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1.  Hif1α deletion reveals pro-neoplastic function of B cells in pancreatic neoplasia 
Cancer discovery  2015;6(3):256-269.
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths worldwide, with an exceedingly low 5-year survival rate. PDAC tumors are characterized by an extensive desmoplastic stromal response and hypovascularity, suggesting that tumor hypoxia could regulate PDAC initiation and/or progression. Using a well-defined, autochthonous KrasG12D-driven murine model, as well as human tumors, we demonstrate that hypoxia and stabilization of hypoxia-inducible factor 1α (HIF1α), a principal mediator of hypoxic adaptation, emerge early during preinvasive stages of PDAC. Surprisingly, pancreas-specific Hif1α deletion drastically accelerated KrasG12D-driven pancreatic neoplasia, and was accompanied by significant increases in intrapancreatic B lymphocytes, featuring prominent influx of a rare “B1b” B cell subtype. Finally, treatment of HIF1α-deficient mice with B cell-depleting αCD20 monoclonal antibodies inhibited progression of pancreatic intraepithelial neoplasia (PanIN). Our data reveal a previously unrecognized role for B cells in promoting pancreatic tumorigenesis, and implicate HIF1α as a critical regulator of PDAC development.
PMCID: PMC4783189  PMID: 26715642
HIF1α; hypoxia; pancreatic cancer; B1 B cells; αCD20
3.  Oncogenes strike a balance between cellular growth and homeostasis 
Altered tumor cell metabolism is now firmly established as a hallmark of human cancer. Downstream of oncogenic events, metabolism is re-wired to support cellular energetics and supply the building blocks for biomass. Rapid, uncontrolled proliferation results in tumor growth beyond the reach of existing vasculature and triggers cellular adaptations to overcome limiting nutrient and oxygen delivery. However, oncogenic activation and metabolic re-programming also elicit cell intrinsic stresses, independent of the tumor microenvironment. To ensure metabolic robustness and stress resistance, pro-growth signals downstream of oncogene activation or tumor suppressor loss simultaneously activate homeostatic processes. Here, we summarize recent literature describing the adaptive mechanisms co-opted by common oncogenes, including mTOR, MYC, and RAS. Recurrent themes in our review include: 1) coordination of oncogene-induced changes in protein and lipid metabolism to sustain endoplasmic reticulum homeostasis, 2) maintenance of mitochondrial functional capacity to support anabolic metabolism, 3) adaptations to sustain intracellular metabolite concentrations required for growth, and 4) prevention of oxidative stress. We also include a discussion of the hypoxia inducible factors (HIFs) and the AMP-dependent protein kinase (AMPK)—stress sensors that are co-opted to support tumor growth. Ultimately, an understanding of the adaptations required downstream of specific oncogenes could reveal targetable metabolic vulnerabilities.
PMCID: PMC4662909  PMID: 26277544
cancer metabolism; stress response; ER stress; autophagy; hypoxia inducible factors; AMPK
4.  MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells 
Cell metabolism  2015;22(6):1009-1019.
The MYC oncogene encodes MYC, a transcription factor that binds the genome through sites termed E-boxes (5′-CACGTG-3′), which are identical to the binding sites of the heterodimeric CLOCK-BMAL1 master circadian transcription factor. Hence, we hypothesized that ectopic MYC expression perturbs the clock by deregulating E-box-driven components of the circadian network in cancer cells. We report here that deregulated expression of MYC or N-MYC disrupts the molecular clock in vitro by directly inducing REV-ERBα to dampen expression and oscillation of BMAL1, and this could be rescued by knockdown of REV-ERB. REV-ERBα expression predicts poor clinical outcome for N-MYC-driven human neuroblastomas that have diminished BMAL1 expression, and reexpression of ectopic BMAL1 in neuroblastoma cell lines suppresses their clonogenicity. Further, ectopic MYC profoundly alters oscillation of glucose metabolism and perturbs glutaminolysis. Our results demonstrate an unsuspected link between oncogenic transformation and circadian and metabolic dysrhythmia, which we surmise to be advantageous for cancer.
