Seeding and Propagation of Untransformed Mouse Mammary Cells in the Lung

Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Science (Impact Factor: 33.61). 09/2008; 321(5897):1841-4. DOI: 10.1126/science.1161621
Source: PubMed


The acquisition of metastatic ability by tumor cells is considered a late event in the evolution of malignant tumors. We report that untransformed mouse mammary cells that have been engineered to express the inducible oncogenic transgenes MYC and Kras(D12), or polyoma middle T, and introduced into the systemic circulation of a mouse can bypass transformation at the primary site and develop into metastatic pulmonary lesions upon immediate or delayed oncogene induction. Therefore, previously untransformed mammary cells may establish residence in the lung once they have entered the bloodstream and may assume malignant growth upon oncogene activation. Mammary cells lacking oncogenic transgenes displayed a similar capacity for long-term residence in the lungs but did not form ectopic tumors.

Download full-text


Available from: Nancy Du, Jan 14, 2014
  • Source
    • "Many of these genes have been validated in vivo by demonstrating that in complex genetically altered mice known to develop metastatic cancer, the loss of expression of a metastatic modifier decreases penetrance of a metastatic phenotype (recent examples include urokinase [Almholt et al. 2005], caveolin 1 [Williams et al. 2004 [Williams et al. , 2005, flotillin-2 [Berger et al. 2012], tetraspanin CD151 [Copeland et al. 2012], Elf5 [Chakrabarti et al. 2012], macrophage inhibitory cytokine-1 [Husaini et al. 2012], breast cancer metastasis suppressor 1 [Cook et al. 2012], KiSS1 [Cho et al. 2012], and Nm22 [Marino et al. 2012]). On the other hand, there is evidence suggesting that both dissemination and colonization at the ectopic site can be determined by the same genes that drive growth of the primary tumor (Husemann et al. 2008; Podsypanina et al. 2008a; Rhim et al. 2012). "

    Preview · Article · Feb 2016
  • Source
    • "Podsypanina et al. [33] used breast cancer metastasis model to study whether mammary gland cell in situ could be induced for metastasis when there was no oncogene-driven change in the primary site. Zeng et al. [34] evaluated the therapeutic effect by the combination of rapamycin and cyclophosphamide in MDA-MB-231 nude mice transplanted tumor model and used BLI to monitor tumor growth and metastasis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Optical molecular imaging, a new medical imaging technique, is developed based on genomics, proteomics and modern optical imaging technique, characterized by non-invasiveness, non-radiativity, high cost-effectiveness, high resolution, high sensitivity and simple operation in comparison with conventional imaging modalities. Currently, it has become one of the most widely used molecular imaging techniques and has been applied in gene expression regulation and activity detection, biological development and cytological detection, drug research and development, pathogenesis research, pharmaceutical effect evaluation and therapeutic effect evaluation, and so forth, This paper will review the latest researches and application progresses of commonly used optical molecular imaging techniques such as bioluminescence imaging and fluorescence molecular imaging.
    Full-text · Article · Feb 2014
  • Source
    • "By turning on expression of a tetracycline-responsive transgene in the adult mouse, one can avoid potential complications caused by overexpression of the oncogene or by Cre recombinase-mediated removal of a LOXP-flanked cassette during development; likewise, expression can then be turned off after tumour formation to investigate the possibility of regression and recurrence. It should be noted that a TetON-PyV mT mouse strain has been reported which is sensitive to inducible mammary tumour progression in the presence of the MMTV-rtTA transgene; however, PyV mT is not coupled to Cre recombinase in this case [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Effective in vivo models of breast cancer are crucial for studying the development and progression of the disease in humans. We sought to engineer a novel mouse model of polyomavirus middle T antigen (PyV mT)-mediated mammary tumorigenesis in which inducible expression of this well-characterized viral oncoprotein is coupled to Cre recombinase (TetO-PyV mT-IRES-Cre recombinase or MIC). MIC mice were crossed to the mouse mammary tumor virus (MMTV)-reverse tetracycline transactivator (rtTA) strain to generate cohorts of virgin females carrying one or both transgenes. Experimental (rtTA/MIC) and control (rtTA or MIC) animals were administered 2 mg/mL doxycycline beginning as early as 8 weeks of age and monitored for mammary tumor formation, in parallel with un-induced controls of the same genotypes. Of the rtTA/MIC virgin females studied, 90% developed mammary tumors with complete penetrance to all glands in response to doxycycline and a T50 of 7 days post-induction, while induced or un-induced controls remained tumor-free after 1 year of induction. Histological analyses of rtTA/MIC mammary glands and tumors revealed that lesions followed the canonical stepwise progression of PyV mT tumorigenesis, from hyperplasia to mammary intraepithelial neoplasia/adenoma, carcinoma, and invasive carcinoma that metastasizes to the lung; at each of these stages expression of PyV mT and Cre recombinase transgenes was confirmed. Withdrawal of doxycycline from rtTA/MIC mice with end-stage mammary tumors led to rapid regression, yet animals eventually developed PyV mT-expressing and -non-expressing recurrent masses with varied tumor histopathologies. We have successfully created a temporally regulated mouse model of PyV mT-mediated mammary tumorigenesis that can be used to study Cre recombinase-mediated genetic changes simultaneously. While maintaining all of the hallmark features of the well-established constitutive MMTV-PyV mT model, the utility of this strain derives from the linking of PyV mT and Cre recombinase transgenes; mammary epithelial cells are thereby forced to couple PyV mT expression with conditional ablation of a given gene. This transgenic mouse model will be an important research tool for identifying synthetic viable genetic events that enable PyV mT tumors to evolve in the absence of a key signaling pathway.
    Full-text · Article · Jan 2014 · Breast cancer research: BCR
Show more