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Hypoxia-Inducible MiR-210 Is an Independent Prognostic Factor and Contributes to Metastasis in Colorectal Cancer  [PDF]
Ailin Qu, Lutao Du, Yongmei Yang, Hui Liu, Juan Li, Lili Wang, Yimin Liu, Zhaogang Dong, Xin Zhang, Xiumei Jiang, Haiyan Wang, Zewu Li, Guixi Zheng, Chuanxin Wang
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0090952
Abstract: MicroRNA-210 (miR-210), the master hypoxamir, plays pleiotropic roles in certain cancers; however, its role in the development of human colorectal cancer remains unclear. Herein, we report that miR-210 is frequently up-regulated in colorectal cancer tissues, with high miR-210 expression significantly correlating with large tumor size, lymph node metastasis, advanced clinical stage and poor prognosis. Functionally, miR-210 overexpression promotes the migration and invasion of colorectal cancer cells. Furthermore, miR-210 can be induced by hypoxia and mediates the hypoxia-induced metastasis of colorectal cancer cells. In addition, vacuole membrane protein 1 (VMP1) is identified as the direct and functional target of miR-210. Thus, miR-210 is a useful biomarker for hypoxic tumor cells and a prognostic factor that plays an essential role in colorectal cancer metastasis.
HIF-1α Contributes to Hypoxia-induced Invasion and Metastasis of Esophageal Carcinoma via Inhibiting E-cadherin and Promoting MMP-2 Expression  [PDF]
Jing,Shao-Wu,Wang,Ya-Di,Kuroda,Masahiro,Su,Jing-Wei
Acta Medica Okayama , 2012,
Abstract: Hypoxia-inducible factor-1α (HIF-1α) has been found to enhance tumor invasion and metastasis, but no study has reported its action in esophageal carcinoma. The goal of this study was to explore the probable mechanism of HIF-1α in the invasion and metastasis of esophageal carcinoma Eca109 cells in vitro and in vivo. mRNA and protein expression of HIF-1α, E-cadherin and matrix metalloproteinase-2 (MMP-2) under hypoxia were detected by RT-PCR and Western blotting. The effects of silencing HIF-1α on E-cadherin, MMP-2 mRNA and protein expression under hypoxia or normoxia were detected by RT-PCR and Western blotting, respectively. The invasive ability of Eca109 cells was tested using a transwell chambers. We established an Eca109-implanted tumor model and observed tumor growth and lymph node metastasis. The expression of HIF-1α, E-cadherin and MMP-2 in xenograft tumors was detected by Western blotting. After exposure to hypoxia, HIF-1α protein was up-regulated, both mRNA and protein levels of E-cadherin were down-regulated and MMP-2 was up-regulated, while HIF-1α mRNA showed no significant change. SiRNA could block HIF-1α effectively, increase E-cadherin expression and inhibit MMP-2 expression. The number of invading cells decreased after HIF-1α was silenced. Meanwhile, the tumor volume was much smaller, and the metastatic rate of lymph nodes and the positive rate were lower in vivo. Our observations suggest that HIF-1α inhibition might be an effective strategy to weaken invasion and metastasis in the esophageal carcinoma Eca109 cell line.