Graphical Abstract
PMCID: PMC4818967  PMID: 26387865
5.  HIF-2α dependent lipid storage promotes endoplasmic reticulum homeostasis in clear cell renal cell carcinoma 
Cancer discovery  2015;5(6):652-667.
Two hallmarks of clear cell renal cell carcinoma (ccRCC) are constitutive hypoxia inducible factor (HIF) signaling and abundant intracellular lipid droplets (LDs). However, regulation of lipid storage and its role in ccRCC are incompletely understood. Transcriptional profiling of primary ccRCC samples revealed that expression of the LD coat protein gene PLIN2 was elevated in tumors and correlated with HIF-2α, but not HIF-1α, activation. HIF-2α dependent PLIN2 expression promoted lipid storage, proliferation, and viability in xenograft tumors. Mechanistically, lipid storage maintained integrity of the endoplasmic reticulum (ER), which is functionally and physically associated with LDs. Specifically, PLIN2 dependent lipid storage suppressed cytotoxic ER stress responses that otherwise result from elevated protein synthetic activity characteristic of ccRCC cells. Thus, in addition to promoting ccRCC proliferation and anabolic metabolism, HIF-2α modulates lipid storage to sustain ER homeostasis, particularly under conditions of nutrient and oxygen limitation, thereby promoting tumor cell survival.
PMCID: PMC4456212  PMID: 25829424
HIF-2α; lipid storage; lipid droplets; clear cell renal cell carcinoma; ER stress
6.  MicroRNA-124 expression counteracts pro-survival stress responses in glioblastoma 
Oncogene  2014;34(17):2204-2214.
Glioblastomas are aggressive adult brain tumors, characterized by inadequately organized vasculature and consequent nutrient and oxygen (O2)-depleted areas. Adaptation to low nutrients and hypoxia supports glioblastoma cell survival, progression, and therapeutic resistance. However, specific mechanisms promoting cellular survival under nutrient and O2 deprivation remain incompletely understood. Here, we show that miR-124 expression is negatively correlated with a hypoxic gene signature in glioblastoma patient samples, suggesting that low miR-124 levels contribute to pro-survival adaptive pathways in this disease. Since miR-124 expression is repressed in various cancers (including glioblastoma), we quantified miR-124 abundance in normoxic and hypoxic regions in glioblastoma patient tissue, and investigated whether ectopic miR-124 expression compromises cell survival, during tumor ischemia. Our results indicate that miR-124 levels are further diminished in hypoxic/ischemic regions within individual glioblastoma patient samples, compared to regions replete in O2 and nutrients. Importantly, we also show that increased miR-124 expression affects the ability of tumor cells to survive under O2 and/or nutrient deprivation. Moreover, miR-124 re-expression increases cell death in vivo, and enhances the survival of mice bearing intracranial xenograft tumors. miR-124 exerts this phenotype in part by directly regulating TEAD1, MAPK14/p38α and SERP1, factors involved in cell proliferation and survival under stress. Simultaneous suppression of these miR-124 targets results in similar levels of cell death as caused by miR-124 restoration. Importantly, we further demonstrate that SERP1 re-introduction reverses the hypoxic cell death elicited by miR-124, indicating the importance of SERP1 in promoting tumor cell survival. In support of our experimental data, we observed a significant correlation between high SERP1 levels and poor patient outcome in glioblastoma patients. Collectively, among the many pro-tumorigeneic properties of miR-124 repression in glioblastoma, we delineated a novel role in promoting tumor cell survival under stressful microenvironments, thereby supporting tumor progression.
