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Related Research Units

Vascular Biology Program Research

Research Overview

The Bielenberg laboratory is interested in cancer biology and the study of metastasis.

Metastasis, the spread of cancer cells to distant sites, is the most common cause of death in cancer patients. There are two main routes by which tumor cells disseminate, through blood vessels and through lymphatic vessels. As tumors grow in size their requirements for nutrients and oxygen (carried in blood) increases. To obtain these necessities, tumor cells induce new blood vessels to sprout into the tumor environment, a process called angiogenesis. Besides providing nutrients, tumor blood vessels also serve as an escape route for tumor cells. Therefore, therapies aimed at inhibiting angiogenesis should not only block tumor growth but also metastasis. Tumor blood vessels are leaky and

lead to increased fluid volume and pressure in the interstitial space. Peri-tumoral lymphatic vessels often grow in size to compensate and drain this increased fluid and sometimes sprout into the tumor. Tumor-associated lymphatic capillaries can increase 10-50 times in diameter. These enlarged lymphatic vessels serve as the primary escape route for tumor cells, and indeed, sentinel lymph node metastases are often the first sign of malignancy. The lymphatic system returns fluid back to the blood vascular system through the thoracic duct, therefore tumor cells exiting through lymphatic vessels can spread throughout the body. Therapies aimed at inhibiting lymphangiogenesis are being explored in the Bielenberg laboratory.

The Bielenberg laboratory is pursuing several projects related to the topic of metastasis and the inhibition of tumor angiogenesis and lymphangiogenesis. Specifically, these include:

  • Examining the effect of Semaphorin 3F, a ligand of Neuropilin 2, on tumor growth, angiogenesis, lymphangiogenesis, and metastasis.
  • Determining the effects of low-dose chemotherapy on tumor-associated lymphangiogenesis.
  • Investigating the expression and regulation of Neuropilin 2, a receptor expressed on blood vessels and lymphatic vessels, in (lymph)angiogenesis models using transgenic mice.
  • Examining the expression, function, and role in metastasis of VEGF receptors including VEGFR2 and Neuropilins in tumor cells.
  • Establishing new tumor model systems to investigate the process of metastasis in breast, prostate, and ovarian cancers.

Research Background

Diane Renee Bielenberg received a BS in Chemistry and Biology from the University of Northern Iowa and a PhD in Cancer Biology from the University of Texas Health Science Center and MD Anderson Cancer Center. Dr. Bielenberg performed her post-doctoral studies as an American Cancer Society Fellow at Harvard Medical School and Children's Hospital. She joined the Vascular Biology Program as an Assistant Professor in 2005. Dr. Bielenberg has received several research grant awards including the Howard Temin Award from the NCI, the Dr. Patricia Wexler Award from the Skin Cancer Foundation, and the Patterson Trust Award. In 2008, Dr. Bielenberg received the Harvard Medical School Young Mentor Award.

Selected Publications

  1. Gagnon ML*, Bielenberg DR*, Gechtman Z, Miao H, Takashima S, Soker S, Klagsbrun M. (2000) Identification of a Natural Soluble Neuropilin-1 that Binds Vascular Endothelial Growth Factor: In Vivo Expression and Anti-tumor Activity. Proc Natl Acad Sci USA, 97(6): 2573-2578. *Both authors contributed equally to the manuscript.
  2. Bielenberg DR, Hida Y, Shimizu A, Kaipainen A, Kreuter M, Kim CC, Klagsbrun M. (2004) Semaphorin 3F, a Chemorepulsant for Endothelial Cells, Induces a Poorly Vascularized, Encapsulated, Nonmetastatic Tumor Phenotype. Journal of Clinical Investigation, 114(9): 1260-1271. Commentary in: Hutchinson, E. (2004). Metastasis - No way out? Nature Reviews Cancer, 4: 921.
  3. Mamluk R, Detmar M, Klagsbrun M, Bielenberg D. (2005) Soluble Neuropilin Targeted to the Skin Inhibits Vascular Permeability. Angiogenesis, 8(3): 217-227.
  4. Bielenberg DR, Pettaway CA, Takashima S, Klagsbrun M. (2006) Neuropilins in Neoplasms; Expression, Regulation, and Function. Experimental Cell Research, 312(5): 584-93.
  5. Bielenberg DR, Klagsbrun M. (2007) Targeting Endothelial and Tumor Cells with Semaphorins. Cancer Metastasis Reviews, 26(3-4): 421-431.
  6. Zwaans BMM, Bielenberg DR. (2007) Potential Therapeutic Strategies for Lymphatic Metastasis. Microvascular Research, 74(2-3): 145-58.

