A Preclinical Murine Model of Hepatic Metastases

Soares, Kevin C.; Foley, Kelly; Olino, Kelly; Leubner, Ashley; Mayo, Skye C.; Jain, Ajay; Jaffee, Elizabeth M.; Schulick, Richard D.; Yoshimura, Kiyoshi; Edil, Barish H.; Li, Zheng

doi:10.3791/51677

Cited by 106 publications

(112 citation statements)

References 12 publications

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“…Intrasplenic injection of cancer cells for modeling hepatic metastases has been described in detail elsewhere (Soares et al, 2014). Briefly, the spleen was divided by placing two ligating clips (Teleflex, #002200) in the center of the spleen, and cells resuspended with 200 μl PBS were slowly injected into the exposed hemispleen.…”

Section: Star Methodsmentioning

confidence: 99%

Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis

Roe

Hwang

Somerville

et al. 2017

Cell

388

387

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Summary Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. In this context, FOXA1-dependent enhancer reprogramming activates a transcriptional program of embryonic foregut endoderm. Collectively, our study implicates enhancer reprogramming, FOXA1 upregulation, and a retrograde developmental transition in PDA metastasis.

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Section: Star Methodsmentioning

confidence: 99%

Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis

Roe

Hwang

Somerville

et al. 2017

Cell

388

387

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“…The cells were maintained in an incubator at 37°C and 5% CO 2 humidified air. Four (n = 4) 5–6 weeks of age male SCID mice (Taconic, NY, USA, #CB17SC-M homozygous) were anesthetized with Isoflurane (Western Medical, CA, USA) and inoculated with 10 × 10 6 Hep3B cells in saline by performing a laparotomy injection in the splenic blood vessels at 9 weeks of age [13]. Mice were housed in an IACUC-compliant facility (under protocol #07–029) as mentioned above but were given standard drinking water.…”

Section: Methodsmentioning

confidence: 99%

Intraperitoneal Injections as an Alternative Method for Micro-CT Contrast Enhanced Detection of Murine Liver Tumors

2019

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Micro-computed tomography (micro-CT) coupled with tissue, or vascular, specific contrast agent has emerged as a powerful tool for detecting and monitoring tumor growth in the liver of murine animals. Intravenous injections of contrast agents can be technically challenging and lead to errors that can considerably influence the outcome of a preclinical study, prompting an alternative method. Here we assessed the effectiveness of intraperitoneal injections of polyiodinated triglycerides emulsions (Fenestra LC) in micro-CT imaging of young SCID (8 weeks) and old BALB/c (48 weeks) mice with xenograft or carcinogen-induced liver tumors, respectively, and determined an optimal acquisition time. Utilizing an intraperitoneal injection is a viable alternative administration route for using Fenestra in detection and quantification of murine liver tumor burden.

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“…An alternative approach that significantly minimizes the development of multi-site metastasis is the intrasplenic injection model. Intrasplenic injection delivers tumor cells via the splenic vein that joins with the superior mesenteric vein to become the portal vein 49,50 . Animals can be monitored for outgrowth of metastatic lesions in the liver because formation of metastases at other sites is rare, and as a result, the animal's overall health is maintained 49,50 .…”

Section: P53mentioning

confidence: 99%

“…Intrasplenic injection delivers tumor cells via the splenic vein that joins with the superior mesenteric vein to become the portal vein 49,50 . Animals can be monitored for outgrowth of metastatic lesions in the liver because formation of metastases at other sites is rare, and as a result, the animal's overall health is maintained 49,50 . However, it is important to note that the intrasplenic model requires splenectomy to avoid splenic tumors 49,50 , a procedure that impacts immune function.…”

Section: P53mentioning

confidence: 99%

“…Animals can be monitored for outgrowth of metastatic lesions in the liver because formation of metastases at other sites is rare, and as a result, the animal's overall health is maintained 49,50 . However, it is important to note that the intrasplenic model requires splenectomy to avoid splenic tumors 49,50 , a procedure that impacts immune function. For example, myocardial ischemia reperfusion injury is characterized by infiltration of Ly6C + monocyte subsets that originate from the spleen and are responsible for phagocytic and proteolytic activity during the wound healing following ischemia 51,52 .…”

Section: P53mentioning

confidence: 99%

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A Portal Vein Injection Model to Study Liver Metastasis of Breast Cancer

Goddard

Fischer

Schedin

2016

JoVE

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Breast cancer is the leading cause of cancer-related mortality in women worldwide. 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. Current rodent models of breast cancer metastasis, including primary tumor cell xenograft and spontaneous tumor models, rarely metastasize to the liver. 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. 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. This model delivers tumor cells to the liver without complications of concurrent metastases in other organs or removal of the spleen. 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. 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. 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. 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.

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A Preclinical Murine Model of Hepatic Metastases

Cited by 106 publications

References 12 publications

Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis

Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis

Intraperitoneal Injections as an Alternative Method for Micro-CT Contrast Enhanced Detection of Murine Liver Tumors

A Portal Vein Injection Model to Study Liver Metastasis of Breast Cancer

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