Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RAMesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449: 557-563

Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Nature (Impact Factor: 41.46). 11/2007; 449(7162):557-63. DOI: 10.1038/nature06188
Source: PubMed

ABSTRACT Mesenchymal stem cells have been recently described to localize to breast carcinomas, where they integrate into the tumour-associated stroma. However, the involvement of mesenchymal stem cells (or their derivatives) in tumour pathophysiology has not been addressed. Here, we demonstrate that bone-marrow-derived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumour xenograft. The breast cancer cells stimulate de novo secretion of the chemokine CCL5 (also called RANTES) from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. This enhanced metastatic ability is reversible and is dependent on CCL5 signalling through the chemokine receptor CCR5. Collectively, these data demonstrate that the tumour microenvironment facilitates metastatic spread by eliciting reversible changes in the phenotype of cancer cells.

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Available from: Kornelia Polyak, Sep 28, 2015
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    • "The endosteal [3] [4], mesenchymal [5] [6] and vascular systems [7] have been identified as the main regulating components of the HSC niches, nevertheless the concept of the niche embodies the physical entity of all its single constituents [8]. In the last years, researchers have become more aware of the fact that the niche itself can be a driver for pathogenesis, particularly in bone metastatic disease or leukemia [9] [10]. This has led to a plethora of new investigative approaches to target not only the replicating cancer cells but also their microenvironment [11]. "
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    ABSTRACT: Advances in tissue-engineering have resulted in a versatile tool-box to specifically design a tailored microenvironment for hematopoietic stem cells (HSCs) in order to study diseases that develop within this setting. However, most current in vivo models fail to recapitulate the biological processes seen in humans. Here we describe a highly reproducible method to engineer humanized bone constructs that are able to recapitulate the morphological features and biological functions of the HSC niches. Ectopic implantation of biodegradable composite scaffolds cultured for 4 weeks with human mesenchymal progenitor cells and loaded with rhBMP-7 resulted in the development of a chimeric bone organ including a large number of human mesenchymal cells which were shown to be metabolically active and capable of establishing a humanized microenvironment supportive of the homing and maintenance of human HSCs. A syngeneic mouse-to-mouse transplantation assay was used to prove the functionality of the tissue-engineered ossicles. We predict that the ability to tissue engineer a morphologically intact and functional large-volume bone organ with a humanized bone marrow compartment will help to further elucidate physiological or pathological interactions between human HSCs and their native niches. Copyright © 2015. Published by Elsevier Ltd.
    Biomaterials 08/2015; 61:103 - 114. DOI:10.1016/j.biomaterials.2015.04.057 · 8.56 Impact Factor
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    • "In this regard, some authors proposed the use of MSCs either as a vector for anticancer therapy or as an adjunct treatment for increasing cancer cell susceptibility to chemotherapies [23] [24]. However, both BM-MSCs and ADSCs are also suspected to promote tumor development and progression, as well as recurrence in different cancer types [25] [26] [27]. MSCs in general have controversially been reported to support [26, 28–31] or to suppress [32] [33] [34] cancer cells. "
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    ABSTRACT: Conventional breast cancer extirpation involves resection of parts of or the whole gland, resulting in asymmetry and disfiguration. Given the unsatisfactory aesthetic outcomes, patients often desire postmastectomy reconstructive procedures. Autologous fat grafting has been proposed for reconstructive purposes for decades to restore form and anatomy after mastectomy. Fat has the inherent advantage of being autologous tissue and the most natural-appearing filler, but given its inconsistent engraftment and retention rates, it lacks reliability. Implementation of autologous fat grafts with cellular adjuncts, such as multipotent adipose-derived stem cells (ADSCs), has shown promising results. However, it is pertinent and critical to question whether these cells could promote any residual tumor cells to proliferate, differentiate, or metastasize or even induce de novo carcinogenesis. Thus far, preclinical and clinical study findings are discordant. A trend towards potential promotion of both breast cancer growth and invasion by ADSCs found in basic science studies was indeed not confirmed in clinical trials. Whether experimental findings eventually correlate with or will be predictive of clinical outcomes remains unclear. Herein, we aimed to concisely review current experimental findings on the interaction of mesenchymal stem cells and breast cancer, mainly focusing on ADSCs as a promising tool for regenerative medicine, and discuss the implications in clinical translation.
    Stem cell International 05/2015; 2015. DOI:10.1155/2015/120949 · 2.81 Impact Factor
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    • "All these different models suggest that in solid cancer, tumor growth is an emerging function sustained by a complex network of interactions generating a tumorigenic field. This complex network of interactions includes not only cancer cells, but also non-tumoral cells (fibroblasts, lymphocytes, macrophages, endothelial cells, etc.), altered physiological parameters (hypoxia, acidosis, etc.), and physical components such as the extracellular matrix [44] [45] [46] [47] [48] [49]. However, the critical role of tumor environment does not exclude the existence in the tumor mass of a subset of cancer cells with cancer stem cell features and capable to regrow a tumor in a non-tumoral environment following implantation in immunocompromised animals . "
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