Publications

  1. Angiogenesis: Biology and Pathology, Second Edition. Cold Spring Harb Perspect Med. 2024 Jul 29. View Abstract
  2. Addendum: Resolvins suppress tumor growth and enhance cancer therapy. J Exp Med. 2024 Mar 04; 221(3). View Abstract
  3. Two sides of the same coin: Non-alcoholic fatty liver disease and atherosclerosis. Vascul Pharmacol. 2024 03; 154:107249. View Abstract
  4. A 3D biomimetic model of lymphatics reveals cell-cell junction tightening and lymphedema via a cytokine-induced ROCK2/JAM-A complex. Proc Natl Acad Sci U S A. 2023 10 10; 120(41):e2308941120. View Abstract
  5. Inhibition of Wnt Signaling in Colon Cancer Cells via an Oral Drug that Facilitates TNIK Degradation. Mol Cancer Ther. 2023 01 03; 22(1):25-36. View Abstract
  6. PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression. Nat Commun. 2022 12 27; 13(1):7959. View Abstract
  7. Promoting Lymphangiogenesis and Lymphatic Growth and Remodeling to Treat Cardiovascular and Metabolic Diseases. Arterioscler Thromb Vasc Biol. 2023 01; 43(1):e1-e10. View Abstract
  8. Neuropilin 2 Is a Novel Regulator of Distal Colon Contractility. Am J Pathol. 2022 11; 192(11):1592-1603. View Abstract
  9. Diabetes and Its Cardiovascular Complications: Comprehensive Network and Systematic Analyses. Front Cardiovasc Med. 2022; 9:841928. View Abstract
  10. Eicosanoid regulation of debris-stimulated metastasis. Proc Natl Acad Sci U S A. 2021 10 12; 118(41). View Abstract
  11. Investigation of the mechanisms of VEGF-mediated compensatory lung growth: the role of the VEGF heparin-binding domain. Sci Rep. 2021 06 04; 11(1):11827. View Abstract
  12. Unbiased Phenotype-Based Screen Identifies Therapeutic Agents Selective for Metastatic Prostate Cancer. Front Oncol. 2020; 10:594141. View Abstract
  13. Epsins 1 and 2 promote NEMO linear ubiquitination via LUBAC to drive breast cancer development. J Clin Invest. 2021 01 04; 131(1). View Abstract
  14. Resolution of eicosanoid/cytokine storm prevents carcinogen and inflammation-initiated hepatocellular cancer progression. Proc Natl Acad Sci U S A. 2020 09 01; 117(35):21576-21587. View Abstract
  15. Characterization of a Murine Model of Oxazolone-Induced Orbital Inflammation. Transl Vis Sci Technol. 2020 07; 9(8):26. View Abstract
  16. A Single Cell Dissociation Approach for Molecular Analysis of Urinary Bladder in the Mouse Following Spinal Cord Injury. J Vis Exp. 2020 06 17; (160). View Abstract
  17. Triangular correlation (TrC) between cancer aggressiveness, cell uptake capability, and cell deformability. Sci Adv. 2020 01; 6(3):eaax2861. View Abstract
  18. Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases. J Clin Invest. 2019 06 17; 129(7):2964-2979. View Abstract
  19. Aspirin-triggered proresolving mediators stimulate resolution in cancer. Proc Natl Acad Sci U S A. 2019 03 26; 116(13):6292-6297. View Abstract
  20. Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor. Proc Natl Acad Sci U S A. 2019 01 29; 116(5):1698-1703. View Abstract
  21. A paradoxical method to enhance compensatory lung growth: Utilizing a VEGF inhibitor. PLoS One. 2018; 13(12):e0208579. View Abstract
  22. Heparin-Binding Epidermal Growth Factor-Like Growth Factor as a Critical Mediator of Tissue Repair and Regeneration. Am J Pathol. 2018 11; 188(11):2446-2456. View Abstract
  23. Epsin deficiency promotes lymphangiogenesis through regulation of VEGFR3 degradation in diabetes. J Clin Invest. 2018 08 31; 128(9):4025-4043. View Abstract
  24. Chemotherapy-generated cell debris stimulates colon carcinoma tumor growth via osteopontin. FASEB J. 2019 01; 33(1):114-125. View Abstract
