Multimodal Imaging of Orthotopic Mouse Model of Endometrial Carcinoma

Abstract

BackgroundOrthotopic endometrial cancer models provide a unique tool for studies of tumour growth and metastatic spread. Novel preclinical imaging methods also have the potential to quantify functional tumour characteristics in vivo, with potential relevance for monitoring response to therapy.MethodsAfter orthotopic injection with luc-expressing endometrial cancer cells, eleven mice developed disease detected by weekly bioluminescence imaging (BLI). In parallel the same mice underwent positron emission tomography–computed tomography (PET-CT) and magnetic resonance imaging (MRI) employing 18F-fluorodeoxyglocose (18F-FDG) or 18F- fluorothymidine (18F-FLT) and contrast reagent, respectively. The mice were sacrificed when moribund, and post-mortem examination included macroscopic and microscopic examination for validation of growth of primary uterine tumours and metastases. PET-CT was also performed on a patient derived model (PDX) generated from a patient with grade 3 endometrioid endometrial cancer.ResultsIncreased BLI signal during tumour growth was accompanied by increasing metabolic tumour volume (MTV) and increasing MTV x mean standard uptake value of the tumour (SUVmean) in 18F-FDG and 18F-FLT PET-CT, and MRI conspicuously depicted the uterine tumour. At necropsy 82% (9/11) of the mice developed metastases detected by the applied imaging methods. 18F-FDG PET proved to be a good imaging method for detection of patient derived tumour tissue.ConclusionsWe demonstrate that all imaging modalities enable monitoring of tumour growth and metastatic spread in an orthotopic mouse model of endometrial carcinoma. Both PET tracers, 18F-FDG and 18F-FLT, appear to be equally feasible for detecting tumour development and represent, together with MRI, promising imaging tools for monitoring of patient-derived xenograft (PDX) cancer models.

Near-Infrared Fluorescent Imaging for Monitoring of Treatment Response in Endometrial Carcinoma Patient-Derived Xenograft Models

“…Interestingly, PDX4 developed a uterine tumor that was clearly depicted on EpCAM-AF680 NIRF images ( Figure 5D), despite the primary tumor sample for that PDX exhibiting low expression of EpCAM on IHC (SI: 4). PDX mice had suspected uterine tumors based on visual inspection of reconstructed 18 F-FDG PET/CT images ( Figure 5A-D, Figure S2). However, in several of the scans from PDX1-3, suspected lesions had standardized uptake values (SUV) below 2.5, which was the threshold used to define tumors in PET images ( Figure 5A-C, Figure S2).…”

“…Thus, PDX models are not only anticipated to capture both the intra-and inter-tumor heterogeneity of endometrial carcinoma, as has been previously demonstrated for breast, lung and pancreatic cancer, but also to faithfully reproduce clinical responses to chemotherapy [16,17]. Critically, orthotopic PDX models, i.e., where primary biopsies are implanted into the organ/microenvironment of origin, are proposed as a superior paradigm of clinical disease compared with subcutaneous PDX [18][19][20]. However, a major caveat of the orthotopic approach, particularly with patient-derived material, is longitudinal and spatio-temporal monitoring of not only disease development and characterization but also for further intervention studies.…”

“…Despite large variations in clinical practice between hospitals, in vivo imaging (including modalities such as transvaginal ultrasound, magnetic resonance imaging (MRI) and computed tomography (CT) with or without positron emission tomography (PET)) play a vital role in both the diagnosis and preoperative risk stratification of endometrial carcinoma patients [21]. Similarly, optical imaging, typically employing bioluminescent reporter genes, have been commonly applied for sensitive, high-throughput imaging of cell line-based xenografts [18,22]. While the use of bioluminescent imaging (BLI) in the development and application of uterine PDXs appears attractive, particularly in comparison to expensive and time-consuming MRI and PET/CT [18], there are caveats.…”

“…Similarly, optical imaging, typically employing bioluminescent reporter genes, have been commonly applied for sensitive, high-throughput imaging of cell line-based xenografts [18,22]. While the use of bioluminescent imaging (BLI) in the development and application of uterine PDXs appears attractive, particularly in comparison to expensive and time-consuming MRI and PET/CT [18], there are caveats. Transduction of bioluminescent reporter genes into primary patient material carries the risk of disrupting the genomic landscape of the selected material.…”

Patient-Derived Xenograft Models for Endometrial Cancer Research

“…It is a form of quantitative whole-body imaging used for the in vivo monitoring of biological processes, such as enzymatic reactions, cellular metabolism, and cell proliferation and migration [41], which makes it an ideal tool for the imaging of cancer [32,42]. …”