Metastasis is a multistep process, referred to as the metastatic cascade, which begins with tumor cell dissemination in the primary tumor and ends with patient mortality due to the seeding and outgrowth of circulating tumor cells within a distant organ 13-15. In contrast, breast cancer patients with lung or bone metastasis have median survival rates of 9 to 27.4 months 8,9 and 16.3 to 56 months 8,10-12, respectively. Liver metastasis in breast cancer patients is an independent prognostic factor for very poor outcomes 4,5, as median survival of breast cancer patients with liver metastasis ranges from 4.8 to 15 months 6-9. The liver is a common site of breast cancer metastasis, along with bone and lung 1-3. This model represents an important tool to study breast cancer metastasis to the liver, and may be applicable to other cancers that frequently metastasize to the liver including colorectal and pancreatic adenocarcinomas. Concentrations of ≤ 10,000 cells/injection results in a latency of ~ 20 - 40 days for development of liver metastases with the higher metastatic 4T1 and D2A1 lines, and > 55 days for the less aggressive D2.OR line. The portal vein injection approach in Balb/c female mice using three syngeneic mammary tumor lines of varying metastatic potential was tested high-metastatic 4T1 cells, moderate-metastatic D2A1 cells, and low-metastatic D2.OR cells. The optimized portal vein protocol employs small injection volumes of 5 - 10 μl, ≥ 32 gauge needles, and hemostatic gauze at the injection site to control for blood loss. This model delivers tumor cells to the liver without complications of concurrent metastases in other organs or removal of the spleen. To address the need for improved liver metastasis models, a murine portal vein injection method that delivers tumor cells firstly and directly to the liver was developed. Intracardiac and intrasplenic injection models do result in liver metastases, however these models can be confounded by concomitant secondary-site metastasis, or by compromised immunity due to removal of the spleen to avoid tumor growth at the injection site. Current rodent models of breast cancer metastasis, including primary tumor cell xenograft and spontaneous tumor models, rarely metastasize to the liver. Liver metastasis is involved in upwards of 30% of cases with breast cancer metastasis, and results in poor outcomes with median survival rates of only 4.8 - 15 months. Breast cancer is the leading cause of cancer-related mortality in women worldwide.
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