  25. Heparin impairs angiogenic signaling and compensatory lung growth after left pneumonectomy. Angiogenesis. 2018 11; 21(4):837-848. View Abstract
  26. Intranasal delivery of VEGF enhances compensatory lung growth in mice. PLoS One. 2018; 13(6):e0198700. View Abstract
  27. Resolvins suppress tumor growth and enhance cancer therapy. J Exp Med. 2018 01 02; 215(1):115-140. View Abstract
  28. Cytochrome P450 monooxygenase lipid metabolites are significant second messengers in the resolution of choroidal neovascularization. Proc Natl Acad Sci U S A. 2017 09 05; 114(36):E7545-E7553. View Abstract
  29. Identification of RUNX1 as a Mediator of Aberrant Retinal Angiogenesis. Diabetes. 2017 07; 66(7):1950-1956. View Abstract
  30. A quantitative method for screening and identifying molecular targets for nanomedicine. J Control Release. 2017 Oct 10; 263:57-67. View Abstract
  31. Deletion of neuropilin 2 enhances detrusor contractility following bladder outlet obstruction. JCI Insight. 2017 02 09; 2(3):e90617. View Abstract
  32. The intragraft microenvironment as a central determinant of chronic rejection or local immunoregulation/tolerance. Curr Opin Organ Transplant. 2017 Feb; 22(1):55-63. View Abstract
  33. Inflammation and Lymphedema Are Exacerbated and Prolonged by Neuropilin 2 Deficiency. Am J Pathol. 2016 11; 186(11):2803-2812. View Abstract
  34. Endothelial epsins as regulators and potential therapeutic targets of tumor angiogenesis. Cell Mol Life Sci. 2017 02; 74(3):393-398. View Abstract
  35. Orbital Angiogenesis and Lymphangiogenesis in Thyroid Eye Disease: An Analysis of Vascular Growth Factors with Clinical Correlation. Ophthalmology. 2016 09; 123(9):2028-36. View Abstract
  36. Development of a prosaposin-derived therapeutic cyclic peptide that targets ovarian cancer via the tumor microenvironment. Sci Transl Med. 2016 Mar 09; 8(329):329ra34. View Abstract
  37. Neuropilin 1 Receptor Is Up-Regulated in Dysplastic Epithelium and Oral Squamous Cell Carcinoma. Am J Pathol. 2016 Apr; 186(4):1055-64. View Abstract
  38. The role of EMT and MET in cancer dissemination. Connect Tissue Res. 2015; 56(5):403-13. View Abstract
  39. The Contribution of Angiogenesis to the Process of Metastasis. Cancer J. 2015 Jul-Aug; 21(4):267-73. View Abstract
  40. Melanocyte pigmentation inversely correlates with MCP-1 production and angiogenesis-inducing potential. FASEB J. 2015 Feb; 29(2):662-70. View Abstract
  41. Lymphatics in development and pathology: introduction to a special issue of Microvascular Research. Microvasc Res. 2014 Nov; 96:1-2. View Abstract
  42. Lymphangiogenesis and metastasis--a closer look at the neuropilin/semaphorin3 axis. Microvasc Res. 2014 Nov; 96:68-76. View Abstract
  43. Regulation of soluble neuropilin 1, an endogenous angiogenesis inhibitor, in liver development and regeneration. Pathology. 2014 Aug; 46(5):416-23. View Abstract
  44. Identification of genes regulating migration and invasion using a new model of metastatic prostate cancer. BMC Cancer. 2014 May 30; 14:387. View Abstract
  45. Neuropilin 1 expression correlates with differentiation status of epidermal cells and cutaneous squamous cell carcinomas. Lab Invest. 2014 Jul; 94(7):752-65. View Abstract
  46. Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment. J Clin Invest. 2014 Jan; 124(1):425-36. View Abstract
  47. Regulation of epithelial plasticity by miR-424 and miR-200 in a new prostate cancer metastasis model. Sci Rep. 2013 Nov 06; 3:3151. View Abstract
