Abstract
BackgroundCancer patients with primary tumors showing extensive hypoxia and highly elevated interstitial fluid pressure (IFP) have poor prognosis. The potential of diffusion-weighted magnetic resonance imaging (DW-MRI) in assessing the hypoxic fraction, IFP, and metastatic propensity of tumors was investigated in this study.MethodsA-07 and R-18 melanoma xenografts were used as general models of human cancer. DW-MRI was performed at 1.5 T, and maps of the apparent diffusion coefficient (ADC) were produced with in-house-made software developed in Matlab. Pimonidazole was used as a hypoxia marker. Tumor cell density and hypoxic fraction were assessed by quantitative analysis of histological sections. IFP was measured with a Millar catheter. Metastatic propensity was determined by examining tumor-bearing mice for pulmonary micrometastases post mortem.ResultsADC decreased with increasing tumor cell density, independent of whether the A-07 and R-18 data were analyzed separately or together. In the A-07 line, ADC decreased with increasing hypoxic fraction and increasing IFP and was lower in metastatic than in nonmetastatic tumors, and in the R-18 line, ADC decreased with increasing hypoxic fraction. There was a strong inverse correlation between ADC and hypoxic fraction as well as between ADC and IFP across the two tumor lines, primarily because low ADC as well as high hypoxic fraction and high IFP were associated with high cell density.ConclusionLow ADC is a potentially useful biomarker of poor prognosis in cancer, since low ADC is mainly a consequence of high cell density, and high cell density may lead to increased hypoxia and interstitial hypertension and, therefore, increased microenvironment-associated metastasis.
Highlights
Cancer patients with primary tumors showing extensive hypoxia and highly elevated interstitial fluid pressure (IFP) have poor prognosis
Altogether, apparent diffusion coefficient (ADC) maps were generated for 35 A-07 and 36 R-18 tumors, IFP and HFPim were measured in 39 A-07 and 38 R-18 tumors, and cell density was determined for 24 A-07 and 22 R-18 tumors
The A-07 tumors showed a median ADC of 1.0 × 10−3 mm2/s, a median IFP of 12 mmHg, a median HFPim of 3.7%, and a median cell density of 1.8 × 105 cells/mm3
Summary
Cancer patients with primary tumors showing extensive hypoxia and highly elevated interstitial fluid pressure (IFP) have poor prognosis. DW-MRI has several potentially useful applications in clinical oncology and is emerging as a powerful tool in the management of cancer patients. This tool is currently being used to distinguish malignant from benign lesions, to differentiate post-therapeutic changes from residual tumor tissue, to detect recurrent tumors, lymph node involvement, and distant metastases, and to predict and monitor response to treatment [3,4,5]. Several studies have suggested that high pretreatment ADC values are indicative of poor response to treatment, possibly because of an association between tumor hypoxia and necrosis [8,9]
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