PMCID: PMC4275412  PMID: 24954504
miR-124; glioblastoma; hypoxia; ischemia; nutrient deprivation
7.  Hypoxia inducible factors regulate filaggrin expression and epidermal barrier function 
A functional epidermal skin barrier requires the formation of a cornified envelope from terminally differentiating keratinocytes. During this process, multiple genetic and environmental signals coordinately regulate protein expression and tissue differentiation. Here we describe a critical role for hypoxia-inducible factors (HIFs) in the regulation of filaggrin expression and skin barrier formation. Similar to other mammalian tissues, fetal epidermis in mice is normally O2-deprived. Simultaneous deletion of Hif1a and Hif2a in murine epidermis revealed defects in keratinocyte terminal differentiation and epidermal barrier formation. Mice lacking Hif1a and Hif2a in the epidermis exhibited dry flaky skin, impaired permeability barrier, and enhanced sensitivity to cutaneous allergens. These defects were correlated with stratum granulosum attenuation and reduced filaggrin expression. Hypoxic treatment of primary keratinocytes induced filaggrin (Flg) gene expression in a HIF1α- and HIF2α-dependent manner, suggesting that one mechanism by which Hif1a and Hif2a loss causes epidermal barrier defects in mice lies in Flg dysregulation. Therefore, low O2 tension is an essential component of the epidermal environment that contributes to skin development and function.
PMCID: PMC4286527  PMID: 24999590
8.  Hypoxia, lipids, and cancer: surviving the harsh tumor microenvironment 
Trends in cell biology  2014;24(8):472-478.
Solid tumors typically develop hostile microenvironments characterized by irregular vascularization and poor oxygen (O2) and nutrient supply. While normal cells modulate anabolic and catabolic pathways in response to changes in nutrient availability, cancer cells exhibit unregulated growth even under nutrient scarcity. Recent studies have demonstrated that constitutive activation of growth-promoting pathways results in a dependence on unsaturated fatty acids for survival under O2 deprivation. In cancer cells, this dependence represents a critical metabolic vulnerability that could be exploited therapeutically. Here we review how this dependence on unsaturated lipids is affected by the microenvironmental conditions faced by cancer cells.
PMCID: PMC4112153  PMID: 24985940
unsaturated lipids; hypoxia; metabolism; SCD1; ER stress
9.  Feedback circuitry between miR-218 repression and RTK activation in Glioblastoma 
Science signaling  2015;8(375):ra42.
Receptor tyrosine kinase (RTK) pathway signaling plays a central role in the growth and progression of Glioblastoma (GBM), a highly aggressive group of brain tumors. We recently reported that miR-218 repression, an essentially uniform feature of human GBM, directly promotes RTK hyperactivation by increasing the expression of key positive signaling effectors, including EGFR, PLCγ1, PIK3CA and ARAF (1). However, enhanced RTK signaling is known to activate compensatory inhibitory feedback mechanisms in both normal and cancer cells. We demonstrate here that miR-218 repression in GBM cells also increases the abundance of additional upstream and downstream signaling mediators, including PDGFRα, RSK2, and S6K1, which collectively function to alleviate inhibitory RTK feedback regulation. In turn, RTK signaling suppresses miR-218 expression via STAT3, which binds directly to the miR-218 locus, along with BCLAF1, to repress its expression. These data identify novel interacting feedback loops by which miR-218 repression promotes increased RTK signaling in high-grade gliomas.
PMCID: PMC4437515  PMID: 25943352
10.  The aryl hydrocarbon receptor promotes IL-10 production by natural killer cells 
The cytokine IL-10 has an important role in limiting inflammation in many settings, including toxoplasmosis. In these studies, an IL-10 reporter mouse was used to identify the sources of this cytokine following challenge with Toxoplasma gondii. During infection, multiple cell types expressed the IL-10 reporter but natural killer cells were a major early source of this cytokine. These IL-10 reporter+ NK cells expressed high levels of the IL-12 target genes T-bet, KLRG1, and IFN-γ, and IL-12 depletion abrogated reporter expression. However, IL-12 signaling alone was not sufficient to promote NK cell IL-10 and activation of the aryl hydrocarbon receptor (AHR) was also required for maximal IL-10 production. NK cells basally expressed the AHR, relevant chaperone proteins, and the AHR nuclear translocator (ARNT), which heterodimerizes with the AHR to form a competent transcription factor. In vitro studies revealed that IL-12 stimulation increased NK cell AHR levels, and the AHR and ARNT were required for optimal production of IL-10. Additionally, NK cells isolated from T. gondii-infected Ahr-/- mice had impaired expression of IL-10, which was associated with increased resistance to this infection. Together, these data identify the AHR as a critical cofactor involved in NK cell production of IL-10.