Gene expression and hypoxia in breast cancer
Elena Favaro, Simon Lord, Adrian L Harris, Francesca M Buffa
Genome Medicine , 2011, DOI: 10.1186/gm271
Abstract: Abnormally low levels of oxygen in cells, known as hypoxia, characterize most solid tumors. Hypoxia is associated with malignant progression, invasion, angiogenesis, changes in metabolism and increased risk of metastasis. It also severely affects treatment outcome because hypoxic tumors are usually resistant to radiotherapy and chemotherapy [1-4]. Up to 60% of locally advanced solid tumors exhibit hypoxic (1% O2 or less, compared to 2 to 9% O2 in the adjacent tissue) and/or anoxic (that is, no measurable oxygen, < 0.01% O2) areas throughout the tumor mass. Studies in breast, uterine cervix and head and neck cancers suggest that the extent of hypoxia is independent of tumor stage, size, histology or grade [5].Hypoxia is caused by several factors: inadequate vascularization (tumor angiogenesis is often characterized by aberrant vessels that have altered perfusion); an increase in diffusion distances that is associated with tumor expansion (oxygen has to travel further to oxygenate tumor cells because of uncontrolled tumor growth); and tumor or therapy-related anemia (caused by reduced oxygen transport capacity) [5]. Cancer cells can adapt to a hostile, low-oxygen environment and this contributes to their malignancy and aggressive phenotype. This adaptation is governed by many factors, including transcriptional and post-transcriptional changes in gene expression. In this respect, up to 1.5% of the human genome is estimated to be transcriptionally responsive to hypoxia [6].Several studies have attempted to characterize the tumor response to hypoxia and its prognostic implications. In particular, recent studies have identified gene and microRNA (miRNA) expression signatures (that is, lists of regulated genes or miRNAs) that are characteristic of this response. Here, we discuss these studies and focus on breast cancer as a type of cancer in which hypoxia has been shown to have clinical implications [5]. We then discuss the use of these signatures in attempts to identify p
Focal DNA Copy Number Changes in Neuroblastoma Target MYCN Regulated Genes  [PDF]
Candy Kumps, Annelies Fieuw, Pieter Mestdagh, Bj?rn Menten, Steve Lefever, Filip Pattyn, Sara De Brouwer, Tom Sante, Johannes Hubertus Schulte, Alexander Schramm, Nadine Van Roy, Tom Van Maerken, Rosa Noguera, Valérie Combaret, Christine Devalck, Frank Westermann, Geneviève Laureys, Angelika Eggert, Jo Vandesompele, Katleen De Preter, Frank Speleman
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0052321
Abstract: Neuroblastoma is an embryonic tumor arising from immature sympathetic nervous system cells. Recurrent genomic alterations include MYCN and ALK amplification as well as recurrent patterns of gains and losses of whole or large partial chromosome segments. A recent whole genome sequencing effort yielded no frequently recurring mutations in genes other than those affecting ALK. However, the study further stresses the importance of DNA copy number alterations in this disease, in particular for genes implicated in neuritogenesis. Here we provide additional evidence for the importance of focal DNA copy number gains and losses, which are predominantly observed in MYCN amplified tumors. A focal 5 kb gain encompassing the MYCN regulated miR-17~92 cluster as sole gene was detected in a neuroblastoma cell line and further analyses of the array CGH data set demonstrated enrichment for other MYCN target genes in focal gains and amplifications. Next we applied an integrated genomics analysis to prioritize MYCN down regulated genes mediated by MYCN driven miRNAs within regions of focal heterozygous or homozygous deletion. We identified RGS5, a negative regulator of G-protein signaling implicated in vascular normalization, invasion and metastasis, targeted by a focal homozygous deletion, as a new MYCN target gene, down regulated through MYCN activated miRNAs. In addition, we expand the miR-17~92 regulatory network controlling TGF? signaling in neuroblastoma with the ring finger protein 11 encoding gene RNF11, which was previously shown to be targeted by the miR-17~92 member miR-19b. Taken together, our data indicate that focal DNA copy number imbalances in neuroblastoma (1) target genes that are implicated in MYCN signaling, possibly selected to reinforce MYCN oncogene addiction and (2) serve as a resource for identifying new molecular targets for treatment.
