Hypoxia- inducible factor 1 is a master regulator of breast cancer metastatic niche formation

Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, and Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2011; 108(39):16369-74. DOI: 10.1073/pnas.1113483108
Source: PubMed


Primary tumors facilitate metastasis by directing bone marrow-derived cells (BMDCs) to colonize the lungs before the arrival of cancer cells. Here, we demonstrate that hypoxia-inducible factor 1 (HIF-1) is a critical regulator of breast cancer metastatic niche formation through induction of multiple members of the lysyl oxidase (LOX) family, including LOX, LOX-like 2, and LOX-like 4, which catalyze collagen cross-linking in the lungs before BMDC recruitment. Only a subset of LOX family members was expressed in any individual breast cancer, but HIF-1 was required for expression in each case. Knockdown of HIF-1 or hypoxia-induced LOX family members reduced collagen cross-linking, CD11b(+) BMDC recruitment, and metastasis formation in the lungs of mice after orthotopic transplantation of human breast cancer cells. Metastatic niche formation is an HIF-1-dependent event during breast cancer progression.

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Available from: Denis Wirtz, Oct 07, 2015
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    • "Other groups have also suggested the involvement of extracellular LOXL2 in metastasis of breast and other tumor types (Barry-Hamilton et al, 2010; Barker et al, 2011; Wong et al, 2014). Additionally, different members of the LOX family, highlighting LOX and LOXL2, have been involved in pre-metastatic niche formation (Erler et al, 2009; Wong et al, 2011, 2014; Canesin et al, 2015), an event presently considered essential for tumor cell homing and micrometastasis (Psaila & Lyden, 2009). Despite the increasing evidence supporting multiple LOXL2 roles in tumorigenesis and metastasis , the mechanistic bases of these pathological functions and their relevance for future therapeutic interventions have not been fully established . "
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    ABSTRACT: Lysyl oxidase-like 2 (LOXL2) is involved in a wide range of physiological and pathological processes, including fibrosis and tumor progression, implicating intracellular and extracellular functions. To explore the specific in vivo role of LOXL2 in physiological and tumor contexts, we generated conditional gain- and loss-of-function mouse models. Germ-line deletion of Loxl2 promotes lethality in half of newborn mice mainly associated to congenital heart defects, while Loxl2 overexpression triggers male sterility due to epididymal dysfunction caused by epithelial disorganization, fibrosis and acute inflammation. Remarkably, when challenged to chemical skin carcinogenesis, Loxl2-overexpressing mice increased tumor burden and malignant progression, while Loxl2-deficient mice exhibit the opposite phenotypes. Loxl2 levels in premalignant tumors negatively correlate with expression of epidermal differentiation markers and components of the Notch1 pathway. We show that LOXL2 is a direct repressor of NOTCH1. Additionally, we identify an exclusive expression pattern between LOXL2 and members of the canonical NOTCH1 pathway in human HNSCC. Our data identify for the first time novel LOXL2 roles in tissue homeostasis and support it as a target for SCC therapy. © 2015 The Authors.
    The EMBO Journal 03/2015; 34(8). DOI:10.15252/embj.201489975 · 10.43 Impact Factor
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    • "Wong et al. (2011) showed a decrease in breast cancer progression with shRNA-mediated knockdown of HIF-1a in MDA- MB-435 and MDA-MB-231 breast cancer cell lines, and in vivo breast cancer model. They suggested using HIF inhibitors as the components of multidrug regimens for breast cancer (Wong et al., 2011). Recently, we were able to show that the chitosan/siRNA or shRNA targeting VEGF nanoplexes have a remarkably suppressive effect on the VEGF expression in breast cancer cells, and in vivo tumor model (Şalva et al., 2010, 2012, 2013; Şalva and Akbuga, 2010). "
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    ABSTRACT: RNA interference (RNAi) holds considerable promise as a novel therapeutic strategy in the silencing of disease-causing genes. The development of effective delivery systems is important for the use of small interfering RNA (siRNA) as therapy. In the present study, we investigated the effect on breast cancer cell lines and the co-delivery of liposomes containing siHIF1-α and siVEGF. In order to achieve the co-delivery of siHIF1-α and siVEGF and to obtain lower cytotoxicity, higher transfection and silencing efficiency, in this study, we used chitosan-coated liposomal formulation as the siRNA delivery system. The obtained particle size and zeta potential values show that the chitosan coating process is an effective parameter for particle size and the zeta potential of liposomes. The liposome formulations loaded with siHIF1-α and siVEGF showed good stability and protected siRNA from serum degradation after 24-h of incubation. The expression level of VEGF mRNA was markedly suppressed in MCF-7 and MDA-MB435 cells transfected with chitosan-coated liposomes containing HIF1-α and VEGF siRNA, respectively (95% and 94%). In vitro co-delivery of siVEGF and siHIF1-α using chitosan-coated liposome significantly inhibited VEGF (89%) and the HIF1-α (62%) protein expression when compared to other liposome formulations in the MDA-MB435 cell. The co-delivery of siVEGF and siHIF1-α was greatly enhanced in the vitro gene silencing efficiency. In addition, chitosan-coated liposomes showed 96% cell viability. Considering the role of VEGF and HIF1-α in breast cancer, siRNA-based therapies with chitosan coated liposomes may have some promises in cancer therapy.
    International Journal of Pharmaceutics 11/2014; 478(1). DOI:10.1016/j.ijpharm.2014.10.065 · 3.65 Impact Factor
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    • "On the other hand, primary tumor-released VEGF can induce MMP-9 on macrophages present in the premetastatic niche, promoting metastasis (Hiratsuka et al., 2002). HIF-1a signaling in primary mammary tumors leads to the induction of members of the lysyl oxidase (LOX) family, preconditioning the lungs for bonemarrow-derived cell recruitment prior to metastatic colonization (Wong et al., 2011). HIF-2a is also expressed in TAMs. "
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    ABSTRACT: The hypoxic response in cells and tissues is mediated by the family of hypoxia-inducible factor (HIF) transcription factors; these play an integral role in the metabolic changes that drive cellular adaptation to low oxygen availability. HIF expression and stabilization in immune cells can be triggered by hypoxia, but also by other factors associated with pathological stress: e.g., inflammation, infectious microorganisms, and cancer. HIF induces a number of aspects of host immune function, from boosting phagocyte microbicidal capacity to driving T cell differentiation and cytotoxic activity. Cellular metabolism is emerging as a key regulator of immunity, and it constitutes another layer of fine-tuned immune control by HIF that can dictate myeloid cell and lymphocyte development, fate, and function. Here we discuss how oxygen sensing in the immune microenvironment shapes immunological response and examine how HIF and the hypoxia pathway control innate and adaptive immunity.
    Immunity 10/2014; 41(4):518-528. DOI:10.1016/j.immuni.2014.09.008 · 21.56 Impact Factor
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