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
  • [Show abstract] [Hide abstract]
    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.
    Oncogene 03/2013; · 8.56 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    Blood 05/2013; · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Antiangiogenic therapy, specially sorafenib, has become the standard of care for patients with advanced hepatocellular carcinoma (HCC), however, the improvement in survival time is not satisfactory. Previous studies have found that, in some circumstances, antiangiogenic therapy promoted tumor metastasis and the mechanistic studies were mainly focus on cancer-cell-autonomous manners. In two experimental metastasis models with tail-vein injection with hepatoma cells and an orthotopic HCC mouse model, we found that pretreatment with two vascular endothelial growth factor receptor (VEGFR) inhibitors, sunitinib and sorafenib, facilitated tumor cell survival in blood stream and promoted lung metastasis from tumors that were subsequently incubated after drug discontinuation, indicating that host response joined into the pro-metastatic effects. An antibody microarray identified that interleukin (IL)-12b was decreased in the peripheral blood of the mice treated with the two VEGFR inhibitors. IL-12b suppression in macrophages and dendritic cells from host organs was found to play a crucial role in treatment-induced metastasis. Supplement with recombinant mouse IL-12b or restoration of IL-12b expression in the host by zoledronic acid, which was previously reported to enhance IL-12 expression in vitro and in vivo, alleviated the metastasis-promoting effects of sunitinib and sorafenib. These studies suggest that host response to VEGFR inhibitors facilitates HCC metastasis and restoration of IL-12b expression could translate into clinical benefits.
    Angiogenesis 05/2013; · 4.41 Impact Factor


Available from