Inhibition of cyclo-oxygenase 2 reduces tumor metastasis and inflammatory signaling during blockade of vascular endothelial growth factor
Jason C Fisher, Jeffrey W Gander, Mary Haley, Sonia L Hernandez, Jianzhong Huang, Yan-Jung Chang, Tessa B Johung, Paolo Guarnieri, Kathleen O'Toole, Darrell J Yamashiro, Jessica J Kandel
Vascular Cell , 2011, DOI: 10.1186/2045-824x-3-22
Abstract: Agents that inhibit vascular endothelial growth factor (VEGF) signaling are increasingly incorporated into treatment regimens for metastatic human cancer, yet the overall benefit of this treatment strategy has been relatively modest [1,2]. Both clinical and experimental studies indicate that many or most malignancies will ultimately progress if VEGF blockade is sustained, and that progression may involve both progressive primary tumor growth and enhanced metastasis. The mechanisms for acquired resistance to this treatment approach are thus of great interest, but are still emerging. We previously found that VEGF inhibition significantly reduced primary tumor growth and the incidence of spontaneous lung metastasis in the orthotopic renal SKNEP1 tumor model over a six week treatment period, and regressed established metastases in late-stage tumors [3,4]. Recent findings, however, indicate that disruption of VEGF signaling and consequent tumor hypoxia may ultimately promote invasion and metastasis in several tumor models [5,6], overcoming the initial anti-metastatic effects of limiting angiogenesis. Prior studies suggest that hypoxia-regulated and proinflammatory genes expressed by tumor cells and stroma, such as COX-2, can promote the establishment of metastatic deposits in the lung. For example, Massague and coworkers previously found that COX-2 and other genes involved in vascular remodeling, identified as components in a "lung metastasis gene signature", functioned collectively to promote metastasis in a breast cancer model [7,8]. More broadly, much recent data supports a role for systemic inflammation in the promotion of metastasis in general [9], including dissemination to the lung [10]. For example, mice genetically prone to autoimmune arthritis are significantly more prone to develop lung metastasis than nonarthritic controls [11]. Recruitment of COX-2-expressing macrophages can create an inflammatory proangiogenic environment that strongly promotes tumor growth
Hypoxia-Induced Aggressiveness of Pancreatic Cancer Cells Is Due to Increased Expression of VEGF, IL-6 and miR-21, Which Can Be Attenuated by CDF Treatment  [PDF]
Bin Bao, Shadan Ali, Aamir Ahmad, Asfar S. Azmi, Yiwei Li, Sanjeev Banerjee, Dejuan Kong, Seema Sethi, Amro Aboukameel, Subhash B. Padhye, Fazlul H. Sarkar
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0050165
Abstract: Hypoxia is known to play critical roles in cell survival, angiogenesis, tumor invasion, and metastasis. Hypoxia mediated over-expression of hypoxia-inducible factor (HIF) has been shown to be associated with therapeutic resistance, and contributes to poor prognosis of cancer patients. Emerging evidence suggest that hypoxia and HIF pathways contributes to the acquisition of epithelial-to-mesenchymal transition (EMT), maintenance of cancer stem cell (CSC) functions, and also maintains the vicious cycle of inflammation-all which lead to therapeutic resistance. However, the precise molecular mechanism(s) by which hypoxia/HIF drives these events are not fully understood. Here, we show, for the first time, that hypoxia leads to increased expression of VEGF, IL-6, and CSC signature genes Nanog, Oct4 and EZH2 consistent with increased cell migration/invasion and angiogenesis, and the formation of pancreatospheres, concomitant with increased expression of miR-21 and miR-210 in human pancreatic cancer (PC) cells. The treatment of PC cells with CDF, a novel synthetic compound inhibited the production of VEGF and IL-6, and down-regulated the expression of Nanog, Oct4, EZH2 mRNAs, as well as miR-21 and miR-210 under hypoxia. CDF also led to decreased cell migration/invasion, angiogenesis, and formation of pancreatospheres under hypoxia. Moreover, CDF decreased gene expression of miR-21, miR-210, IL-6, HIF-1α, VEGF, and CSC signatures in vivo in a mouse orthotopic model of human PC. Collectively, these results suggest that the anti-tumor activity of CDF is in part mediated through deregulation of tumor hypoxic pathways, and thus CDF could become a novel, and effective anti-tumor agent for PC therapy.
