Honors & Awards

  • DoD Breast Cancer Pre-doctoral Fellowship, Department of Defense (2006-2008)
  • Young Investigator Award & Oral Presentation, Radiation Research Society (2008)
  • Young Investigator Travel Award, International Congress of Radiation Research (2007)

Professional Education

  • Doctor of Philosophy, Duke University (2010)
  • Bachelor of Science, Ewha Women's University, Biological Sciences (2003)

Stanford Advisors

Research & Scholarship

Current Research and Scholarly Interests

Tumor Hypoxia and Radioresistance


All Publications

  • NADPH oxidase-mediated reactive oxygen species production activates hypoxia-inducible factor-1 (HIF-1) via the ERK pathway after hyperthermia treatment PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Moon, E. J., Sonveaux, P., Porporato, P. E., Danhier, P., Gallez, B., Batinic-Haberle, I., Nien, Y., Schroeder, T., Dewhirst, M. W. 2010; 107 (47): 20477-20482


    Hyperthermia (HT) is a strong adjuvant treatment with radiotherapy and chemotherapy because it causes tumor reoxygenation. However, the detailed molecular mechanisms of how HT enhances tumor oxygenation have not been elucidated. Here we report that 1 h of HT activates hypoxia-inducible factor-1 (HIF-1) in tumors and its downstream targets, vascular endothelial growth factor (VEGF) and pyruvate dehydrogenase kinase 1 (PDK1). Consistent with HIF-1 activation and up-regulation of its downstream genes, HT also enhances tumor perfusion/vascularization and decreases oxygen consumption. As a result, tumor hypoxia is reduced after HT, suggesting that these physiological changes contribute to HT-induced tumor reoxygenation. Because HIF-1 is a potent regulator of tumor vascularization and metabolism, our findings suggest that HIF-1 plays a role in HT-induced tumor reoxygenation by transactivating its downstream targets. We demonstrate that NADPH oxidase-mediated reactive oxygen species production, as a mechanism, up-regulates HIF-1 after HT. Furthermore, we determine that this pathway is initiated by increased transcription of NADPH oxidase-1 through the ERK pathway. In conclusion, this study determines that, although HIF-1 is a good therapeutic target, the timing of its inhibition needs to be optimized to achieve the most beneficial outcome when it is combined with other treatments of HT, radiation, and chemotherapy.

    View details for DOI 10.1073/pnas.1006646107

    View details for Web of Science ID 000284529000061

    View details for PubMedID 21059928

  • The potential role of intrinsic hypoxia markers as prognostic variables in cancer ANTIOXIDANTS & REDOX SIGNALING Moon, E. J., Brizel, D. M., Chi, J. A., Dewhirst, M. W. 2007; 9 (8): 1237-1294


    Tumor hypoxia is related to tumor progression and therapy resistance, which leads to poor patient outcome. It has been suggested that measuring the hypoxic status of a tumor helps to predict patient outcome and to select more targeted treatment. However, current methods using needle electrodes or exogenous markers have limitations due to their invasiveness or necessity for preinjection. Recent studies showed that hypoxia-regulated genes could be alternatively used as endogenous hypoxia markers. This is a review of 15 hypoxia-regulated genes, including hypoxia-inducible factor-1 and its targets, and their correlation with tumor hypoxia and patient outcome from 213 studies. Though most of the studies showed significance of these genes in predicting prognosis, there was no definitive prognostic and hypoxia marker. In conclusion, this review suggests the need for further studies with standardized methods to examine gene expression, as well as the use of multiple gene expressions.

