Abstract
BackgroundAldehyde dehydrogenase 1A1 (ALDH1A1), a member of aldehyde dehydrogenase family, is a marker of stemness in breast cancer. During tumor progression cancer stem cells (CSCs) have been reported to secrete angiogenic factors to orchestrate the formation of pathological angiogenesis. This vasculature can represent the source of self-renewal of CSCs and the route for further tumor spreading. The aim of the present study has been to assess whether ALDH1A1 controls the output of angiogenic factors in breast cancer cells and regulates tumor angiogenesis in a panel of in vitro and in vivo models.MethodsStemness status of breast cancer cells was evaluated by the ability to form turmorspheres in vitro. A transwell system was used to assess the angiogenic features of human umbilical vein endothelial cells (HUVEC) when co-cultured with breast cancer cells MCF-7 harboring different levels of ALDH1A1. Under these conditions, we survey endothelial proliferation, migration, tube formation and permeability. Moreover, in vivo, MCF-7 xenografts in immunodeficient mice allow to evaluate blood flow, expression of angiogenic factors and microvascular density (MVD).ResultsIn MCF-7 we observed that ALDH1A1 activity conferred stemness property and its expression correlated with an activation of angiogenic factors. In particular we observed a significant upregulation of hypoxia inducible factor-1α (HIF-1α) and proangiogenic factors, such as vascular endothelial growth factor (VEGF). High levels of ALDH1A1, through the retinoic acid pathway, were significantly associated with VEGF-mediated angiogenesis in vitro. Co-culture of HUVEC with ALDH1A1 expressing tumor cells promoted endothelial proliferation, migration, tube formation and permeability. Conversely, downregulation of ALDH1A1 in MCF-7 resulted in reduction of proangiogenic factor release/expression and impaired HUVEC angiogenic functions. In vivo, when subcutaneously implanted in immunodeficient mice, ALDH1A1 overexpressing breast tumor cells displayed a higher expression of VEGF and MVD.ConclusionIn breast tumors, ALDH1A1 expression primes a permissive microenvironment by promoting tumor angiogenesis via retinoic acid dependent mechanism. In conclusion, ALDH1A1 might be associated to progression and diffusion of breast cancer.
Highlights
Aldehyde dehydrogenase 1A1 (ALDH1A1), a member of aldehyde dehydrogenase family, is a marker of stemness in breast cancer
High levels of aldehyde dehydrogenase 1A1 (ALDH1A1) expression and activity have been proposed as a reliable Cancer stem cells (CSC) marker, since they are associated with cancer stem-like features, as cell self-protection, differentiation, expansion, and therapy resistance [6]
We identify a novel role of ALDH1A1 in some breast tumor cells lines, which, through Retinoic acid receptor (RAR)-dependent vascular endothelial growth factor (VEGF) expression regulates tumor angiogenesis
Summary
Aldehyde dehydrogenase 1A1 (ALDH1A1), a member of aldehyde dehydrogenase family, is a marker of stemness in breast cancer. Angiogenesis is instrumental for metastasis spreading, as it enables tumor cells entry into the circulatory system, and drives the formation of pre-metastatic vascular niche [2] This functional unit contains endothelial cells (ECs), tumor cells and cancer stem cells (CSCs) which express and secrete a number of factors that activate stromal and ECs to grow and migrate, orchestrating the formation of the pathological vascular niches [2,3,4]. The CSC niche, characterized by hypoxia, has been reported to undergo a metabolic switch to a more invasive program [5], and to promote tumor neovascularization by producing high levels of proangiogenic factors such as vascular endothelial growth factor (VEGF), and interleukin 8 (IL-8) In this context, inhibition of EC responsiveness to angiogenic factors, and suppression of proangiogenic phenotype in tumor cells may attenuate aggressiveness of CSCs. characterization of molecular signatures governing the cellular dynamics within these pathological niches may curb tumor burden. We identify a novel role of ALDH1A1 in some breast tumor cells lines, which, through RAR-dependent VEGF expression regulates tumor angiogenesis
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