Conversion of Stationary to Invasive Tumor Initiating Cells (TICs): Role of Hypoxia in Membrane Type 1-Matrix Metalloproteinase (MT1-MMP) Trafficking  [PDF]
Jian Li, Stanley Zucker, Ashleigh Pulkoski-Gross, Cem Kuscu, Mihriban Karaayvaz, Jingfang Ju, Herui Yao, Erwei Song, Jian Cao
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038403
Abstract: Emerging evidence has implicated the role of tumor initiating cells (TICs) in the process of cancer metastasis. The mechanism underlying the conversion of TICs from stationary to invasive remains to be characterized. In this report, we employed less invasive breast cancer TICs, SK-3rd, that displays CD44high/CD24low with high mammosphere-forming and tumorigenic capacities, to investigate the mechanism by which stationary TICs are converted to invasive TICs. Invasive ability of SK-3rd TICs was markedly enhanced when the cells were cultured under hypoxic conditions. Given the role of membrane type 1-matrix metalloproteinase (MT1-MMP) in cancer invasion/metastasis, we explored a possible involvement of MT1-MMP in hypoxia-induced TIC invasion. Silencing of MT1-MMP by a shRNA approach resulted in diminution of hypoxia-induced cell invasion in vitro and metastasis in vivo. Under hypoxic conditions, MT1-MMP redistributed from cytoplasmic storage pools to the cell surface of TICs, which coincides with the increased cell invasion. In addition, CD44, a cancer stem-like cell marker, inversely correlated with increased cell surface MT1-MMP. Interestingly, cell surface MT1-MMP gradually disappeared when the hypoxia-treated cells were switched to normoxia, suggesting the plasticity of TICs in response to oxygen content. Furthermore, we dissected the pathways leading to upregulated MT1-MMP in cytoplasmic storage pools under normoxic conditions, by demonstrating a cascade involving Twist1-miR10b-HoxD10 leading to enhanced MT1-MMP expression in SK-3rd TICs. These observations suggest that MT1-MMP is a key molecule capable of executing conversion of stationary TICs to invasive TICs under hypoxic conditions and thereby controlling metastasis.
Hypoxia Promotes Migration and Induces CXCR4 Expression via HIF-1α Activation in Human Osteosarcoma  [PDF]
Mingjun Guo, Chengkui Cai, Guangyi Zhao, Xiuchun Qiu, Haien Zhao, Qiong Ma, Liying Tian, Xuelian Li, Yunsheng Hu, Bo Liao, Baoan Ma, Qingyu Fan
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0090518
Abstract: Background Cellular adaptation to a hypoxic microenvironment is essential for tumor progression and is largely mediated by HIF-1α through coordinated regulation of hypoxia-responsive genes. The chemokine SDF-1α and its unique receptor CXCR4 have been implicated in organ-specific metastases of many cancers. In this study, we investigated the response of osteosarcoma cells to hypoxia and the expression of CXCR4 and HIF-1α in human osteosarcoma specimens and explored the roles of CXCR4 and HIF-1α in the cell migration process. Methodology/Principal Findings We performed immunohistochemistry, immunocytochemistry, quantitative real-time PCR, Western blots and fluorescent reporter assays to evaluate the correlation between CXCR4 and HIF-1α expression in human osteosarcoma specimens or SOSP-9607 cells under normoxic and hypoxic conditions. Transwell assays were used to assess cell migration under different conditions. Exposure of SOSP-9607 cells to hypoxic conditions resulted in significantly increased migration. When SOSP-9607 cells were subjected to hypoxic conditions, the mRNA and protein levels of CXCR4 were significantly increased in a time-dependent manner. Moreover, siHIF-1α significantly decreased the mRNA and protein levels of CXCR4 under hypoxia, whereas pcDNA-HIF-1α significantly increased the mRNA and protein levels of CXCR4 under normoxia. A luciferase reporter gene study showed that siHIF-1α reduced pGL3-CXCR4 luciferase activity. Furthermore, coexpression of HIF-1α and CXCR4 was significantly higher in patients with distant metastasis compared with those without metastasis. Conclusions/Significance The hypoxia-HIF-1α-CXCR4 pathway plays a crucial role during the migration of human osteosarcoma cells, and targeting this pathway might represent a novel therapeutic strategy for patients suffering from osteosarcoma.