  48. Epoxyeicosanoids promote organ and tissue regeneration. Proc Natl Acad Sci U S A. 2013 Aug 13; 110(33):13528-33. View Abstract
  49. Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. Cancer Discov. 2013 May; 3(5):578-89. View Abstract
  50. All vessels are not created equal. Am J Pathol. 2013 Apr; 182(4):1087-91. View Abstract
  51. Netrin-1 promotes glioblastoma cell invasiveness and angiogenesis by multiple pathways including activation of RhoA, cathepsin B, and cAMP-response element-binding protein. J Biol Chem. 2013 Jan 25; 288(4):2210-22. View Abstract
  52. Cytoskeletal stiffness, friction, and fluidity of cancer cell lines with different metastatic potential. Clin Exp Metastasis. 2013 Mar; 30(3):237-50. View Abstract
  53. Increased smooth muscle contractility in mice deficient for neuropilin 2. Am J Pathol. 2012 Aug; 181(2):548-59. View Abstract
  54. DIAPH3 governs the cellular transition to the amoeboid tumour phenotype. EMBO Mol Med. 2012 Aug; 4(8):743-60. View Abstract
  55. a(V)ß(3) integrin-targeted PLGA-PEG nanoparticles for enhanced anti-tumor efficacy of a Pt(IV) prodrug. ACS Nano. 2012 May 22; 6(5):4530-9. View Abstract
  56. Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice. J Clin Invest. 2012 Jan; 122(1):178-91. View Abstract
  57. Increased endothelial progenitor cells and vasculogenic factors in higher-staged arteriovenous malformations. Plast Reconstr Surg. 2011 Oct; 128(4):260e-269e. View Abstract
  58. ADAM12 transmembrane and secreted isoforms promote breast tumor growth: a distinct role for ADAM12-S protein in tumor metastasis. J Biol Chem. 2011 Jun 10; 286(23):20758-68. View Abstract
  59. Vitamin D binding protein-macrophage activating factor directly inhibits proliferation, migration, and uPAR expression of prostate cancer cells. PLoS One. 2010 Oct 18; 5(10):e13428. View Abstract
  60. Notch3 in human breast cancer cell lines regulates osteoblast-cancer cell interactions and osteolytic bone metastasis. Am J Pathol. 2010 Sep; 177(3):1459-69. View Abstract
  61. Role of class 3 semaphorins and their receptors in tumor growth and angiogenesis. Clin Cancer Res. 2009 Nov 15; 15(22):6763-70. View Abstract
  62. Lipocalin 2 promotes breast cancer progression. Proc Natl Acad Sci U S A. 2009 Mar 10; 106(10):3913-8. View Abstract
  63. Metastasis: two assays explore the two roads traveled. Nat Methods. 2008 May; 5(5):384-5. View Abstract
  64. Targeting EGFR activity in blood vessels is sufficient to inhibit tumor growth and is accompanied by an increase in VEGFR-2 dependence in tumor endothelial cells. Microvasc Res. 2008 May; 76(1):15-22. View Abstract
  65. Semaphorin-induced cytoskeletal collapse and repulsion of endothelial cells. Methods Enzymol. 2008; 443:299-314. View Abstract
  66. Judah Folkman's contribution to the inhibition of angiogenesis. Lymphat Res Biol. 2008; 6(3-4):203-7. View Abstract
  67. Targeting endothelial and tumor cells with semaphorins. Cancer Metastasis Rev. 2007 Dec; 26(3-4):421-31. View Abstract
  68. Potential therapeutic strategies for lymphatic metastasis. Microvasc Res. 2007 Sep-Nov; 74(2-3):145-58. View Abstract
  69. PPARalpha deficiency in inflammatory cells suppresses tumor growth. PLoS One. 2007 Feb 28; 2(2):e260. View Abstract
  70. Behavioral profiling of human transitional cell carcinoma ex vivo. Cancer Res. 2006 Mar 15; 66(6):3078-86. View Abstract
  71. Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Cancer Res. 2006 Feb 15; 66(4):2173-80. View Abstract
  72. Neuropilins in neoplasms: expression, regulation, and function. Exp Cell Res. 2006 Mar 10; 312(5):584-93. View Abstract
