Research

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Diane  Bielenberg, PhD

Diane Bielenberg
Program:
Vascular Biology Program
Hospital Title:
Research Associate
Academic Title:
Assistant Professor Department of Surgery Harvard Medical School

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.

About Diane Bielenberg

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.

Key Publications

  • 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.
  • 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.
  • Mamluk R, Detmar M, Klagsbrun M, Bielenberg D. (2005) Soluble Neuropilin Targeted to the Skin Inhibits Vascular Permeability. Angiogenesis, 8(3): 217-227.
  • Bielenberg DR, Pettaway CA, Takashima S, Klagsbrun M. (2006) Neuropilins in Neoplasms; Expression, Regulation, and Function. Experimental Cell Research, 312(5): 584-93.
  • Bielenberg DR, Klagsbrun M. (2007) Targeting Endothelial and Tumor Cells with Semaphorins. Cancer Metastasis Reviews, 26(3-4): 421-431.
  • Zwaans BMM, Bielenberg DR. (2007) Potential Therapeutic Strategies for Lymphatic Metastasis. Microvascular Research, 74(2-3): 145-58.

Publications

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  1. Mucka P, Levonyak N, Geretti E, Zwaans BM, Li X, Adini I, Klagsbrun M, Adam RM, Bielenberg DR. Inflammation and Lymphedema Are Exacerbated and Prolonged by Neuropilin 2 Deficiency. Am J Pathol. 2016 Nov; 186(11):2803-2812.
  2. Wong LL, Lee NG, Amarnani D, Choi CJ, Bielenberg DR, Freitag SK, D'Amore PA, Kim LA. Orbital Angiogenesis and Lymphangiogenesis in Thyroid Eye Disease: An Analysis of Vascular Growth Factors with Clinical Correlation. Ophthalmology. 2016 Sep; 123(9):2028-36.
  3. Wang S, Blois A, El Rayes T, Liu JF, Hirsch MS, Gravdal K, Palakurthi S, Bielenberg DR, Akslen LA, Drapkin R, Mittal V, Watnick RS. Development of a prosaposin-derived therapeutic cyclic peptide that targets ovarian cancer via the tumor microenvironment. Sci Transl Med. 2016 Mar 9; 8(329):329ra34.
  4. Shahrabi-Farahani S, Gallottini M, Martins F, Li E, Mudge DR, Nakayama H, Hida K, Panigrahy D, D'Amore PA, Bielenberg DR. Neuropilin 1 Receptor Is Up-Regulated in Dysplastic Epithelium and Oral Squamous Cell Carcinoma. Am J Pathol. 2016 Apr; 186(4):1055-64.
  5. Banyard J, Bielenberg DR. The role of EMT and MET in cancer dissemination. Connect Tissue Res. 2015; 56(5):403-13.
  6. Bielenberg DR, Zetter BR. The Contribution of Angiogenesis to the Process of Metastasis. Cancer J. 2015 Jul-Aug; 21(4):267-73.
  7. Bielenberg DR, D'Amore PA. Lymphatics in development and pathology: introduction to a special issue of Microvascular Research. Microvasc Res. 2014 Nov; 96:1-2.
  8. Panigrahy D, Adini I, Mamluk R, Levonyak N, Bruns CJ, D'Amore PA, Klagsbrun M, Bielenberg DR. Regulation of soluble neuropilin 1, an endogenous angiogenesis inhibitor, in liver development and regeneration. Pathology. 2014 Aug; 46(5):416-23.
  9. Migliozzi MT, Mucka P, Bielenberg DR. Lymphangiogenesis and metastasis--a closer look at the neuropilin/semaphorin3 axis. Microvasc Res. 2014 Nov; 96:68-76.
  10. Banyard J, Chung I, Migliozzi M, Phan DT, Wilson AM, Zetter BR, Bielenberg DR. Identification of genes regulating migration and invasion using a new model of metastatic prostate cancer. BMC Cancer. 2014 May 30; 14:387.
