Abstract
Hypoxia in solid tumors is associated with treatment resistance and increased metastatic potential. Although hypoxia has been reported in pancreatic cancer patients, there is little direct evidence that this contributes to their overall poor prognosis. To address this, we examined the associations between hypoxia and biological aggression in a series of patient-derived xenografts grown orthotopically. Early passage xenografts were established from 16 patients undergoing surgery for pancreatic cancer and maintained in the pancreas of immune-deprived mice. Hypoxic cells were labeled using the 2-nitroimidazole probe EF5 and stained for immunofluorescence microscopy of tissue sections or as cell suspensions for flow cytometry. Bromodeoxyuridine (BrdUrd) uptake, microvessel density, cleaved caspase-3, and the differentiation markers E-cadherin, cytokeratin 19, and vimentin were analyzed in relation to hypoxia. Orthotopic implants closely resembled the histology of the original surgical samples. The 16 primary xenografts showed a wide range in their growth rates and metastatic potential, reminiscent of the spectrum of behavior seen in the clinic. EF5 labeling, tumor growth rates, and metastatic patterns were highly consistent within replicates, indicating a significant transmissible (genetic or epigenetic) component. Hypoxia was highly correlated with rapid tumor growth, increased BrdUrd uptake, and with spontaneous metastasis formation. mRNA expression analysis showed increased expression of genes involved in cell survival and proliferation in the hypoxic models. The results suggest that hypoxia is a major adverse prognostic factor in pancreatic cancer patients and support the introduction of techniques to measure hypoxia directly in patients and the development of treatment protocols to target hypoxia.
Highlights
Hypoxia occurs in solid tumors when the consumption of oxygen exceeds its delivery by the vascular system [1]
In a recent article describing the genetic evolution of pancreatic cancers, it was suggested that cancer cells adapted to hypoxia could undergo additional genetic changes that enhance metastasis formation [10]
To address the question of whether hypoxia plays an important role in pancreatic cancer patients, we studied a series of early passage xenografts established from pancreatectomy samples and grown orthotopically
Summary
Hypoxia occurs in solid tumors when the consumption of oxygen exceeds its delivery by the vascular system [1]. In most large clinical studies, the outcome is worse for patients with hypoxic tumors, consistent with the long-held idea that hypoxia confers both radiation and chemotherapy resistance [2,3,4]. The hypoxic microenvironment is hostile to cancer cell survival. Hypoxia tolerance can occur due to genetic changes such as p53 loss that enhance cell survival [7], or due to cellular responses to hypoxia, driven, for example, by hypoxiainducible factors (HIF) or the unfolded protein response, that modify gene expression, cell phenotype, and metabolism [8, 9]. In a recent article describing the genetic evolution of pancreatic cancers, it was suggested that cancer cells adapted to hypoxia could undergo additional genetic changes that enhance metastasis formation [10]. Hypoxia might be a cause of genetic change, as well as a consequence
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