Abstract
Mouse models of human diseases are an essential part of the translational pipeline. Orthotopic tumour mouse models are increasingly being used in cancer research due to their increased clinical relevance over subcutaneous xenograft models, particularly in relation to metastatic disease. In this study, we have developed orthotopic colorectal cancer liver metastases (CRCLM) and primary cholangiocarcinoma (CCA) models in BALB/c nude mice using minimally invasive ultrasound-guided intrahepatic injection. Due to its minimally invasive nature, the method reduced risk from surgical complications whilst being fast and easy to perform and resulted in measurable tumour volumes 1 to 3 weeks post-injection. Tumour volumes were monitored in vivo by weekly high-frequency ultrasound (HF-US) and/or twice weekly bioluminescence imaging (BLI) and confirmed with end-point histology. Take rates were high for human CRC cells (>73%) and for CCA cells (90%). We have demonstrated that this method reliably induces CRCLM and CCAs, in which tumour volume can be monitored throughout using HF-US and/or BLI. This provides a promising experimental tool for future testing of cancer therapeutics in an orthotopic model.
Highlights
Metastatic cancer is the leading cause of death for patients diagnosed with colorectal cancer (CRC) with a five-year survival of stage-IV disease at diagnosis just 7–8%1
This model has the advantage of producing bile duct obstruction, the development of the model involved invasive surgery and does not utilise human-derived cancer cells
The human colorectal adenocarcinoma cell line, SW620, that was first derived from a lymph node metastasis was used with or without Matrigel in BALB/c nude mice to assess the feasibility of generating colorectal cancer liver metastases (CRCLM)
Summary
Metastatic cancer is the leading cause of death for patients diagnosed with colorectal cancer (CRC) with a five-year survival of stage-IV disease at diagnosis just 7–8%1. Caecal injections are technically more challenging with a higher risk of post-surgical complications, but with the advantage of allowing the study of invasion from the primary site This results in the slow (up to four months) and unreliable formation of metastases in the liver in addition to lung, lymph nodes and peritoneal tumours[10]. Immune compromised or competent mice can be used depending on the cell lines used (patient-derived and/or human xenografts or syngeneic grafts) for testing of cytotoxic or immunotherapies, respectively To this end, we have developed a minimally-invasive method to create orthotopic liver tumours that recapitulate cancers in the liver. TFK-1, an extra-hepatic CCA cell line transfected to express luciferase (TFKLuc2B2), was used for the generation of an orthotopic CCA model which had the advantage of longitudinal tumour growth monitoring using BLI as well as HF-US imaging
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