PMCID: PMC3955958  PMID: 24403534
NK cell; IL-10; aryl hydrocarbon receptor
11.  Hypoxia-Dependent Modification of Collagen Networks Promotes Sarcoma Metastasis 
Cancer discovery  2013;3(10):10.1158/2159-8290.CD-13-0118.
Intratumoral hypoxia and expression of Hypoxia Inducible Factor 1α (HIF1α) correlate with metastasis and poor survival in sarcoma patients. We demonstrate here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF1α enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF1α or PLOD2 expression disrupts collagen modification, cell migration and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSLKrasG12D/+; Trp53fl/fl murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF1α-deficient tumors, and analysis of human sarcomas reveal elevated HIF1α and PLOD2 expression in metastatic primary lesions. Pharmacological inhibition of PLOD enzymatic activity suppresses metastases. Collectively, these data indicate that HIF1α controls sarcoma metastasis through PLOD2-dependent collagen modification and organization in primary tumors. We conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination.
PMCID: PMC3822914  PMID: 23906982
metastasis; sarcoma; HI1α; PLOD2; collagen; hypoxia
Molecular cancer research : MCR  2015;13(8):1227-1237.
Glioblastoma multiforme (GBM) is notoriously resistant to therapy, and the development of a durable cure will require the identification of broadly relevant regulators of GBM cell tumorigenicity and survival. Here, we identify Sprouty2 (SPRY2), a known regulator of receptor tyrosine kinases (RTKs), as one such regulator. SPRY2 knockdown reduced proliferation and anchorage-independent growth in GBM cells and slowed xenograft tumor growth in mice. SPRY2 knockdown also promoted cell death in response to co-inhibition of the epidermal growth factor receptor (EGFR) and the c-MET receptor in GBM cells, an effect that involved regulation of the ability of the p38 mitogen activated protein kinase (MAPK) to drive cell death in response to inhibitors. Analysis of clinical tumor specimens further demonstrated that SPRY2 protein is definitively expressed in GBM tissue, that SPRY2 expression is elevated in GBM tumors expressing EGFR variant III (EGFRvIII), and that elevated SPRY2 mRNA expression portends reduced GBM patient survival. Overall, these results identify SPRY2 and the pathways it regulates as novel candidate biomarkers and therapeutic targets in GBM.
Implications: SPRY2, counter to its roles in other cancer settings, promotes glioma cell and tumor growth and cellular resistance to targeted inhibitors of oncogenic RTKs; thus, making SPRY2 and the cell signaling processes it regulates potential novel therapeutic targets in glioma.
PMCID: PMC4679183  PMID: 25934697
epidermal growth factor receptor; c-MET receptor; p38 mitogen activated protein kinase; gefitinib
13.  Loss of pVHL is sufficient to cause HIF dysregulation in primary cells but does not promote tumor growth 
Cancer cell  2003;3(1):75-88.
Inactivation of the von Hippel-Lindau (VHL) gene is associated with the development of highly vascularized tumors. pVHL targets the α-subunits of Hypoxia Inducible Factor (HIF) for ubiquitin-mediated degradation in an oxygen-dependent manner. Although pVHL-deficient tumor cell lines demonstrate constitutive stabilization and activation of HIF, it has yet to be shown that loss of murine Vhl alone is sufficient to dysregulate HIF. We utilized a genetic approach to demonstrate that loss of Vhl is sufficient not only to stabilize HIF-α subunits under normoxia, but also fully activate HIF-mediated responses. These studies have implications for the hierarchy of signaling events leading to HIF stabilization, nuclear translocation, and target gene expression. We further demonstrate that loss of murine Vhl does not promote teratocarcinoma growth, indicating that other genetic changes must occur to facilitate Vhl-mediated tumorigenesis.
