Restricted Water Diffusion in Diffusion-Weighted Magnetic Resonance Imaging in Pancreatic Cancer is Associated with Tumor Hypoxia

SIMPLE SUMMARY: Pancreatic cancer is characterized by a dense network of connective tissue surrounding clusters of cancer cells, the so-called stroma. This ubiquitous connective tissue impairs the delivery of oxygen to cancer cells. This results in hypoxia, which renders the cancer more aggressive and more resistant to treatment. In the present study, we investigated whether the extent of hypoxia in pancreatic cancer can be predicted by magnetic resonance imaging (MRI), a widely used medical imaging technique. More specifically, we used an MRI sequence which can quantitate the random motion (i.e., diffusion) of water molecules within the cancer tissue, namely diffusion-weighted (DW) MRI. We found that the random motion of water molecules is lower in cancer lesions with high hypoxia compared to those with low hypoxia. The findings from our study imply that DW-MRI can be used to identify pancreatic cancer lesions with high hypoxia which are at high risk for treatment failure. ABSTRACT: Hypoxia is a hallmark of pancreatic cancer (PDAC) due to its compact and extensive fibrotic tumor stroma. Hypoxia contributes to high lethality of this disease, by inducing a more malignant phenotype and resistance to radiation and chemotherapy. Thus, non-invasive methods to quantify hypoxia could be helpful for treatment decisions, for monitoring, especially in non-resectable tumors, or to optimize personalized therapy. In the present study, we investigated whether tumor hypoxia in PDAC is reflected by diffusion-weighted magnetic resonance imaging (DW-MRI), a functional imaging technique, frequently used in clinical practice for identification and characterization of pancreatic lesions. DW-MRI assesses the tissue microarchitecture by measuring the diffusion of water molecules, which is more restricted in highly compact tissues. As reliable surrogate markers for hypoxia, we determined Blimp-1 (B-lymphocyte induced maturation protein), a transcription factor, as well as vascular endothelial growth factor (VEGF), which are up-regulated in response to hypoxia. In 42 PDAC patients, we observed a close association between restricted water diffusion in DW-MRI and tumor hypoxia in matched samples, as expressed by high levels of Blimp-1 and VEGF in tissue samples of the respective patients. In summary, our data show that DW-MRI is well suited for the evaluation of tumor hypoxia in PDAC and could potentially be used for the identification of lesions with a high hypoxic fraction, which are at high risk for failure of radiochemotherapy.