A spontaneously metastatic model of bladder cancer: imaging characterization (original) (raw)
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Optimized Mouse Model for the Imaging of Tumor Metastasis upon Experimental Therapy
PLoS ONE, 2011
Development of new cancer treatments focuses increasingly on the relation of cancer tissue with its microenvironment. A major obstacle for the development of new anti-cancer therapies has been the lack of relevant animal models that would reproduce all the events involved in disease progression from the early-stage primary tumor until the development of mature metastatic tissue. To this end, we have developed a readily imageable mouse model of colorectal cancer featuring highly reproducible formation of spontaneous liver metastases derived from intrasplenic primary tumors. We optimized several experimental variables, and found that the correct choice of cell line and the genetic background, as well as the age of the recipient mice, were critical for establishing a useful model system. Among a panel of colorectal cancer cell lines tested, the epithelial carcinoma HT29 line was found to be the most suitable in terms of producing homogeneous tumor growth and metastases. In our hands, SCID mice at the age of 125 days or older were the most suitable in supporting consistent HT29 tumor growth after splenic implantation followed by reproducible metastasis to the liver. A magnetic resonance imaging (MRI) protocol was optimized for use with this mouse model, and demonstrated to be a powerful method for analyzing the antitumor effects of an experimental therapy. Specifically, we used this system to with success to verify by MRI monitoring the efficacy of an intrasplenically administered oncolytic adenovirus therapy in reducing visceral tumor load and development of liver metastases. In summary, we have developed a highly optimized mouse model for liver metastasis of colorectal cancer, which allows detection of the tumor load at the whole body level and enables an accurate timing of therapeutic interventions to target different stages of cancer progression and metastatic development.
Academic Radiology, 2013
Rationale and Objectives: Liver is a common site for distal metastases in colon and rectal cancer. Numerous clinical studies have analyzed the relative merits of different imaging modalities for detection of liver metastases. Several exciting new therapies are being investigated in preclinical models. But, technical challenges in preclinical imaging make it difficult to translate conclusions from clinical studies to the preclinical environment. This study addresses the technical challenges of preclinical magnetic resonance imaging (MRI) and micro-computed tomography (CT) to enable comparison of state-of-the-art methods for following metastatic liver disease.
International Journal of Molecular Imaging, 2014
Metastatic spread is the leading cause of death from cancer. Early detection of cancer at primary and metastatic sites by noninvasive imaging modalities would be beneficial for both therapeutic intervention and disease management. Noninvasive imaging modalities such as bioluminescence (optical), positron emission tomography (PET)/X-ray computed tomography (CT), and magnetic resonance imaging (MRI) can provide complementary information and accurately measure tumor growth as confirmed by histopathology. Methods. We validated two metastatic tumor models, MDA-MD-231-Luc and B16-F10-Luc intravenously injected, and 4T1-Luc cells orthotopically implanted into the mammary fat pad. Longitudinal whole body bioluminescence imaging (BLI) evaluated metastasis, and tumor burden of the melanoma cell line (B16-F10-Luc) was correlated with (PET)/CT and MRI. In addition, ex vivo imaging evaluated metastasis in relevant organs and histopathological analysis was used to confirm imaging. Results. BLI revealed successful colonization of cancer cells in both metastatic tumor models over a 4-week period. Furthermore, lung metastasis of B16-F10-Luc cells imaged by PET/CT at week four showed a strong correlation ( 2 = 0.9) with histopathology. The presence and degree of metastasis as determined by imaging correlated ( 2 = 0.7) well with histopathology findings. Conclusions. We validated two metastatic tumor models by longitudinal noninvasive imaging with good histopathology correlation.
Cancer Research, 2009
The metastatic cell population, ranging from solitary cells to actively growing metastases, is heterogeneous and unlikely to respond uniformly to treatment. However, quantification of the entire experimental metastatic cell population in whole organs is complicated by requirements of an imaging modality with the large field of view and high spatial resolution necessary to detect both single cells and metastases in the same organ. Thus, it is difficult to assess differential responses of these distinct metastatic populations to therapy. Here, we develop a magnetic resonance imaging (MRI) technique capable of quantifying the full population of metastatic cells in a secondary organ. B16F1 mouse melanoma cells were labeled with micron-sized iron oxide particles (MPIO) and injected into mouse liver via the mesenteric vein. Livers were removed immediately or at day 9 or 11, following doxorubicin or vehicle control treatment, and imaged using a 3T clinical magnetic resonance scanner and custom-built gradient coil. Both metastases (>200 μm) and MPIO-labeled single cells were detected and quantified from MR images as areas of hyperintensity or hypointensity (signal voids), respectively. We found that 1 mg/kg doxorubicin treatment inhibited metastasis growth (n = 11 per group; P = 0.02, t test) but did not decrease the solitary metastatic cell population in the same livers (P > 0.05). Thus, the technique presented here is capable of quickly quantifying the majority of the metastatic cell population, including both growing metastases and solitary cells, in whole liver by MRI and can identify differential responses of growing metastases and solitary cells to therapy.
