Gaustad Jon-Vidar, Simonsen Trude G, Wegner Catherine S, Rofstad Einar K
Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Front Oncol. 2019 Aug 29;9:845. doi: 10.3389/fonc.2019.00845. eCollection 2019.
The purpose of the study was to investigate vascularization, oxygenation, and the effect of sunitinib treatment in pancreatic ductal adenocarcinoma (PDAC). BxPC-3 and Capan-2 xenografts grown in dorsal window chambers were used as preclinical models of human PDAC. Tumor angiogenesis and the morphology and function of tumor vascular networks were studied by intravital microscopy, and tumor hypoxia was assessed by immunohistochemistry. The PDAC models differed in vessel distribution and oxygenation, and the differences were induced by the initial tumor angiogenesis. In both models, sunitinib treatment reduced intratumor and peritumor vessel densities by selectively removing small-diameter vessels. Sunitinb treatment resulted in a general decrease in vessel density and scattered hypoxia in BxPC-3 tumors, and depleted most vessels and induced massive hypoxia in central parts of Capan-2 tumors. The study demonstrates that PDAC xenografts can differ in vascularization, and the differences can impact oxygenation and effects of treatment. Neoadjuvant sunitinib treatment is inappropriate in combination with conventional therapy for human PDACs resembling the PDAC xenografts used here, because sunitinib-induced hypoxia can impair the effect of most conventional therapies.
本研究的目的是调查胰腺导管腺癌（PDAC）中的血管生成、氧合作用以及舒尼替尼治疗的效果。在背窗室中生长的BxPC-3和Capan-2异种移植瘤被用作人类PDAC的临床前模型。通过活体显微镜研究肿瘤血管生成以及肿瘤血管网络的形态和功能，并通过免疫组织化学评估肿瘤缺氧情况。PDAC模型在血管分布和氧合方面存在差异，这些差异是由初始肿瘤血管生成引起的。在两种模型中，舒尼替尼治疗通过选择性去除小直径血管降低了肿瘤内和肿瘤周围的血管密度。舒尼替尼治疗导致BxPC-3肿瘤的血管密度普遍降低并出现散在性缺氧，而在Capan-2肿瘤中心部分则使大多数血管耗竭并诱导大量缺氧。该研究表明，PDAC异种移植瘤在血管生成方面可能存在差异，这些差异会影响氧合作用和治疗效果。对于类似于此处所用PDAC异种移植瘤的人类PDAC，新辅助舒尼替尼治疗与传统疗法联合使用并不合适，因为舒尼替尼诱导的缺氧会削弱大多数传统疗法的效果。