    View details for DOI 10.1089/ars.2007.1623

    View details for Web of Science ID 000248169100015

    View details for PubMedID 17571959

  • Tumor cells upregulate normoxic HIF-1a in response to doxorubicin. Cancer research Cao, Y., Eble, J. M., Moon, E., Yuan, H., Weitzel, D. H., Landon, C. D., Nien, C. Y., Hanna, G., Rich, J. N., Provenzale, J. M., Dewhirst, M. W. 2013; 73 (20): 6230-6242


    Hypoxia-inducible factor 1 (HIF-1) is a master transcription factor that controls cellular homeostasis. Although its activation benefits normal tissue, HIF-1 activation in tumors is a major risk factor for angiogenesis, therapeutic resistance, and poor prognosis. HIF-1 activity is usually suppressed under normoxic conditions because of rapid oxygen-dependent degradation of HIF-1α. Here, we show that, under normoxic conditions, HIF-1α is upregulated in tumor cells in response to doxorubicin, a chemotherapeutic agent used to treat many cancers. In addition, doxorubicin enhanced VEGF secretion by normoxic tumor cells and stimulated tumor angiogenesis. Doxorubicin-induced accumulation of HIF-1α in normoxic cells was caused by increased expression and activation of STAT1, the activation of which stimulated expression of iNOS and its synthesis of nitric oxide (NO) in tumor cells. Mechanistic investigations established that blocking NO synthesis or STAT1 activation was sufficient to attenuate the HIF-1α accumulation induced by doxorubicin in normoxic cancer cells. To our knowledge, this is the first report that a chemotherapeutic drug can induce HIF-1α accumulation in normoxic cells, an efficacy-limiting activity. Our results argue that HIF-1α-targeting strategies may enhance doxorubicin efficacy. More generally, they suggest a broader perspective on the design of combination chemotherapy approaches with immediate clinical impact.

    View details for DOI 10.1158/0008-5472.CAN-12-1345

    View details for PubMedID 23959856

  • Sickle Erythrocytes Target Cytotoxics to Hypoxic Tumor Microvessels and Potentiate a Tumoricidal Response PLOS ONE Terman, D. S., Viglianti, B. L., Zennadi, R., Fels, D., Boruta, R. J., Yuan, H., Dreher, M. R., Grant, G., Rabbani, Z. N., Moon, E., Lan, L., Eble, J., Cao, Y., Sorg, B., Ashcraft, K., Palmer, G., Telen, M. J., Dewhirst, M. W. 2013; 8 (1)


    Resistance of hypoxic solid tumor niches to chemotherapy and radiotherapy remains a major scientific challenge that calls for conceptually new approaches. Here we exploit a hitherto unrecognized ability of sickled erythrocytes (SSRBCs) but not normal RBCs (NLRBCs) to selectively target hypoxic tumor vascular microenviroment and induce diffuse vaso-occlusion. Within minutes after injection SSRBCs, but not NLRBCs, home and adhere to hypoxic 4T1 tumor vasculature with hemoglobin saturation levels at or below 10% that are distributed over 70% of the tumor space. The bound SSRBCs thereupon form microaggregates that obstruct/occlude up to 88% of tumor microvessels. Importantly, SSRBCs, but not normal RBCs, combined with exogenous prooxidant zinc protoporphyrin (ZnPP) induce a potent tumoricidal response via a mutual potentiating mechanism. In a clonogenic tumor cell survival assay, SSRBC surrogate hemin, along with H(2)O(2) and ZnPP demonstrate a similar mutual potentiation and tumoricidal effect. In contrast to existing treatments directed only to the hypoxic tumor cell, the present approach targets the hypoxic tumor vascular environment and induces injury to both tumor microvessels and tumor cells using intrinsic SSRBC-derived oxidants and locally generated ROS. Thus, the SSRBC appears to be a potent new tool for treatment of hypoxic solid tumors, which are notable for their resistance to existing cancer treatments.

    View details for DOI 10.1371/journal.pone.0052543

    View details for Web of Science ID 000313551500017

    View details for PubMedID 23326340

  • Targeting the Lactate Transporter MCT1 in Endothelial Cells Inhibits Lactate-Induced HIF-1 Activation and Tumor Angiogenesis PLOS ONE Sonveaux, P., Copetti, T., De Saedeleer, C. J., Vegran, F., Verrax, J., Kennedy, K. M., Moon, E. J., Dhup, S., Danhier, P., Frerart, F., Gallez, B., Ribeiro, A., Michiels, C., Dewhirst, M. W., Feron, O. 2012; 7 (3)