PMCID: PMC4120823  PMID: 12559177
14.  Restricted expression of miR-30c-2-3p and miR-30a-3p in Clear Cell Renal Carcinomas enhances HIF2α activity 
Cancer discovery  2013;4(1):53-60.
Inactivation of the von-Hippel Lindau (VHL) tumor suppressor gene occurs in 90% of human clear cell renal cell carcinomas (ccRCC), and leads to the stable expression of the hypoxia inducible factors HIF1α and HIF2α. The constitutive expression of HIF1α in a majority of VHL-deficient tumors is counterintuitive, given that HIF1α functions as a tumor suppressor in ccRCC, whereas HIF2α clearly enhances tumor growth. We demonstrate here that miR-30c-2-3p and miR-30a-3p specifically bind and inhibit expression of HIF2α transcripts, and that the locus encoding miR-30c-2-3p and miR-30a-3p is selectively repressed in “H1H2” VHL-deficient tumors expressing both HIF1α and HIF2α proteins. Inhibiting miR-30a-3p expression increases HIF2α levels in H1H2 ccRCC cells, and promotes cellular proliferation, angiogenesis, and xenograft tumor growth. Our results indicate that miR-30c-2-3p and miR-30a-3p repression enhances HIF2α expression, and suggest a mechanism whereby the tumor suppressive effects of constitutive HIF1α expression are attenuated in VHL-deficient H1H2 tumors.
PMCID: PMC3947282  PMID: 24189146
15.  Molecular Pathways: Targeting MYC-induced Metabolic Reprogramming and Oncogenic Stress in Cancer 
MYC is a multi-functional transcription factor that is deregulated in many human cancers. MYC impacts a collaborative genetic program that orchestrates cell proliferation, metabolism, and stress responses. Although the progression of MYC-amplified tumors shows robust dependence on MYC activity, directly targeting MYC as a therapeutic method has proven to be technically difficult. Therefore, alternative approaches are currently under development with a focus on interference with MYC-mediated downstream effects. To fuel rapid cell growth, MYC reprograms cancer cell metabolism in a way that is substantially different from normal cells. The MYC-induced metabolic signature is characterized by enhanced glucose and glutamine uptake, increased lactate production, and altered amino acid metabolism. Targeting MYC-reprogrammed cancer cell metabolism is considered to be promising based on multiple preclinical studies. In addition, the increased biosynthetic demand of MYC-driven tumors coupled with limited nutrient access within tumor microenvironments create multiple levels of oncogenic stress, which can also be utilized as tumor-specific targets for pharmacological intervention. Presumably, the best therapeutic strategy for treating MYC-amplified tumors is combined targeting of multiple MYC-mediated pathways, especially those involved in regulating cell proliferation, metabolism, and oncogenic stress.
PMCID: PMC3818456  PMID: 23897900
16.  Nutrient-sensing pathways and metabolic regulation in stem cells 
The Journal of Cell Biology  2013;203(1):23-33.
Stem cells exert precise regulation to maintain a balance of self-renewal and differentiation programs to sustain tissue homeostasis throughout the life of an organism. Recent evidence suggests that this regulation is modulated, in part, via metabolic changes and modifications of nutrient-sensing pathways such as mTOR and AMPK. It is becoming increasingly clear that stem cells inhibit oxidative phosphorylation in favor of aerobic glycolysis for energy production. Recent progress has detailed the molecular mechanisms of this metabolic phenotype and has offered insight into new metabolic pathways that may be involved in stem cell homeostasis.
