Selective Killing of Hypoxia-Inducible Factor-1–Active Cells Improves Survival in a Mouse Model of Invasive and Metastatic Pancreatic Cancer

Abstract

Purpose: Pancreatic cancer is characterized by intratumoral hypoxia, early and aggressive local invasion, and metastatic potential. Hypoxia-inducible factor-1 (HIF-1) is the major transcriptional activator of hypoxia-responsive genes and intratumoral hypoxia is associated with increased risk of metastasis. However, the behavior of the cells having HIF-1 activity during the malignant progression in pancreatic cancer has not been tested. Experimental Design: We orthotopically transplanted pancreatic cancer cells stably transfected with a HIF-1-dependent luciferase reporter gene and monitored HIF-1 activity in vivo in control and POP33-treated mice. POP33 is a novel prodrug, which has potential to increase caspase-3 activity and induce apoptosis in HIF-1-active/hypoxic cells. Results: In vivo optical imaging showed that HIF-1 activity proceeded along with local invasion, the peritoneal dissemination, and the liver metastasis. HIF-1-active hypoxic cells were selectively eradicated by POP33. Moreover, selective killing of HIF-1-active hypoxic cells significantly suppressed malignant progression, resulting in a significant improvement in survival rate. Conclusions: These results show that HIF-1-active cells constitute a large proportion of invading and metastatic cells and suggest that eradication of these cells may improve the outcome in advanced pancreatic cancer, a condition for which no effective therapy currently exists.Pancreatic cancer is one of the most lethal solid tumors of the gastrointestinal tract. The high mortality rate of pancreatic cancer is due to the high incidence of metastatic disease at the time of diagnosis, a fulminant clinical course, and the lack of adequate systemic therapies. Peritoneal and extrapancreatic seeding is observed during end-stage pancreatic cancer. Pancreatic cancer is characterized by extensive invasion into surrounding tissues and metastasis to distant organs, even at an early stage. The prognosis of patients is poor (1) and new systemic agents are urgently needed.Intratumoral hypoxia is a major factor contributing to cancer progression (1-4). This situation is exacerbated by the high oxygen demands of rapidly proliferating tumor cells, poor lymphatic drainage resulting in high interstitial pressure, and shunting of blood through immature tumor vasculature (3). The evidence for hypoxia in pancreatic cancers includes their characteristic avascular appearance on computed tomography (5) and low intratumoral oxygen tension measurements (6). Furthermore, the expression of target genes of hypoxia-inducible factor-1 (HIF-1), the major transcription factor activated under hypoxic conditions, is elevated in pancreatic cancers (2, 7-11). They include proangiogenic factors such as vascular endothelial growth factor (VEGF), growth/survival factors such as insulin-like growth factor, and extracellular matrix remodeling proteins such as metalloproteinase-9 (12). Thus, HIF-1 activity may play a crucial role in malignant progression of pancreatic cancers.Orthotopic implantation of h...

Investigation into metastatic processes and the therapeutic effects of gemcitabine on human pancreatic cancer using an orthotopic SUIT‑2 pancreatic cancer mouse model

“…The SUIT-2 orthotopic pancreatic cancer mouse model has been used in other studies for evaluating promising new anticancer agents (14,(17)(18)(19)(20) evaluated the tumor reduction effects by measuring tumor weight in a mouse model. SUIT-2 is reported not only in an orthotopic but also in a subcutaneous model, a peritoneal dissemination model, and a lung metastasis model.…”

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

“…5). Gastric cancer cells leaving the primary tumor are exposed to low oxygen levels in the peritoneal cavity [41]. The binding ability of scirrhous gastric cancer cells is increased by hypoxic (1% O 2 ) conditions in comparison to normoxic (21% O 2 ) conditions.…”

Non-invasive monitoring of hypoxia-inducible factor activation by optical imaging during antiangiogenic treatment in a xenograft model of ovarian carcinoma

“…The subsequent linear increase in the HIF reporter could be explained by a number of interpretations: i) although 9xHRE-luc reporter was strictly silent in OVCAR-3 cells in vitro, we cannot rule out a significant basal activity of the reporter in vivo, ii) compensation of hypoxia by neovascularization once the angiogenic switch is operating and iii) secondary peaks of HIF reporter could be masked by decreased cell viability (necrosis). The reported dynamics of functional HIF reporters monitored by optical imaging were highly variable depending on the tumor model: subcutaneous allograft (26) vs. subcutaneous orthotopic xenograft (24) or our data in subcutaneous xenografts. This variability most probably reflects differences in tumor growth rate and patterns of tumor vascularization.…”

“…Relevance of tumor hypoxia and HIFs in cancer progression has led to the development of HIF-targeting strategies (17,(22)(23)(24) and non-invasive in vivo imaging techniques to monitor intratumoral hypoxia or HIF stabilization or activation (25)(26)(27). In addition to the activation of the HIF pathway as a consequence of tumoral hypoxia, specific genetic lesions lead to the constitutive stabilization of HIF, the paradigm being the inactivation of VHL in clear cell carcinomas and pheochromocytomas (28).…”