    Switching to a glycolytic metabolism is a rapid adaptation of tumor cells to hypoxia. Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating tumor cells, it also creates a gradient of lactate that mirrors the gradient of oxygen in tumors. More than a metabolic waste, the lactate anion is known to participate to cancer aggressiveness, in part through activation of the hypoxia-inducible factor-1 (HIF-1) pathway in tumor cells. Whether lactate may also directly favor HIF-1 activation in endothelial cells (ECs) thereby offering a new druggable option to block angiogenesis is however an unanswered question. In this study, we therefore focused on the role in ECs of monocarboxylate transporter 1 (MCT1) that we previously identified to be the main facilitator of lactate uptake in cancer cells. We found that blockade of lactate influx into ECs led to inhibition of HIF-1-dependent angiogenesis. Our demonstration is based on the unprecedented characterization of lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in vascular endothelial growth factor receptor 2 (VEGFR2) and basic fibroblast growth factor (bFGF) expression. Furthermore, using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of tumor angiogenesis through intravital microscopy and immunohistochemistry, we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects. Together with the previous demonstration of MCT1 being a key regulator of lactate exchange between tumor cells, the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities.

    View details for DOI 10.1371/journal.pone.0033418

    View details for Web of Science ID 000303129700060

    View details for PubMedID 22428047

  • Thresholds for thermal damage to normal tissues: An update INTERNATIONAL JOURNAL OF HYPERTHERMIA Yarmolenko, P. S., Moon, E. J., Landon, C., Manzoor, A., Hochman, D. W., Viglianti, B. L., Dewhirst, M. W. 2011; 27 (4): 320-343


    The purpose of this review is to summarise a literature survey on thermal thresholds for tissue damage. This review covers published literature for the consecutive years from 2002-2009. The first review on this subject was published in 2003. It included an extensive discussion of how to use thermal dosimetric principles to normalise all time-temperature data histories to a common format. This review utilises those same principles to address sensitivity of a variety of tissues, but with particular emphasis on brain and testis. The review includes new data on tissues that were not included in the original review. Several important observations have come from this review. First, a large proportion of the papers examined for this review were discarded because time-temperature history at the site of thermal damage assessment was not recorded. It is strongly recommended that future research on this subject include such data. Second, very little data is available examining chronic consequences of thermal exposure. On a related point, the time of assessment of damage after exposure is critically important for assessing whether damage is transient or permanent. Additionally, virtually no data are available for repeated thermal exposures which may occur in certain recreational or occupational activities. For purposes of regulatory guidelines, both acute and lasting effects of thermal damage should be considered.

    View details for DOI 10.3109/02656736.2010.534527

    View details for Web of Science ID 000290734300002

    View details for PubMedID 21591897

  • Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer JOURNAL OF APPLIED PHYSIOLOGY Jones, L. W., Viglianti, B. L., Tashjian, J. A., Kothadia, S. M., Keir, S. T., Freedland, S. J., Potter, M. Q., Moon, E. J., Schroeder, T., Herndon, J. E., Dewhirst, M. W. 2010; 108 (2): 343-348


    Recent epidemiologic studies report that regular exercise may be associated with substantial reductions in cancer-specific and all-cause mortality following a breast cancer diagnosis. The mechanisms underlying this relationship have not been identified. We investigated the effects of long-term voluntary wheel running on growth and progression using an animal model of human breast cancer. We also examined effects on the central features of tumor physiology, including markers of tumor blood perfusion/vascularization, hypoxia, angiogenesis, and metabolism. Athymic female mice fed a high-fat diet were orthotopically (direct into the mammary fat pad) implanted with human breast cancer cells (MDA-MB-231 at 1 x 10(6)) into the right dorsal mammary fat pad and randomly assigned (1:1) to voluntary wheel running (n = 25) or a nonintervention (sedentary) control group (n = 25). Tumor volume was measured every three days using digital calipers. All experimental animals were killed when tumor volume reached > or = 1,500 mm(3). Kaplan-Meier (KM) analysis indicated that tumor growth (survival) was comparable between the experimental groups (exercise 44 days vs. control 48 days; KM proportional hazard ratio = 1.41, 95% confidence interval, 0.77-2.58, P = 0.14). However, tumors from exercising animals had significantly improved blood perfusion/vascularization relative to the sedentary control group (P < 0.05). Histological analyses indicated that intratumoral hypoxia levels (as assessed by hypoxia-inducible factor 1) were significantly higher in the exercise group relative to sedentary control (P < 0.05). Aerobic exercise can significantly increase intratumoral vascularization, leading to "normalization" of the tissue microenvironment in human breast tumors. Such findings may have important implications for inhibiting tumor metastasis and improving the efficacy of conventional cancer therapies.

