The hypoxia-related signaling pathways of vasculogenic mimicry in tumor treatment

Li, Shuixian; Meng, Wen; Guan, Zhonghong; Guo, Yintong; Han, Xiuzhen

doi:10.1016/j.biopha.2016.03.010

Cited by 80 publications

(47 citation statements)

References 77 publications

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“…As tumor cells grow, their microenvironment becomes increasingly hypoxic. Tumors as small as 1–2 mm in diameter may show signs of hypoxia and may depend on angiogenesis for additional growth [17]. Under hypoxic conditions, a signaling pathway involving the crucial oxygen response regulator hypoxia-inducible factor (HIF) is activated.…”

Section: Discussionmentioning

confidence: 99%

HIF-1α promoted vasculogenic mimicry formation in hepatocellular carcinoma through LOXL2 up-regulation in hypoxic tumor microenvironment

Wang

Zhao

Zhu

et al. 2017

J Exp Clin Cancer Res

170

133

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BackgroundThe incidence and mortality rates of hepatocellular carcinoma (HCC) have steadily increased in recent years. A hypoxic microenvironment is one of the most important characteristics of solid tumors which has been shown to promote tumor metastasis, epithelial-mesenchymal transition and angiogenesis. Epithelial-mesenchymal transition and vasculogenic mimicry have been regarded as crucial contributing factors to cancer progression. HIF-1α functions as a master transcriptional regulator in the adaptive response to hypoxia. Lysyl oxidases like 2 (LOXL2) is a member of the lysyl oxidase family, which main function is to catalyze the covalent cross-linkages of collagen and elastin in the extracellular matrix. Recent work has demonstrated that HIF-1α promotes the expression of LOXL2, which is believed to amplify tumor aggressiveness. LOXL2 has shown to promote metastasis and is correlated with poor prognosis in hepatocellular carcinoma. The purpose of our study is to explore the role of HIF-1α in progression and metastasis of hepatocellular carcinoma by promoting the expression of LOXL2 as well as the potential regulatory mechanism.MethodsHIF-1α, LOXL2 expression and CD31/periodic acid-Schiff double staining in HCC patient samples were examined by immunohistochemical staining. shRNA plasmids against HIF-1α was used to determine whether LOXL2 been increased by HIF-1α. We monitored a series of rescue assays to demonstrate our hypothesis that LOXL2 is required and sufficient for HIF-1α induced EMT and VM formation, which mediates cellular transformation and takes effect in cellular invasion. Then we performed GeneChip® Human Transcriptome Array (HTA) 2.0 in HepG2 cells, HepG2 cells overexpressed LOXL2 and HepG2 cells treated with CoCl2.ResultsIn clinical HCC tissues, it confirmed a positive relationship between HIF-1α and LOXL2 protein. Importantly, HIF-1α and LOXL2 high expression and the presence of vasculogenic mimicry were correlated to poor prognosis. HIF-1α was found to induce EMT, HCC cell migration, invasion and VM formation by regulating LOXL2. The results of microarray assays were analyzed.ConclusionHIF-1α plays an important role in the development of HCC by promoting HCC metastasis, EMT and VM through up-regulating LOXL2. This study highlights the potential therapeutic value of targeting LOXL2 for suppression of HCC metastasis and progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0533-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

HIF-1α promoted vasculogenic mimicry formation in hepatocellular carcinoma through LOXL2 up-regulation in hypoxic tumor microenvironment

Wang

Zhao

Zhu

et al. 2017

J Exp Clin Cancer Res

170

133

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“…Hypoxic states occur in tumors, including glioblastomas, when uncontrolled cell proliferation outpaces the available oxygen supply, leading to intratumoral necrosis23. Tumor hypoxia is associated with metastases4, recurrences5 and resistance to chemotherapy and radiation therapy678.…”

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confidence: 99%

Hypoxia induces H19 expression through direct and indirect Hif-1α activity, promoting oncogenic effects in glioblastoma

Nie

et al. 2017

Sci Rep

105

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H19 expression is elevated in many human tumors including glioblastomas, suggesting an oncogenic role for the long noncoding RNA; yet the upregulation of H19 in glioblastomas remains unclear. Here we report that hypoxia significantly stimulated H19 expression in glioblastoma cell lines, which was related to hypoxia-inducible factors 1α (Hif-1α). Hif-1α promoted H19 expression in U87 and U251 cells. Meanwhile PTEN is an advantageous factor to affect H19 expression, through attenuating Hif-1α stability. Hif-1α also positively correlates with H19 in human glioblastoma samples depending on PTEN status. ChIP and luciferase reporter assays showed that Hif-1α induced H19 transcription through directly binding to the H19 promoter. Furthermore, Hif-1α upregulated specific protein 1 (SP1) expression in glioblastomas cells in vitro and in vivo, and SP1 also strongly interacted with the H19 promoter to promote H19 expression under hypoxia. We also showed that H19 acts as a molecular sponge that binds miR-181d, relieving inhibition of β-catenin expression. Therefore, H19 participates in hypoxia-driven migration and invasion in glioblastoma cells. In summary, our results uncover the mechanisms that stimulate H19 expression under hypoxia to promote malignant effects in glioblastomas and suggest H19 might be a promising therapeutic target.

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“…One proposed alternative mechanism, independent of the formation of endothelial vessels, is vasculogenic mimicry (VM) which describes the ability of tumor cells with "stemness" characteristics to independently form vascular networks and to promote invasion and metastatic potential (70). The main stimulus for VM is hypoxia and the process resembles epithelial-to-mesenchymal transition (EMT), since the tumor cells with stem-like plasticity adopt endothelial characteristics (71).…”

Section: Discussionmentioning

confidence: 99%

Targeting angiogenesis in small cell lung cancer

Stratigos

Matikas

Voutsina

et al. 2016

Transl. Lung Cancer Res.

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Small cell lung cancer (SCLC) is a highly aggressive and lethal malignancy. Despite high initial response rates to systemic chemotherapy, the disease eventually relapses; further treatment only modestly improves outcomes and overall survival (OS) for patients with extensive stage disease is less than one year.Little progress has been made during the past decades, with no new drugs approved. Consequently, the development of novel strategies is an unmet need. The inhibition of angiogenesis, a defining characteristic of cancer, has demonstrated modest efficacy in several human malignancies, including non-small cell lung cancer (NSCLC). However, results from clinical trials in SCLC have been disappointing, and no anti-angiogenic agent has received regulatory approval due to lack of clinical efficacy. The elucidation of underlying mechanisms responsible for tumor resistance to angiogenic therapy and the simultaneous blockade of multiple elements that play a role in angiogenesis need to be further explored.

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The hypoxia-related signaling pathways of vasculogenic mimicry in tumor treatment

Cited by 80 publications

References 77 publications

HIF-1α promoted vasculogenic mimicry formation in hepatocellular carcinoma through LOXL2 up-regulation in hypoxic tumor microenvironment

HIF-1α promoted vasculogenic mimicry formation in hepatocellular carcinoma through LOXL2 up-regulation in hypoxic tumor microenvironment

Hypoxia induces H19 expression through direct and indirect Hif-1α activity, promoting oncogenic effects in glioblastoma

Targeting angiogenesis in small cell lung cancer

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