MicroRNA and Protein Profiling of Brain Metastasis Competent Cell-Derived Exosomes  [PDF]
Laura Camacho, Paola Guerrero, Dario Marchetti
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073790
Abstract: Exosomes are small membrane vesicles released by most cell types including tumor cells. The intercellular exchange of proteins and genetic material via exosomes is a potentially effective approach for cell-to-cell communication and it may perform multiple functions aiding to tumor survival and metastasis. We investigated microRNA and protein profiles of brain metastatic (BM) versus non-brain metastatic (non-BM) cell-derived exosomes. We studied the cargo of exosomes isolated from brain-tropic 70W, MDA-MB-231BR, and circulating tumor cell brain metastasis-selected markers (CTC1BMSM) variants, and compared them with parental non-BM MeWo, MDA-MB-231P and CTC1P cells, respectively. By performing microRNA PCR array we identified one up-regulated (miR-210) and two down-regulated miRNAs (miR-19a and miR-29c) in BM versus non-BM exosomes. Second, we analyzed the proteomic content of cells and exosomes isolated from these six cell lines, and detected high expression of proteins implicated in cell communication, cell cycle, and in key cancer invasion and metastasis pathways. Third, we show that BM cell-derived exosomes can be internalized by non-BM cells and that they effectively transport their cargo into cells, resulting in increased cell adhesive and invasive potencies. These results provide a strong rationale for additional investigations of exosomal proteins and miRNAs towards more profound understandings of exosome roles in brain metastasis biogenesis, and for the discovery and application of non-invasive biomarkers for new therapies combating brain metastasis.
M402, a Novel Heparan Sulfate Mimetic, Targets Multiple Pathways Implicated in Tumor Progression and Metastasis  [PDF]
He Zhou,Sucharita Roy,Edward Cochran,Radouane Zouaoui,Chia Lin Chu,Jay Duffner,Ganlin Zhao,Sean Smith,Zoya Galcheva-Gargova,Juliane Karlgren,Nancy Dussault,Rain Y. Q. Kwan,Erick Moy,Marishka Barnes,Alison Long,Chris Honan,Yi Wei Qi,Zachary Shriver,Tanmoy Ganguly,Birgit Schultes,Ganesh Venkataraman,Takashi Kei Kishimoto
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0021106
Abstract: Heparan sulfate proteoglycans (HSPGs) play a key role in shaping the tumor microenvironment by presenting growth factors, cytokines, and other soluble factors that are critical for host cell recruitment and activation, as well as promoting tumor progression, metastasis, and survival. M402 is a rationally engineered, non-cytotoxic heparan sulfate (HS) mimetic, designed to inhibit multiple factors implicated in tumor-host cell interactions, including VEGF, FGF2, SDF-1α, P-selectin, and heparanase. A single s.c. dose of M402 effectively inhibited seeding of B16F10 murine melanoma cells to the lung in an experimental metastasis model. Fluorescent-labeled M402 demonstrated selective accumulation in the primary tumor. Immunohistological analyses of the primary tumor revealed a decrease in microvessel density in M402 treated animals, suggesting anti-angiogenesis to be one of the mechanisms involved in-vivo. M402 treatment also normalized circulating levels of myeloid derived suppressor cells in tumor bearing mice. Chronic administration of M402, alone or in combination with cisplatin or docetaxel, inhibited spontaneous metastasis and prolonged survival in an orthotopic 4T1 murine mammary carcinoma model. These data demonstrate that modulating HSPG biology represents a novel approach to target multiple factors involved in tumor progression and metastasis.
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