Abstract
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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease associated with poor prognosis and a 5-year survival rate of 5–7% [1, 2]
Several studies have demonstrated that poor blood supply and severe hypoxia in the primary tumor is associated with poor prognosis for PDAC patients [4,5,6]
Clinical trials designed to normalize tumor vasculature have not been reported for PDAC patients, but in a recent review, Li et al concluded that the vascular normalization strategy has shown great clinical potential and represents a promising future direction of vasculature-targeted treatment in pancreatic cancer [9]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease associated with poor prognosis and a 5-year survival rate of 5–7% [1, 2]. In the 1970s, Folkman demonstrated that tumor growth is angiogenesis-dependent, and suggested that antiangiogenic therapy could suppress tumor growth by starving tumor cells [7]. After this pioneering work, several antiangiogenic drugs were developed and tested in clinical trials [8]. Jain and others demonstrated that antiangiogenic therapy can be designed to normalize tumor vasculature [10]. Clinical trials designed to normalize tumor vasculature have not been reported for PDAC patients, but in a recent review, Li et al concluded that the vascular normalization strategy has shown great clinical potential and represents a promising future direction of vasculature-targeted treatment in pancreatic cancer [9]. Vascular normalization is debated because some investigators have shown that antiangiogenic drugs fail to normalize the vasculature in some preclinical models [15, 16]
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