PMCID: PMC3798256  PMID: 24127214
17.  MYC Degradation under Low O2 Tension Promotes Survival by Evading Hypoxia-Induced Cell Death 
Molecular and Cellular Biology  2013;33(17):3494-3504.
Cells encounter oxygen deprivation (hypoxia) in various physiological and pathological contexts. Adaptation to hypoxic stress occurs in part by suppressing MYC, a key regulator of cellular metabolism, proliferation, and survival. Hypoxia has been reported to inhibit MYC through multiple means, including disruption of MYC transcriptional complexes and decreased MYC protein abundance. Here we identify enhanced proteasomal degradation and cathepsin-mediated proteolysis as important mechanisms for hypoxic MYC inhibition in human colon carcinoma cells. MYC protein levels were similarly reduced in hypoxic primary keratinocytes. Increased MYC turnover at low O2 tension was dependent on the E3 ubiquitin ligases FBXW7 and DDB1, as well as hypoxic induction of cathepsins D and S. Reduced MYC protein levels coincided with hypoxic inhibition of RNA polymerase III-dependent MYC target genes, which MYC regulates independently of its binding partner MAX. Finally, MYC overexpression in hypoxic cells promoted cell cycle progression but also enhanced cell death via increased expression of the proapoptotic genes NOXA and PUMA. Collectively, these results indicate that hypoxic cells promote MYC degradation as an adaptive strategy to reduce proliferation, suppress biosynthetic processes, and promote cell survival under low O2 tension.
PMCID: PMC3753854  PMID: 23816886
18.  ATF4 Regulates MYC-mediated Neuroblastoma Cell Death upon Glutamine Deprivation 
Cancer cell  2012;22(5):631-644.
Oncogenic Myc alters mitochondrial metabolism, making it dependent on exogenous glutamine (Gln) for cell survival. Accordingly, Gln deprivation selectively induces apoptosis in MYC-overexpressing cells via unknown mechanisms. Using MYCN-amplified neuroblastoma as a model, we identify PUMA, NOXA and TRB3 as executors of Gln-starved cells. Gln depletion in MYC-transformed cells induces apoptosis through ATF4-dependent, but p53-independent, PUMA and NOXA induction. MYC-transformed cells depend on both glutamate-oxaloacetate transaminase and glutamate dehydrogenase to maintain Gln homeostasis and suppress apoptosis. Consequently, either ATF4 agonists or glutaminolysis inhibitors potently induce apoptosis in vitro and inhibit tumor growth in vivo. These results reveal mechanisms whereby Myc sensitizes cells to apoptosis and validate ATF4 agonists and inhibitors of Gln metabolism as potential Myc-selective cancer therapeutics.
PMCID: PMC3510660  PMID: 23153536
19.  Segmental Transarterial Embolization in a Translational Rat Model of Hepatocellular Carcinoma 
To develop a clinically relevant, minimally invasive technique for transarterial embolization in a translational rat model of hepatocellular carcinoma (HCC).
Materials and Methods
Oral diethylnitrosamine was administered to 53 male Wistar rats ad libitum for 12 weeks. Tumor induction was monitored using magnetic resonance imaging. Minimally invasive lobar or segmental transarterial embolization was performed through a left common carotid artery approach. Necropsy was performed to evaluate periprocedural mortality. Histologic analysis of tumors that received embolization was performed to assess percent tumor necrosis.
Severe cirrhosis and autochthonous HCCs were characterized in a cohort of rats composed of two groups of rats identically treated with diethylnitrosamine with median survival times of 101 days and 105 days (n = 10/group). A second cohort was used to develop minimally invasive transarterial embolization of HCCs (n = 10). In a third cohort, lobar embolization was successfully performed in 9 of 10 rats and demonstrated a high rate of periprocedural mortality (n = 5). Necropsy performed for periprocedural mortality after lobar embolization demonstrated extensive tissue necrosis within the liver (n = 3) and lungs (n = 2), indicating nontarget embolization as the likely cause of mortality. In a fourth cohort of rats, a segmental embolization technique was successfully applied in 10 of 13 rats. Segmental embolization resulted in a reduction in periprocedural mortality (P = .06) relative to selective embolization and a 19% increase in average tumor necrosis (P = .04).
