DCE-MRI of Tumor Hypoxia and Hypoxia-Associated Aggressiveness

Abstract

Tumor hypoxia is associated with resistance to treatment, aggressive growth, metastatic dissemination, and poor clinical outcome in many cancer types. The potential of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to assess the extent of hypoxia in tumors has been investigated in several studies in our laboratory. Cervical carcinoma, melanoma, and pancreatic ductal adenocarcinoma (PDAC) xenografts have been used as models of human cancer, and the transfer rate constant (Ktrans) and the extravascular extracellular volume fraction (ve) have been derived from DCE-MRI data by using Tofts standard pharmacokinetic model and a population-based arterial input function. Ktrans was found to reflect naturally occurring and treatment-induced hypoxia when hypoxia was caused by low blood perfusion, radiation responsiveness when radiation resistance was due to hypoxia, and metastatic potential when metastasis was hypoxia-induced. Ktrans was also associated with outcome for patients with locally-advanced cervical carcinoma treated with cisplatin-based chemoradiotherapy. Together, the studies imply that DCE-MRI can provide valuable information on the hypoxic status of cervical carcinoma, melanoma, and PDAC. In this communication, we review and discuss the studies and provide some recommendations as to how DCE-MRI data can be analyzed and interpreted to assess tumor hypoxia.

Assessment of Hypoxic Tissue Fraction and Prediction of Survival in Cervical Carcinoma by Dynamic Contrast-Enhanced MRI

“…The numerical values of the constants in the Lund arterial input function were as follows: A = 5.10 mM, B = 14.2 s −1 , C = 0.99 mM, and D = 0.159 s −1 ( 22 ). Plots of Gd-DTPA concentration versus time and the corresponding model fits for individual voxels in the human tumors have been reported previously ( 22 , 33 ), and illustrate that the quality of the DCE-MRI acquisition and analysis was sufficient to produce good model fits. After DCE-MRI, the patients were treated with concurrent cisplatin-based chemoradiation therapy with curative intent.…”

“…Plots of Gd-DOTA concentration versus time and the corresponding model fits for individual voxels in BK-12, ED-15, HL-16, and LA-19 tumors have been reported previously and illustrate the quality of the DCE-MRI acquisition and analysis ( 12 ). The time resolution was sufficient to produce good model fits using Tofts generalized pharmacokinetic model and the population-based arterial input function, but was too low to measure individual arterial input functions in large arteries within the field of view and for using Tofts extended pharmacokinetic model which includes the contribution from intravascular contrast agent ( 18 , 33 ). Tumors were resected for histological examination immediately after DCE-MRI.…”

A highly annotated database of genes associated with platinum resistance in cancer

“…Hypoxia and the endoplasmic reticulum stress response Hypoxia. Cells in solid tumors are exposed to hypoxic conditions, and extensive hypoxia is correlated with platinum resistance and tumor progression [55]. Hypoxic transcriptional programs are mainly activated by the HIF transcription factors but can also be activated by other stress signaling pathways.…”

Advances in PET and MRI imaging of tumor hypoxia

“…Also, chronic hypoxia, as well as transient changes in pO 2 , are affected not only by oxygen supply (perfusion) but also by a variety of factors, including hemoglobin saturation and vascular architecture. Recently, Gaustad et al showed that the Ktrans parameter derived from DCE-MRI compartmental analysis data is associated with tumor hypoxia in xenograft models of cervical carcinoma, melanoma, and pancreas ( 190 ). We present in Figure 4 an example of multimodality imaging of a patient with head and neck cancer.…”