Mok Wilson, Boucher Yves, Jain Rakesh K
Department of Radiation Oncology, Edwin L. Steele Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Cancer Res. 2007 Nov 15;67(22):10664-8. doi: 10.1158/0008-5472.CAN-07-3107.
Oncolytic viral vectors show enormous potential for the treatment of many solid tumors. However, these vectors often suffer from insufficient delivery within tumors, which limits their efficacy in both preclinical and clinical settings. We have previously shown that tumor collagen can significantly hinder diffusion, and that its degradation can enhance the distribution and efficacy of an oncolytic herpes simplex virus (HSV) vector. Here, we identify two members of the matrix metalloproteinase (MMP) family of enzymes, MMP-1 and MMP-8, which can modulate the tumor matrix and enhance HSV delivery and efficacy. We show that overexpression of MMP-1 and MMP-8 in the human soft tissue sarcoma HSTS26T leads to a significant depletion of tumor-sulfated glycosaminoglycans. This increases the hydraulic conductivity of these tumors and enhances the flow of virus during injection. In control tumors, injected virus accumulates primarily in the periphery of the tumor. In contrast, we observed a more widespread distribution of virus around the injection site in MMP-1- and MMP-8-expressing tumors. Due to this enhanced vector delivery, MMP-expressing tumors respond significantly better to oncolytic HSV treatment than control tumors. Thus, these findings introduce a new approach to improve the delivery and efficacy of oncolytic viral vectors: modulation of tumor glycosaminoglycans to enhance convection.
溶瘤病毒载体在治疗多种实体瘤方面显示出巨大潜力。然而，这些载体在肿瘤内的递送往往不足，这限制了它们在临床前和临床环境中的疗效。我们之前已经表明，肿瘤胶原蛋白会显著阻碍扩散，其降解可增强溶瘤单纯疱疹病毒（HSV）载体的分布和疗效。在此，我们鉴定出基质金属蛋白酶（MMP）家族的两种酶成员，即MMP-1和MMP-8，它们可调节肿瘤基质并增强HSV的递送及疗效。我们发现，在人软组织肉瘤HSTS26T中过表达MMP-1和MMP-8会导致肿瘤硫酸化糖胺聚糖显著减少。这增加了这些肿瘤的水力传导率，并在注射过程中增强了病毒的流动。在对照肿瘤中，注射的病毒主要积聚在肿瘤周边。相比之下，我们在表达MMP-1和MMP-8的肿瘤中观察到病毒在注射部位周围分布更广泛。由于这种增强的载体递送，表达MMP的肿瘤对溶瘤HSV治疗的反应明显优于对照肿瘤。因此，这些发现引入了一种改善溶瘤病毒载体递送和疗效的新方法：调节肿瘤糖胺聚糖以增强对流。