Minimally invasive, segmental embolization mimicking the currently applied clinical approach is feasible in a translational rat model of HCC and offers the critical advantage of reduced nontarget embolization relative to lobar embolization.
PMCID: PMC4853022  PMID: 25863596
20.  HIF1α and HIF2α: sibling rivalry in hypoxic tumor growth and progression 
Nature reviews. Cancer  2011;12(1):9-22.
Hypoxia inducible factors (HIFs) are broadly expressed in human cancers, and HIF1α and HIF2α were previously suspected of promoting tumor progression through largely overlapping functions. However, this relatively simple model has now been challenged in light of recent data from genome-wide analyses of human tumors, genetically engineered mouse models of cancer, and systems biology approaches that reveal unique and sometimes opposing HIFa activities in both normal physiology and disease. These effects are mediated in part through regulation of unique target genes, as well as direct and indirect interactions with important oncoproteins and tumor suppressors, including MYC and p53. As HIF inhibitors are currently under clinical evaluation as cancer therapeutics, a more thorough understanding of unique roles performed by HIF1α and HIF2α in human neoplasia is warranted. This Review summarizes our rapidly changing understanding of shared and independent HIF1α and HIF2α activities in tumor growth and progression, and the implications for using selective HIF inhibitors as cancer therapeutics.
PMCID: PMC3401912  PMID: 22169972
21.  O2 Regulates Skeletal Muscle Progenitor Differentiation through Phosphatidylinositol 3-Kinase/AKT Signaling 
Molecular and Cellular Biology  2012;32(1):36-49.
Skeletal muscle stem/progenitor cells, which give rise to terminally differentiated muscle, represent potential therapies for skeletal muscle diseases. Delineating the factors regulating these precursors will facilitate their reliable application in human muscle repair. During embryonic development and adult regeneration, skeletal muscle progenitors reside in low-O2 environments before local blood vessels and differentiated muscle form. Prior studies established that low O2 levels (hypoxia) maintained muscle progenitors in an undifferentiated state in vitro, although it remained unclear if progenitor differentiation was coordinated with O2 availability in vivo. In addition, the molecular signals linking O2 to progenitor differentiation are incompletely understood. Here we show that the muscle differentiation program is repressed by hypoxia in vitro and ischemia in vivo. Surprisingly, hypoxia can significantly impair differentiation in the absence of hypoxia-inducible factors (HIFs), the primary developmental effectors of O2. In order to maintain the undifferentiated state, low O2 levels block the phosphatidylinositol 3-kinase/AKT pathway in a predominantly HIF1α-independent fashion. O2 deprivation affects AKT activity by reducing insulin-like growth factor I receptor sensitivity to growth factors. We conclude that AKT represents a key molecular link between O2 and skeletal muscle differentiation.
PMCID: PMC3255700  PMID: 22006022
22.  Endothelial HIF-2α regulates murine pathological angiogenesis and revascularization processes 
The Journal of Clinical Investigation  2012;122(4):1427-1443.
