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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    • "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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    • "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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    • "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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