title: DW-MRI in assessment of the hypoxic fraction, interstitial fluid pressure, and metastatic propensity of melanoma xenografts.
abstract: BACKGROUND
  Cancer 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.
  
  
  METHODS
  A-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.
  
  
  RESULTS
  ADC 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.
  
  
  CONCLUSIONS
  Low 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.
authors: Tord
authors: T
authors: Hompland
authors: Christine
authors: C
authors: Ellingsen
authors: Kanthi
authors: K
authors: Galappathi
authors: Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Nydalen, Box 4953, Oslo N-0424, Norway. einar.k.rofstad@rr-research.no.
authors: Einar K
authors: EK
authors: Rofstad
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology* / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays / Q000379:methods