Mouse Models of Colorectal Cancer and Liver Metastases

Heijstek, MW; Kranenburg, Onno; Rinkes, Inne H.M. Borel

doi:10.1159/000085342

Cited by 99 publications

(84 citation statements)

References 96 publications

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“…This was thus far not achieved in those models which exhibit a far higher resemblance to clinical situations, likely due to their complexity or due to the fact that they involve events that are less dissectible over the often long time period of tumor growth or metastasis formation (34,43,44). The gelatinases are often found to be differentially expressed during physiologic and pathologic processes, such as development, wound healing, and cancer progression (10,45), suggesting that each gelatinase has a particular role in these processes.…”

Section: Discussionmentioning

confidence: 99%

Distinct Functionality of Tumor Cell–Derived Gelatinases during Formation of Liver Metastases

Gerg

Kopitz²,

Schaten³

et al. 2008

Molecular Cancer Research

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The specific spatiotemporal role of the matrix metalloproteinase 2 (MMP-2) and MMP-9 (gelatinase) during metastasis is still under debate. Host cells have been described as major contributors to these MMPs during metastasis. Here, we show strong overexpression of MMP-2 and MMP-9 by tumor cells of clinical liver specimen of recurrent metachronous metastases, leading us to address the importance of tumor cell -derived MMP-2 or MMP-9 during liver metastasis. Thus far, distinction of their roles was impossible due to lack of inhibitors which can act exclusively on tumor cells or distinguish MMP-2 from MMP-9. We therefore used short hairpin RNA interference technology in the well-established syngeneic L-CI.5s lymphoma model, in which we could analyze the time course of experimental liver colonization (arrest/invasion of single tumor cells, outgrowth, and invasion within the parenchyma) in immunocompetent mice and correlate these steps with MMP-2 or MMP-9 expression levels. In parental tumor cells, MMP-9 expression closely correlated with the invasive phases of liver colonization, whereas MMP-2 expression remained unaltered. Specific knockdown of MMP-9 revealed a close correlation between invasion-dependent events and tumor cell -derived MMP-9 expression. In contrast, knockdown of MMP-2 did not significantly alter the metastatic potential of the cells but led to a marked inhibition of metastatic foci growth. These findings explain the efficacy of gelatinase-specific synthetic inhibitors on invasion and growth of tumor cells and attribute distinct functions of MMP-2 and MMP-9 to aspects of liver metastasis. (Mol Cancer Res 2008;6(3):341 -51)

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Section: Discussionmentioning

confidence: 99%

Distinct Functionality of Tumor Cell–Derived Gelatinases during Formation of Liver Metastases

Gerg

Kopitz²,

Schaten³

et al. 2008

Molecular Cancer Research

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“…19 Classically, visualization of apoptosis of ECs was performed using the terminal transferase-mediated dUTP nick end-labeling (TUNEL) method. However, the low sensitivity makes the TUNEL staining method unreliable to identify apoptotic cells.…”

Section: Double Immunolabeling Of Human Endothelial Cell Apoptosismentioning

confidence: 99%

“…As none of the existing mouse models mimics all the characteristics of human CRC, 19 we explored the engraftment of human specimens in nude mice as an alternative with special attention paid to the vascular compartment. The evolution of blood vessels inside the tumors was followed for a month.…”

mentioning

confidence: 99%

Differential transplantability of human endothelial cells in colorectal cancer and renal cell carcinoma primary xenografts

Sanz

Cuesta

Salas

et al. 2009

Laboratory Investigation

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In vivo models of human tumor vasculature are essential for the study of tumor angiogenesis and validation of therapeutic targets. To date, however, few standardized animal models of human tumor angiogenesis have been characterized. It was recently shown that human renal cell and prostate carcinoma primary xenografts, established from biopsy specimens, contained vessels lined mainly by human endothelial cells 1 month after implantation in immunodeficient mice. We selected colorectal cancer (CRC) as a primary xenograft model and studied the response of the vascular compartment to the new microenvironment during the same lapse of time. Immunohistochemical analysis of the origin of endothelial cells demonstrated that, in contrast to the mentioned study, human endothelial cells were rapidly substituted by their murine counterparts (nearly 50% by day 10 after implantation). Apoptotic human endothelial cells could not be detected 10 days after implantation, suggesting that apoptosis is not the mechanism underlying their replacement. Interestingly, host endothelial cells were found to colocalize with human laminin, suggesting a colonization of human vascular basement membranes after human endothelial cell disappearance. To rule out that the differences observed between the fate of human vasculature in the CRC model and those previously reported were because of methodological aspects, we established renal cell carcinoma (RCC) primary xenografts using the same protocol. In clear contrast with CRC xenografts, vasculature within RCC xenografts was mostly of human origin 35 days after implantation. These results support the notion of angiogenic heterogeneity in malignant neoplasms. Elucidation of the molecular mechanisms that determine persistence or disappearance of human endothelial cells in different tumor contexts can help to shed light on the intimate regulation of the angiogenic process.

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“…To date, no in vivo model of CRC has demonstrated predictable and reproducible distant metastatic outgrowth within relevant target organs from an orthotopically-established primary colorectal tumour [2][3][4][5] . The lack of available models has precluded investigations into the route(s) of metastatic spread to distant organs.…”

Section: Resultsmentioning

confidence: 99%

“…Investigations into CRC metastatic routes, however, have been precluded by the lack of availability of relevant in vivo metastatic models of CRC. Indeed, despite the wide availability of xenograft, chemical-induced and genetically-engineered mouse models of CRC [2][3][4][5] , tumours in these models fail to reproducibly metastasize to the regional intestinal lymph nodes and liver-the target organs relevant to human CRC.…”

mentioning

confidence: 99%

Lymph node-independent liver metastasis in a model of metastatic colorectal cancer

Enquist¹,

Good²,

Jubb³

et al. 2014

Nat Commun

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Deciphering metastatic routes is critically important as metastasis is a primary cause of cancer mortality. In colorectal cancer (CRC), it is unknown whether liver metastases derive from cancer cells that first colonize intestinal lymph nodes, or whether such metastases can form without prior lymph node involvement. A lack of relevant metastatic CRC models has precluded investigations into metastatic routes. Here we describe a metastatic CRC mouse model and show that liver metastases can manifest without a lymph node metastatic intermediary. Colorectal tumours transplanted onto the colonic mucosa invade and metastasize to specific target organs including the intestinal lymph nodes, liver and lungs. Importantly, this metastatic pattern differs from that observed following caecum implantation, which invariably involves peritoneal carcinomatosis. Anti-angiogenesis inhibits liver metastasis, yet anti-lymphangiogenesis does not impact liver metastasis despite abrogating lymph node metastasis. Our data demonstrate direct hematogenous spread as a dissemination route that contributes to CRC liver malignancy.

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Mouse Models of Colorectal Cancer and Liver Metastases

Cited by 99 publications

References 96 publications

Distinct Functionality of Tumor Cell–Derived Gelatinases during Formation of Liver Metastases

Distinct Functionality of Tumor Cell–Derived Gelatinases during Formation of Liver Metastases

Differential transplantability of human endothelial cells in colorectal cancer and renal cell carcinoma primary xenografts

Lymph node-independent liver metastasis in a model of metastatic colorectal cancer

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