Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Amsterdam UMC location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands.
Amsterdam UMC location University of Amsterdam, Department Experimental Immunology, Amsterdam Infection and Immunity Center, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands.
Biomed Pharmacother. 2024 Sep;178:117261. doi: 10.1016/j.biopha.2024.117261. Epub 2024 Aug 5.
Long-term anti-angiogenesis leads to pruned vasculature, densely deposited extracellular matrix (ECM), and consequently reduced chemotherapy delivery in esophagogastric cancer (EGC). To address this issue, we evaluated the efficacy of adding a hyaluronidase or a NO-donor to the regimen of chemotherapy and anti-angiogenic drugs.
A patient-derived EGC xenograft model was developed. Grafted mice were randomly assigned to four experimental groups and one control group. The experimental groups received DC101, a murine angiogenesis inhibitor, and nab-paclitaxel (NPTX), with the addition of hyaluronidase (PEGPH20), or NO-donor (nitroglycerine, NTG), or their combination, respectively. We compared tumor growth during 17 days of treatment. We performed immunohistochemistry for ECM components hyaluronan (HA) and collagen, CD31 for endothelial cells, and γH2AX for DNA damage. The positively stained areas were quantified, and vessel diameters were measured using QuPath software.
Prolonged DC101 treatment induced deposition of HA (p<0.01) and collagen (p<0.01). HA was effectively degraded by PEGPH20 (p<0.001), but not by NTG as expected. Both PEGPH20 (p<0.05) and NTG (p<0.01) dilated vessels collapsed in response to long-term DC101 treatment. However, only PEGPH20 (rather than NTG) was found to significantly inhibit tumor growth (p<0.05) in combination with NPTX and DC101.
These findings suggest that the mechanical barrier of HA is the major reason responsible for the resistance developed during prolonged anti-angiogenesis in EGC. Incorporating PEGPH20 into the existing treatment regimen is promising to improve outcomes for patients with EGC.
长期的抗血管生成作用会导致血管结构被修剪、细胞外基质（ECM）大量沉积，从而降低胃癌（EGC）的化疗药物输送。为了解决这个问题，我们评估了在化疗和抗血管生成药物方案中加入透明质酸酶或一氧化氮供体的疗效。
建立了一个源自患者的 EGC 异种移植模型。移植的小鼠被随机分配到四个实验组和一个对照组。实验组分别接受 DC101（一种鼠抗血管生成抑制剂）和 nab-紫杉醇（NPTX），并分别加入透明质酸酶（PEGPH20）、NO 供体（硝化甘油，NTG）或两者的组合。我们比较了 17 天治疗期间的肿瘤生长情况。我们对 ECM 成分透明质酸（HA）和胶原蛋白、内皮细胞的 CD31 以及 DNA 损伤的 γH2AX 进行了免疫组织化学染色。使用 QuPath 软件对阳性染色区域进行定量，并测量血管直径。
延长 DC101 治疗会诱导 HA（p<0.01）和胶原蛋白（p<0.01）的沉积。PEGPH20 可有效降解 HA（p<0.001），但 NTG 却不能（如预期的那样）。PEGPH20（p<0.05）和 NTG（p<0.01）都能使因长期 DC101 治疗而塌陷的血管扩张。然而，只有 PEGPH20（而不是 NTG）与 NPTX 和 DC101 联合使用时，才发现能显著抑制肿瘤生长（p<0.05）。
这些发现表明，HA 的机械屏障是导致 EGC 中抗血管生成治疗长期产生耐药性的主要原因。将 PEGPH20 纳入现有的治疗方案有望改善 EGC 患者的治疗效果。