  73. Neuron restrictive silencer factor NRSF/REST is a transcriptional repressor of neuropilin-1 and diminishes the ability of semaphorin 3A to inhibit keratinocyte migration. J Biol Chem. 2006 Feb 03; 281(5):2721-9. View Abstract
  74. Soluble neuropilin targeted to the skin inhibits vascular permeability. Angiogenesis. 2005; 8(3):217-27. View Abstract
  75. Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest. 2004 Nov; 114(9):1260-71. View Abstract
  76. Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of angiogenesis. Am J Pathol. 2004 Jun; 164(6):2139-51. View Abstract
  77. Epidermal hyperplasia overlying human melanoma correlates with tumour depth and angiogenesis. Melanoma Res. 2003 Aug; 13(4):379-87. View Abstract
  78. Evidence for the causal role of endogenous interferon-alpha/beta in the regulation of angiogenesis, tumorigenicity, and metastasis of cutaneous neoplasms. Clin Exp Metastasis. 2002; 19(7):609-15. View Abstract
  79. Role of neuropilins and semaphorins in angiogenesis and cancer. Ann Hematol. 2002; 81 Suppl 2:S74. View Abstract
  80. Critical determinants of neoplastic angiogenesis. Cancer J. 2000 May; 6 Suppl 3:S225-36. View Abstract
  81. Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: In vivo expression and antitumor activity. Proc Natl Acad Sci U S A. 2000 Mar 14; 97(6):2573-8. View Abstract
  82. Expression of interferon-beta is associated with growth arrest of murine and human epidermal cells. J Invest Dermatol. 1999 May; 112(5):802-9. View Abstract
  83. Progressive growth of infantile cutaneous hemangiomas is directly correlated with hyperplasia and angiogenesis of adjacent epidermis and inversely correlated with expression of the endogenous angiogenesis inhibitor, IFN-beta. Int J Oncol. 1999 Mar; 14(3):401-8. View Abstract
  84. Suppression of angiogenesis, tumorigenicity, and metastasis by human prostate cancer cells engineered to produce interferon-beta. Cancer Res. 1999 Feb 15; 59(4):872-9. View Abstract
  85. Molecular regulation of UVB-induced cutaneous angiogenesis. J Invest Dermatol. 1998 Nov; 111(5):864-72. View Abstract
  86. Constitutive expression of interferon beta in differentiated epithelial cells exposed to environmental stimuli. Cancer Biother Radiopharm. 1998 Oct; 13(5):375-82. View Abstract
  87. Molecular determinants of angiogenesis in cancer metastasis. Cancer J Sci Am. 1998 May; 4 Suppl 1:S58-66. View Abstract
  88. Suppression of tumorigenicity and metastasis in murine UV-2237 fibrosarcoma cells by infection with a retroviral vector harboring the interferon-beta gene. Cancer Immunol Immunother. 1998 May; 46(3):137-46. View Abstract
  89. Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic interferon-alpha administration. Cancer Res. 1998 Feb 15; 58(4):808-14. View Abstract
  90. Abrogation of tumorigenicity and metastasis of murine and human tumor cells by transfection with the murine IFN-beta gene: possible role of nitric oxide. Clin Cancer Res. 1997 Dec; 3(12 Pt 1):2283-94. View Abstract
  91. Nitric oxide-mediated apoptosis of K-1735 melanoma cells is associated with downregulation of Bcl-2. Oncogene. 1997 Aug 14; 15(7):771-9. View Abstract
  92. Inhibition of colony formation in agarose of metastatic human breast carcinoma and melanoma cells by synthetic glycoamine analogs. Clin Exp Metastasis. 1996 May; 14(3):253-67. View Abstract
  93. Level and function of epidermal growth factor receptor predict the metastatic potential of human colon carcinoma cells. Clin Cancer Res. 1995 Jan; 1(1):19-31. View Abstract

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