such as collagens and hyaluronic acid (HA). Although candidate drugs targeting ECM components have shown promise in increasing penetration of chemotherapeutic agents, severe adverse effects associated with systemic depletion of ECM in peripheral healthy tissues limits their use at higher, more effective doses. Currently, few strategies exist that preferentially degrade ECM in tumor tissue over healthy tissues. In light of this, we have developed an attenuated, tumor-targeting Salmonella typhimurium (ST) expressing functional bacterial hyaluronidase (bHs-ST), capable of degrading human HA deposited within PDAC tumors. Our data show that bHs-ST (i) targets and colonizes orthotopic human PDAC tumors following systemic administration and (ii) is efficiently induced in vivo to deplete tumor-derived HA, which in turn (iii) significantly increases diffusion of Salmonella typhimurium within desmoplastic tumors. BHs-ST represents a promising new tumor ECM-targeting strategy that may be instrumental in minimizing off-tumor toxicity while maximizing drug delivery into highly desmoplastic tumors.