How can grafted breast cancer models be optimized?

Mollard, Séverine; Mousseau, Yoanne; Baaj, Yasser; Richard, Laurence; Cook-Moreau, Jeanne; Monteil, Jacques; Funalot, Benoît; Sturtz, Franck

doi:10.4161/cbt.12.10.18139

Cited by 33 publications

(28 citation statements)

References 118 publications

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“…Mortality in human breast cancer patients is mainly due to metastasis into distant organs, commonly bone, lung, liver and brain . As already shown for different monotransgenic WAP‐T mouse lines, induced NP8 mice rarely developed metastases, mostly in the lungs .…”

Section: Resultsmentioning

confidence: 74%

Mutant p53 promotes epithelial‐mesenchymal plasticity and enhances metastasis in mammary carcinomas of WAP‐T mice

Lenfert

Maenz

Heinlein

et al. 2014

Intl Journal of Cancer

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To study the postulated mutant p53 (mutp53) "gain of function" effects in mammary tumor development, progression and metastasis, we crossed SV40 transgenic WAP-T mice with mutant p53 transgenic WAP-mutp53 mice. Compared to tumors in monotransgenic WAP-T mice, tumors in bitransgenic WAP-T x WAP-mutp53 mice showed higher tumor grading, enhanced vascularization, and significantly increased metastasis. Bitransgenic tumors revealed a gene signature associated with the oncogenic epithelial-mesenchymal transition pathway (EMT gene signature). In cultures of WAP-T tumor-derived G-2 cancer cells, which are comprised of subpopulations displaying "mesenchymal" and "epithelial" phenotypes, this EMT gene signature was associated with the "mesenchymal" compartment. Furthermore, ectopic expression of mutp53 in G-2 cells sufficed to induce a strong EMT phenotype. In contrast to these in vitro effects, monotransgenic and bitransgenic tumors were phenotypically similar suggesting that in vivo the tumor cell phenotype might be under control of the tumor microenvironment. In support, orthotopic transplantation of G-2 cells as well as of G-2 cells expressing ectopic mutp53 into syngeneic mice resulted in tumors with a predominantly epithelial phenotype, closely similar to that of endogenous primary tumors. We conclude that induction of an EMT gene signature by mutp53 in bitransgenic tumors primarily promotes tumor cell plasticity, that is, the probability of tumor cells to undergo EMT processes under appropriate stimuli, thereby possibly increasing their potential to disseminate and metastasize.

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Section: Resultsmentioning

confidence: 74%

Mutant p53 promotes epithelial‐mesenchymal plasticity and enhances metastasis in mammary carcinomas of WAP‐T mice

Lenfert

Maenz

Heinlein

et al. 2014

Intl Journal of Cancer

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“…Our results suggest that the ability to control or block crosstalk between the S1P and PDGF-B pathways may be particularly useful in antiangiogenic and/or anti-atherosclerotic treatments since VSMC migration represents an important pathophysiological step for both. The Walker 256 model of breast cancer presents several advantages [35]. It is a highly vascularized orthotopic model of a superficial tumor (breast), and grows in immunocompetent animals.…”

Section: Discussionmentioning

confidence: 99%

Fingolimod potentiates the effects of sunitinib malate in a rat breast cancer model

Mousseau

Mollard

Durand

et al. 2011

Breast Cancer Res Treat

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Most of the antiangiogenic strategies used in oncology principally target endothelial cells through the vascular endothelial growth factor (VEGF) pathway. Multiple kinase inhibitors can secondarily reduce mural cell stabilization of the vessels by blocking platelet-derived growth factor receptor (PDGFR) activity. However, sphingosine-1-phosphate (S1P), which is also implicated in mural cell recruitment, has yet to be targeted in clinical practice. We therefore investigated the potential of a simultaneous blockade of the PDGF and S1P pathways on the chemotactic responses of vascular smooth muscle cells (VSMCs) and the resulting effects of this blockade on breast tumor growth. Due to crosstalk between the S1P and PDGF pathways, we used AG1296 and/or VPC-23019 to inhibit PDGFR-β and S1PR1/S1PR3 receptors, respectively. We showed that S1PR1 and S1PR3 are the principal receptors that mediate the S1P chemotactic signal on rat VSMCs and that they act synergistically with PDGFR-β during PDGF-B signaling. We also showed that simultaneous blockade of the PDGFR-β and S1PR1/S1PR3 signals had a synergistic effect, decreasing VSMC migration velocity toward endothelial cell and breast carcinoma cell-secreted cytokines by 65-90%. This blockade also strongly decreased the ability of VSMCs to form a three-dimensional cell network. Similar results were obtained with the combination of sunitinib malate (a VEGFR/PDGFR kinase inhibitor) and fingolimod (an S1P analog). Sunitinib malate is a clinically approved cancer treatment, whereas fingolimod is currently indicated only for treatment of multiple sclerosis. Orally administered, the combination of these drugs greatly decreased rat breast tumor growth in a syngeneic cancer model (Walker 256). This bi-therapy did not exert cumulative toxicity and histological analysis of the tumors revealed normalization of the tumor vasculature. The simultaneous blockade of these signaling pathways with sunitinib malate and fingolimod may provide an effective means of reducing tumor angiogenesis, and may improve the delivery of other chemotherapies.

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“…However, M5 cells did not produce tumours in mice in our conditions, and were less invasive in vitro than M25 cells. A successful tumourigenic in vivo assay depends on several aspects: the site of injection, cell concentration or the need of additional hormonal supplementation . Also, nude mice present T lymphocyte deficiency, but still have an immune response led by B cells and cytokines, as interferons and perforins, which may interfere in tumour development …”

Section: Discussionmentioning

confidence: 99%

Transcriptomic profile reveals molecular events associated to focal adhesion and invasion in canine mammary gland tumour cell lines

Cordeiro

Xavier

Rochetti

et al. 2017

Vet Comparative Oncology

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The prevalence of cancer in animals has increased significantly over the years. Mammary tumours are the most common neoplasia in dogs, in which around 50% are presented in the malignant form. Hence, the development and characterization of in vitro models for the study of canine tumours are important for the improvement of cancer diagnosis and treatment. Thus, the aim of this study was to characterize cell lines derived from canine mammary gland neoplasias which could be further used for basic and applied oncology research. Samples of canine mammary carcinomas were taken for cell culture and 2 cell lines were established and characterized in terms of cell morphology, tumourigenicity and global gene expression. Both cell lines presented spindle-shape morphology and shown common malignant features as in vitro invasion potential and expression of epithelial and mesenchymal proteins. Also, we found gene expression patterns between the 2 cell cultures in comparison to the normal mammary gland tissue. Cells from M25 culture showed a higher invasion and in vivo tumourigenic potential, associated to the overexpression of genes involved in focal adhesion and extracellular matrix communication, such as FN1, ITGA8 and THBS2. The phenotypic characterization of these cells along with their global gene expression profile potentially determine new therapeutic targets for mammary tumours.

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How can grafted breast cancer models be optimized?

Cited by 33 publications

References 118 publications

Mutant p53 promotes epithelial‐mesenchymal plasticity and enhances metastasis in mammary carcinomas of WAP‐T mice

Mutant p53 promotes epithelial‐mesenchymal plasticity and enhances metastasis in mammary carcinomas of WAP‐T mice

Fingolimod potentiates the effects of sunitinib malate in a rat breast cancer model

Transcriptomic profile reveals molecular events associated to focal adhesion and invasion in canine mammary gland tumour cell lines

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