Changes in intratumor heterogeneity in blood perfusion in intradermal human melanoma xenografts during tumor growth assessed by DCE-MRI

The purpose of this study was to use dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to search for systematic intratumor heterogeneity in blood perfusion in human melanoma xenografts growing intradermally in BALB/c-nu/nu mice. Six xenografted tumors of an amelanotic human melanoma line (A-07) were included in the study. DCE-MRI was performed daily for 5 days by using spoiled-gradient recalled sequences. Tumor images of E.F (E is initial extraction fraction and F is perfusion) were produced by subjecting DCE-MRI data to Kety analysis. E.F was used as a measure of tumor blood perfusion, since comparative studies have shown that E.F is closely related to blood perfusion in A-07 tumors. The E.F images indicated that the intratumor heterogeneity in blood perfusion was similar in all investigated tumors. The blood perfusion was low in the center of the tumors and increased toward the tumor periphery in the dorsal and ventral direction by a factor of 3-4, but not in the lateral and medial direction. The magnitude of the heterogeneity increased by a factor of approximately 2 during tumor growth. In conclusion, intradermal human melanoma xenografts show significant systematic intratumor heterogeneity in blood perfusion.     

Assessment of extravascular extracellular space fraction in human melanoma xenografts by DCE-MRI and kinetic modeling

Tumor aggressiveness and response to therapy are influenced by the extravascular extracellular space fraction (EESF) of the malignant tissue. The EESF may, therefore, be an important prognostic parameter for cancer patients. The aim of this study was to investigate whether gadopentetate dimeglumine (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to assess the EESF of tumors. Amelanotic human melanoma xenografts (A-07, R-18) were used as preclinical models of human cancer. Images of E.F (E is the initial extraction fraction of Gd-DTPA and F is perfusion) and lambda (the partition coefficient of Gd-DTPA) were obtained by Kety analysis of DCE-MRI data. Our study was based on the hypothesis that lambda is governed by the EESF and is not influenced significantly by microvascular density (MVD) or blood perfusion. To test this hypothesis, we searched for correlations between lambda and E.F, MVD or EESF by comparing lambda images with E.F images, histological preparations from the imaged tissue and the radial heterogeneity in EESF obtained by invasive imaging. Positive correlations were found between lambda and EESF. Thus, median lambda was larger in A-07 tumors than in R-18 tumors by a factor of 4.2 (P<.00001), consistent with the histological observation that EESF is approximately fourfold larger in A-07 tumors than in R-18 tumors. The radial heterogeneity in lambda in A-07 and R-18 tumors was almost identical to the radial heterogeneity in EESF. Moreover, lambda was larger in tissue regions with high EESF than in tissue regions with low EESF in A-07 tumors (P=.048). On the other hand, significant correlations between lambda and MVD or E.F could not be detected. Consequently, Kety analysis of Gd-DTPA-based DCE-MRI series of xenografted tumors provides lambda images that primarily reflect the EESF of the tissue.