A transgenic mouse model for the ductal carcinoma in situ (DCIS) of the mammary gland

Schulze-Garg, Christine; Löhler, Jürgen; Gocht, Andreas; Deppert, Wolfgang

doi:10.1038/sj.onc.1203281

Cited by 87 publications

(123 citation statements)

References 42 publications

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“…This implies that the spatial distribution of MMP9 þ cells coincides with collIV disruption in adenocarcinomas from CEACAM1null/ WAP-T mice, and concurs with poor vessel maturation and stabilization. In comparison to hemizygous WAP-T or WAP-T Â CEACAM1 endo þ mice (manuscript in preparation), in which metastases were only occasionally observed, we found a 10-fold increase in pulmonary metastasis of mammary adenocarcinomas in CEACAM1null/WAP-T mice (Schulze-Garg et al, 2000;W Deppert, personal communication). This implies that the frequency of metastasis may be a consequence of the alteration of the vascular phenotype in CEACAM1…”

Section: Ceacam1 Is Required For Vessel Maturationmentioning

confidence: 94%

“…In this report, we compared the effects of transgenic overexpression of endothelial and tumor cell CEA-CAM1 and systemic lack of CEACAM1 on mammary adenocarcinoma vascularization and growth in vitro and in vivo in three transgenic mouse lines: whey-acidic protein promoter-driven large T-antigen driven expression (WAP-T) mice, WAP-T Â CEACAM1 endo þ mice with Tie2-driven overexpression of CEACAM1 and a CEACAM1 À line, CEACAM1null/WAP-T mice (Schulze-Garg et al, 2000;Horst et al, 2006;Leung et al, 2006). WAP-T mice have been characterized previously (Schulze-Garg et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…WAP-T mice have been characterized previously (Schulze-Garg et al, 2000). In brief, tumor development is initiated after involution by the simian virus 40 early gene region under the control of the wheyacidic protein promoter (for details see Heinlein et al (2008) and Wegwitz et al (2010)).…”

Section: Introductionmentioning

confidence: 99%

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CEACAM1 creates a pro-angiogenic tumor microenvironment that supports tumor vessel maturation

et al. 2011

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We have studied the effects of carcinoembryonic antigenrelated cell adhesion molecule 1 (CEACAM1) on tumor angiogenesis in murine ductal mammary adenocarcinomas. We crossed transgenic mice with whey acidic protein promoter-driven large T-antigen expression (WAP-T mice) with oncogene-induced mammary carcinogenesis with CEACAM1null mice, and with Tie2-Ceacam1 transgenics, in which the Tie2 promoter drives endothelial overexpression of CEACAM1 (WAP-T Â CEACAM1 endo þ mice), and analyzed tumor vascularization, angiogenesis and vessel maturation in these mice. Using flat-panel volume computed tomography (fpVCT) and histology, we found that WAP-T Â CEACAM1 endo þ mice exhibited enhanced tumoral vascularization owing to CEACAM1 þ vessels in the tumor periphery, and increased intratumoral angiogenesis compared with controls. In contrast, vascularization of CEACAM1null/WAP-T-derived tumors was poor, and tumor vessels were dilated, leaky and showed poor pericyte coverage. Consequently, the tumoral vasculature could not be visualized in CEACAM1null/WAP-T mice by fpVCT, and we observed poor organization of the perivascular extracellular matrix (ECM), accompanied by the accumulation of collagen IV-degrading matrix metalloproteinase 9 þ (MMP9 þ ) leukocytes and stromal cells. Vascular instability and alterations in ECM structure were accompanied by a significant increase in pulmonary metastases in CEACAM1-null/WAP-T mice, whereas only occasional metastases were observed in CEACAM1 þ hosts. In CEACAM1 þ hosts, intratumoral vessels did not express CEACAM1, but they were intact, extensively covered with pericytes and framed by a well-organized perivascular ECM. MMP9 þ accessory cells were largely absent. Orthotopic transplantation of primary WAP-T-and CEACAM1null/WAP-T tumors into all three mouse lines confirmed that a CEACAM1 þ host environment is a prerequisite for productive angiogenic remodeling of the tumor microenvironment. Hence, CEACAM1 expression in the tumor periphery determines the vascular phenotype in a tumor, whereas systemic absence of CEACAM1 interferes with the formation of an organized tumor matrix and intratumoral vessel maturation.

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Section: Ceacam1 Is Required For Vessel Maturationmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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CEACAM1 creates a pro-angiogenic tumor microenvironment that supports tumor vessel maturation

et al. 2011

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“…19 In these mice, SV40 T-Ag induces the development of mammary carcinoma associated with genomic instability and aneuploidy. 20 Histopathology of such specimens sometimes reveals a highly fresh tissue samples and examined prior to fixation, the majority of cells in the single cell suspension are still able to exclude trypan blue, indicating the integrity of the plasma membrane.…”

Section: Resultsmentioning

confidence: 99%

“…Mammary carcinoma originated from transgenic Balb/c WAP-T mice. 19 H&E staining, pathology and tumor grading was carried out as described elsewhere. 20 All mice were housed and handled in accordance with official regulations for care and use of laboratory animals.…”

Section: Methodsmentioning

confidence: 99%

A rapid and optimization-free procedure allows the in vivo detection of subtle cell cycle and ploidy alterations in tissues by flow cytometry

Heinlein

Deppert

Braithwaite³

et al. 2010

Cell Cycle

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Mammary Gland Cancer

Barkan

Montagna

Ried

et al. 2004

Mouse Models of Human Cancer

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It has been 20 years since the first genetically engineered mouse model of mammary cancer was published (Stewart et al., ) using transgenic technology. Since the first report there have been well over 100 mouse models of mammary cancer developed which have provided critical insights into the functions of numerous genes involved in mammary oncogenesis. Advances in manipulating the mouse genome have provided the technology to induce mammary cancers in mice that arise from genetic mutations that have been identified in human cancer, thus generating models based upon molecular lesions relevant to the human disease. Recent work has focused on validating these models as systems which represent, at least in part, various aspects of the human disease and which may be used for preclinical testing of novel therapies. The challenge remains to establish the predictive value of such models for chemoprevention and therapeutic response for treating human breast cancer.

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A transgenic mouse model for the ductal carcinoma in situ (DCIS) of the mammary gland

Cited by 87 publications

References 42 publications

CEACAM1 creates a pro-angiogenic tumor microenvironment that supports tumor vessel maturation

CEACAM1 creates a pro-angiogenic tumor microenvironment that supports tumor vessel maturation

A rapid and optimization-free procedure allows the in vivo detection of subtle cell cycle and ploidy alterations in tissues by flow cytometry

Mammary Gland Cancer

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