    View details for DOI 10.1152/japplphysiol.00424.2009

    View details for Web of Science ID 000274158300016

    View details for PubMedID 19959769

  • Analysis of HIF-1 inhibition by manassantin A and analogues with modified tetrahydrofuran configurations BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Kasper, A. C., Moon, E. J., Hu, X., Park, Y., Wooten, C. M., Kim, H., Yang, W., Dewhirst, M. W., Hong, J. 2009; 19 (14): 3783-3786


    We have shown that manassantin A downregulated the HIF-1alpha expression and inhibited the secretion of VEGF. We have also demonstrated that the 2,3-cis-3,4-trans-4,5-cis-configuration of the tetrahydrofuran is critical to the HIF-1 inhibition of manassantin A.

    View details for DOI 10.1016/j.bmcl.2009.04.071

    View details for Web of Science ID 000267762600019

    View details for PubMedID 19423348

  • Nucleophilic Addition of Organozinc Reagents to 2-Sulfonyl Cyclic Ethers: Stereoselective Synthesis of Manassantins A and B ORGANIC LETTERS Kim, H., Kasper, A. C., Moon, E. J., Park, Y., Wooten, C. M., Dewhirst, M. W., Hong, J. 2009; 11 (1): 89-92


    A convergent route to the synthesis of manassantins A and B, potent inhibitors of HIF-1, is described. Central to the synthesis is a stereoselective addition of an organozinc reagent to a 2-benzenesulfonyl cyclic ether to achieve the 2,3-cis-3,4-trans-4,5-cis-tetrahydrofuran of the natural products. Preliminary structure-activity relationships suggested that the (R)-configuration at C-7 and C-7''' is not critical for HIF-1 inhibition. In addition, the hydroxyl group at C-7 and C-7''' can be replaced with a carbonyl group without loss of activity.

    View details for DOI 10.1021/ol8024617

    View details for Web of Science ID 000262018700023

    View details for PubMedID 19111058

  • Hyaluronic acid induces osteopontin via the phosphatidylinositol 3-kinase/Akt pathway to enhance the motility of human glioma cells CANCER RESEARCH Kim, M. S., Park, M. J., Moon, E. J., Kim, S. J., Lee, C. H., Yoo, H., Shin, S. H., Song, E. S., Lee, S. H. 2005; 65 (3): 686-691


    Hyaluronic acid (HA) binds to cell-surface receptors such as CD44, and seems to be involved in cell adhesion, motility, and tumor progression in brain. To identify gene expression changes that are initiated by HA, we explored human cytokine arrays in U87MG glioma cells and identified osteopontin, a secreted matrix protein, as a transcriptional target of HA. Interestingly, expression of osteopontin was induced by HA in glioma cells lacking functional PTEN, a tumor suppressor gene (U87MG, U251MG, and U373MG), but not in wild-type (wt)-PTEN-harboring cells (LN18 and LN428). To confirm the role of PTEN, adenoviral (Ad)-wt-PTEN was used to induce ectopic expression of wt-PTEN in U87MG cells, leading to reduced HA-mediated osteopontin induction. Reciprocally, transfection with dominant-negative Akt repressed HA-induced osteopontin expression. Furthermore, HA promoted the motility of glioma cells, and down-regulation of induced osteopontin activity via a neutralizing anti-osteopontin antibody repressed HA-induced motility in vitro. Together, these results strongly suggest that induction of osteopontin expression by HA is dependent on activation of the phosphatidylinositol 3-kinase/Akt pathway. Furthermore, our data indicate that PTEN can effectively modulate the expression of osteopontin, and HA-induced osteopontin plays an important role in the motility response induced by HA in human glioma cells.

    View details for Web of Science ID 000226739600003

    View details for PubMedID 15705860

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