Department of Biomedical Sciences, College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon, 400-712, Republic of Korea.
Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, 133-791, Seoul, Republic of Korea; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Cancer Lett. 2017 Jun 28;396:155-166. doi: 10.1016/j.canlet.2017.03.009. Epub 2017 Mar 15.
Pancreatic cancer is a highly lethal disease for which limited therapeutic options are available. Pancreatic cancer exhibits a pronounced collagen-rich stromal reaction, which induces chemoresistance by inhibiting drug diffusion into the tumor. Complementary treatment with oncolytic virus such as an oncolytic adenovirus expressing relaxin (YDC002) is an innovative treatment option for combating chemoresistant pancreatic cancer. Here, we examined the ability of combined treatment with gemcitabine and YDC002, which degrades extracellular matrix (ECM), to efficiently treat chemoresistant and desmoplastic pancreatic cancer. Gemcitabine alone exhibited similarly low cytotoxicity toward pancreatic cancer cells throughout the concentration range (1-50 μM) used, whereas the combination of YDC002 and a subtherapeutic dose of gemcitabine (0.01-0.05 μM) resulted in potent anticancer effects through effective induction of apoptosis. Importantly, YDC002 combined with gemcitabine significantly attenuated the expression of major ECM components including collagens, fibronectin, and elastin in tumor spheroids and xenograft tumors compared with gemcitabine alone, resulting in potent induction of apoptosis, gemcitabine-mediated cytotoxicity, and an oncolytic effect through degradation of tumor ECM. Our results demonstrate that YDC002 can selectively degrade aberrant ECM and attenuate the ECM-induced chemoresistance observed in desmoplastic pancreatic tumor, resulting in a potent antitumor effect through effective induction of apoptosis.
胰腺癌是一种高度致命的疾病，目前可用的治疗方法有限。胰腺癌表现出明显的富含胶原的基质反应，通过抑制药物扩散到肿瘤中，诱导化疗耐药。与溶瘤病毒（如表达松弛素的溶瘤腺病毒 YDC002）联合治疗是治疗化疗耐药胰腺癌的一种创新治疗选择。在这里，我们研究了联合使用吉西他滨和 YDC002（降解细胞外基质）治疗化疗耐药和纤维形成性胰腺癌的能力。吉西他滨在整个浓度范围（1-50 μM）内对胰腺癌细胞的细胞毒性相似较低，而 YDC002 与亚治疗剂量的吉西他滨（0.01-0.05 μM）联合使用，通过有效诱导细胞凋亡产生强大的抗癌作用。重要的是，与单独使用吉西他滨相比，YDC002 联合吉西他滨可显著下调肿瘤球体和异种移植瘤中主要细胞外基质成分（包括胶原、纤维连接蛋白和弹性蛋白）的表达，从而通过降解肿瘤细胞外基质有效诱导细胞凋亡、吉西他滨介导的细胞毒性和溶瘤作用。我们的研究结果表明，YDC002 可以选择性地降解异常细胞外基质并减轻纤维形成性胰腺肿瘤中观察到的细胞外基质诱导的化疗耐药，通过有效诱导细胞凋亡产生强大的抗肿瘤作用。