Localized tissue hypoxia is a consequence of vascular compromise or rapid cellular proliferation and is a potent inducer of compensatory angiogenesis. The oxygen-responsive transcriptional regulator hypoxia-inducible factor 2α (HIF-2α) is highly expressed in vascular ECs and, along with HIF-1α, activates expression of target genes whose products modulate vascular functions and angiogenesis. However, the mechanisms by which HIF-2α regulates EC function and tissue perfusion under physiological and pathological conditions are poorly understood. Using mice in which Hif2a was specifically deleted in ECs, we demonstrate here that HIF-2α expression is required for angiogenic responses during hindlimb ischemia and for the growth of autochthonous skin tumors. EC-specific Hif2a deletion resulted in increased vessel formation in both models; however, these vessels failed to undergo proper arteriogenesis, resulting in poor perfusion. Analysis of cultured HIF-2α–deficient ECs revealed cell-autonomous increases in migration, invasion, and morphogenetic activity, which correlated with HIF-2α–dependent expression of specific angiogenic factors, including delta-like ligand 4 (Dll4), a Notch ligand, and angiopoietin 2. By stimulating Dll4 signaling in cultured ECs or restoring Dll4 expression in ischemic muscle tissue, we rescued most of the HIF-2α–dependent EC phenotypes in vitro and in vivo, emphasizing the critical role of Dll4/Notch signaling as a downstream target of HIF-2α in ECs. These results indicate that HIF-1α and HIF-2α fulfill complementary, but largely nonoverlapping, essential functions in pathophysiological angiogenesis.
PMCID: PMC3314446  PMID: 22426208
23.  Hypoxia-Induced Angiogenesis 
Genes & Cancer  2011;2(12):1117-1133.
The vascular network delivers oxygen (O2) and nutrients to all cells within the body. It is therefore not surprising that O2 availability serves as a primary regulator of this complex organ. Most transcriptional responses to low O2 are mediated by hypoxia-inducible factors (HIFs), highly conserved transcription factors that control the expression of numerous angiogenic, metabolic, and cell cycle genes. Accordingly, the HIF pathway is currently viewed as a master regulator of angiogenesis. HIF modulation could provide therapeutic benefit for a wide array of pathologies, including cancer, ischemic heart disease, peripheral artery disease, wound healing, and neovascular eye diseases. Hypoxia promotes vessel growth by upregulating multiple pro-angiogenic pathways that mediate key aspects of endothelial, stromal, and vascular support cell biology. Interestingly, recent studies show that hypoxia influences additional aspects of angiogenesis, including vessel patterning, maturation, and function. Through extensive research, the integral role of hypoxia and HIF signaling in human disease is becoming increasingly clear. Consequently, a thorough understanding of how hypoxia regulates angiogenesis through an ever-expanding number of pathways in multiple cell types will be essential for the identification of new therapeutic targets and modalities.
PMCID: PMC3411127  PMID: 22866203
angiogenesis; hypoxia; HIFs; vascular diseases; cancer; anti-angiogenic therapies
24.  HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation 
Cancer cell  2007;12(2):108-113.
O2 deprivation (hypoxia) and cellular proliferation engage opposite cellular pathways, yet often coexist during tumor growth. The ability of cells to grow during hypoxia results in part from crosstalk between hypoxia inducible factors (HIFs) and the proto-oncogene c-Myc. Acting alone, HIF and c-Myc partially regulate complex adaptations undertaken by tumor cells growing in low O2. However, acting in concert, these transcription factors reprogram metabolism, protein synthesis and cell cycle progression, to “fine tune” adaptive responses to hypoxic environments.
PMCID: PMC3215289  PMID: 17692803
25.  Hypoxia Inducible Factors: Central Regulators of the Tumor Phenotype 
Low oxygen levels are a defining characteristic of solid tumors, and responses to hypoxia contribute substantially to the malignant phenotype. Hypoxia-induced gene transcription promotes characteristic tumor behaviors including angiogenesis, invasion, metastasis, de-differentiation and enhanced glycolytic metabolism. These effects are mediated, at least in part, by targets of the Hypoxia Inducible Factors (HIFs). The HIFs function as heterodimers, made up of an oxygen-labile α-subunit and a stable (β-subunit, also referred to as ARNT. HIF-1α and HIF-2α stimulate the expression of overlapping as well as unique transcriptional targets, and their induction can have distinct biological effects. New targets and novel mechanisms of dysregulation place the HIFs in an ever more central role in tumor biology, and have led to development of pharmacological inhibitors of their activity.
PMCID: PMC3215290  PMID: 17208433

Results 1-25 (103)