Cancer Research, 2005
Liver metastasis is a clinically significant contributor to the mortality associated with melanoma, colon, and breast cancer. Preclinical mouse models are essential to the study of liver metastasis, yet their utility has been limited by the inability to study this dynamic process in a noninvasive and longitudinal manner. This study shows that three-dimensional high-frequency ultrasound can be used to noninvasively track the growth of liver metastases and evaluate potential chemotherapeutics in experimental liver metastasis models. Liver metastases produced by mesenteric vein injection of B16F1 (murine melanoma), PAP2 (murine H-ras-transformed fibroblast), HT-29 (human colon carcinoma), and MDA-MB-435/HAL (human breast carcinoma) cells were identified and tracked longitudinally. Tumor size and location were verified by histologic evaluation. Tumor volumes were calculated from the three-dimensional volumetric data, with individual liver metastases showing exponential growth. The importance of volumetric imaging to reduce uncertainty in tumor volume measurement was shown by comparing threedimensional segmented volumes with volumes estimated from diameter measurements and the assumption of an ellipsoid shape. The utility of high-frequency ultrasound imaging in the evaluation of therapeutic interventions was established with a doxorubicin treatment trial. These results show that three-dimensional high-frequency ultrasound imaging may be particularly well suited for the quantitative assessment of metastatic progression and the evaluation of chemotherapeutics in preclinical liver metastasis models. (Cancer Res 2005; 65(12): 5231-7)
Magnetic Resonance in Medicine, 2004
Dynamic contrast-enhanced MRI (DCEMRI) data were acquired from metastatic and nonmetastatic tumors in rodents to follow the uptake and washout of a low-molecular-weight contrast agent (Gd-DTPA) and a contrast agent with higher molecular weight (P792). The concentration vs. time curves calculated for the tumor rims and centers were analyzed using the two-compartment model (TCM) and a newly developed empirical mathematical model (EMM). The EMM provided improved fits to the experimental data compared to the TCM. Parameters derived from the empirical model showed that the contrast agent washout rate was significantly slower in metastatic tumors than in nonmetastatic tumors for both Gd-DTPA (P < 0.03) and P792 (P < 0.04). The effects of the tumor on blood flow in "normal" tissue immediately adjacent to the tumors were evident: Gd-DTPA uptake and washout rates were much lower in muscle near the tumor (P < 0.05) than normal muscle farther from the tumor. The results suggest that accurate fits of DCEMRI data provide kinetic parameters that distinguish between metastatic and relatively benign cancers. In addition, a comparison of the dynamics of Gd-DTPA and P792 provides information regarding the microenvironment of tumors.
Abdominal Imaging, 2010
To compare contrast-enhanced US (CE-US), multidetector-CT (MDCT), 1.5 Tesla MR with extra-cellular (Gd-enhanced) and intracellular (SPIO-enhanced) contrast agents and PET/CT, in the detection of hepatic metastases from colorectal cancer. A total of 34 patients with colo-rectal adenocarcinoma underwent preoperatively CE-US, MDCT, Gd- and SPIO-enhanced MR imaging (MRI), and PET/CT. Each set of images was reviewed independently by two blinded observers. The ROC method was used to analyze the results, which were correlated with surgical findings, intraoperative US, histopathology, and MDCT follow-up. A total of 57 hepatic lesions were identified: 11 hemangiomas, 29 cysts, 1 focal fatty liver, 16 metastases (dimensional distribution: 5/16 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 5 mm; 3/16 between 5 mm and &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;10 mm; 8/16 ≥ 10 mm). Six of 34 patients were classified as positive for the presence of at least one metastasis. Considering all the metastases and those ≥ 10 mm, ROC areas showed no significant differences between Gd- and SPIO-enhanced MRI, which performed significantly better than the other modalities (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Considering the lesions &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;10 mm, ROC areas showed no significant differences between all modalities; however MRI presented a trend to perform better than the other techniques. Considering the patients, ROC areas showed no significant differences between all the modalities; however PET/CT seemed to perform better than the others. Gd- and SPIO-enhanced MRI seem to be the most accurate modality in the identification of liver metastases from colo-rectal carcinoma. PET/CT shows a trend to perform better than the other modalities in the identification of patients with liver metastases.
Journal of Magnetic Resonance Imaging, 2008
Purpose-To test the hypothesis that diffusion-weighted (DW)-PROPELLER (periodically rotated overlapping parallel lines with enhanced reconstruction) MRI provides more accurate liver tumor necrotic fraction (NF) and viable tumor volume (VTV) measurements than conventional DW-SE-EPI (spin echo echo-planar imaging) methods. Materials and Methods-Our institutional Animal Care and Use Committee approved all experiments. In six rabbits implanted with 10 VX2 liver tumors, DW-PROPELLER and DW-SE-EPI scans were performed at contiguous axial slice positions covering each tumor volume. Apparent diffusion coefficient maps of each tumor were used to generate spatially resolved tumor viability maps for NF and VTV measurements. We compared NF, whole tumor volume (WTV), and VTV measurements to corresponding reference standard histological measurements based on correlation and concordance coefficients and the Bland-Altman analysis. Results-DW-PROPELLER generally improved image quality with less distortion compared to DW-SE-EPI. DW-PROPELLER NF, WTV, and VTV measurements were strongly correlated and satisfactorily concordant with histological measurements. DW-SE-EPI NF measurements were weakly correlated and poorly concordant with histological measurements. Bland-Altman analysis demonstrated that DWPROPELLER WTV and VTV measurements were less biased from histological measurements than the corresponding DW-SE-EPI measurements. Conclusion-DW-PROPELLER MRI can provide spatially resolved liver tumor viability maps for accurate NF and VTV measurements, superior to DW-SE-EPI approaches. DWPROPELLER measurements may serve as a noninvasive surrogate for pathology, offering the potential for more accurate assessments of therapy response than conventional anatomic size measurements.