Peering into the aftermath: The inhospitable host?

Sunnybrook Research Institute, Department of Molecular and Cellular Biology, Sunnybrook Health Sciences Centre, Toronto, Canada.
Nature medicine (Impact Factor: 27.14). 10/2010; 16(10):1084-5. DOI: 10.1038/nm1010-1084
Source: PubMed
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    ABSTRACT: In addition to its direct effects on tumor cells, chemotherapy can rapidly activate various host processes that contribute to therapy resistance and tumor regrowth. The host response to chemotherapy consists of changes in numerous cell types and cytokines. Examples include the acute mobilization and tumor homing of pro-angiogenic bone marrow-derived cells, activation of cells in the tumor microenvironment to produce systemic or paracrine factors, and tissue-specific responses that provide a protective niche for tumor cells. All of these factors reduce chemotherapy efficacy, and blocking the host response at various levels may therefore significantly improve treatment outcome. However, before the combination of conventional chemotherapy with agents blocking specific aspects of the host response can be implemented into clinical practice, a better understanding of the molecular mechanisms behind the host response is required.Oncogene advance online publication, 25 March 2013; doi:10.1038/onc.2013.94.
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    ABSTRACT: Resistance of tumour cells to chemotherapy can severely affect the efficacy of this anticancer treatment. The non-tumour cells of the organ in which the tumour resides may aid the emergence of such resistance.
    Nature 12/2010; 468(7324):637-8. · 38.60 Impact Factor
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    ABSTRACT: Host responses to chemotherapy can induce resistance mechanisms that facilitate tumor re-growth. To determine the contribution of bone marrow-derived cells (BMDCs) in this process, we exposed tumor-bearing mice to several chemotherapeutic agents and evaluated the influx and functional contribution of a genetically traceable subpopulation of BMDC (VE-Cad-Cre-EYFP). Treatment of tumor-bearing mice with different chemotherapeutics resulted in a three to ten fold increase in the influx of VE-Cad-Cre-EYFP. This enhanced influx was accompanied by a significant increase in angiogenesis. Expression profile analysis revealed a progressive change in the EYPF population with loss of endothelial markers and increase mononuclear markers. In the tumor at least two specific populations of VE-Cad-Cre-EYFP BMDCs were identified: Gr1(+)/CD11b(+) and Tie2(high)/PECAM(low) cells both located in perivascular areas. A common signature of the EYFP population that exits the bone marrow is an increase in Notch. Inducible inactivation of Notch in the EYFP+ BMDCs impaired homing of these BMDC to the tumor. Importantly, Notch deletion reduced therapy-enhanced angiogenesis and it was associated with increased anti-tumor effect of the chemotherapy. These findings revealed the functional significance of a specific population of supportive BMDCs in response to chemotherapeutics and uncover a new potential strategy to enhance anti-cancer therapy.
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