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  12. Shahrabi-Farahani S, Wang L, Zwaans BM, Santana JM, Shimizu A, Takashima S, Kreuter M, Coultas L, D'Amore PA, Arbeit JM, Akslen LA, Bielenberg DR. Neuropilin 1 expression correlates with differentiation status of epidermal cells and cutaneous squamous cell carcinomas. Lab Invest. 2014 Jul; 94(7):752-65.
  13. Panigrahy D, Kalish BT, Huang S, Bielenberg DR, Le HD, Yang J, Edin ML, Lee CR, Benny O, Mudge DK, Butterfield CE, Mammoto A, Mammoto T, Inceoglu B, Jenkins RL, Simpson MA, Akino T, Lih FB, Tomer KB, Ingber DE, Hammock BD, Falck JR, Manthati VL, Kaipainen A, D'Amore PA, Puder M, Zeldin DC, Kieran MW. Epoxyeicosanoids promote organ and tissue regeneration. Proc Natl Acad Sci U S A. 2013 Aug 13; 110(33):13528-33.
  14. Catena R, Bhattacharya N, El Rayes T, Wang S, Choi H, Gao D, Ryu S, Joshi N, Bielenberg D, Lee SB, Haukaas SA, Gravdal K, Halvorsen OJ, Akslen LA, Watnick RS, Mittal V. 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.
  15. Bielenberg DR, D'Amore PA. All vessels are not created equal. Am J Pathol. 2013 Apr; 182(4):1087-91.
  16. Coughlin MF, Bielenberg DR, Lenormand G, Marinkovic M, Waghorne CG, Zetter BR, Fredberg JJ. Cytoskeletal stiffness, friction, and fluidity of cancer cell lines with different metastatic potential. Clin Exp Metastasis. 2013 Mar; 30(3):237-50.
  17. Bielenberg DR, Seth A, Shimizu A, Pelton K, Cristofaro V, Ramachandran A, Zwaans BM, Chen C, Krishnan R, Seth M, Huang L, Takashima S, Klagsbrun M, Sullivan MP, Adam RM. Increased smooth muscle contractility in mice deficient for neuropilin 2. Am J Pathol. 2012 Aug; 181(2):548-59.
  18. Hager MH, Morley S, Bielenberg DR, Gao S, Morello M, Holcomb IN, Liu W, Mouneimne G, Demichelis F, Kim J, Solomon KR, Adam RM, Isaacs WB, Higgs HN, Vessella RL, Di Vizio D, Freeman MR. DIAPH3 governs the cellular transition to the amoeboid tumour phenotype. EMBO Mol Med. 2012 Aug; 4(8):743-60.
  19. Graf N, Bielenberg DR, Kolishetti N, Muus C, Banyard J, Farokhzad OC, Lippard SJ. 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.
  20. Lu L, Bischoff J, Mulliken JB, Bielenberg DR, Fishman SJ, Greene AK. Increased endothelial progenitor cells and vasculogenic factors in higher-staged arteriovenous malformations. Plast Reconstr Surg. 2011 Oct; 128(4):260e-269e.
  21. Gregory KJ, Zhao B, Bielenberg DR, Dridi S, Wu J, Jiang W, Huang B, Pirie-Shepherd S, Fannon M. 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.
  22. Gaur P, Bielenberg DR, Samuel S, Bose D, Zhou Y, Gray MJ, Dallas NA, Fan F, Xia L, Lu J, Ellis LM. Role of class 3 semaphorins and their receptors in tumor growth and angiogenesis. Clin Cancer Res. 2009 Nov 15; 15(22):6763-70.
  23. Bielenberg DR. Metastasis: two assays explore the two roads traveled. Nat Methods. 2008 May; 5(5):384-5.
  24. Amin DN, Bielenberg DR, Lifshits E, Heymach JV, Klagsbrun M. 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.
  25. Bielenberg DR, Shimizu A, Klagsbrun M. Semaphorin-induced cytoskeletal collapse and repulsion of endothelial cells. Methods Enzymol. 2008; 443:299-314.
  26. Bielenberg DR, Klagsbrun M. Targeting endothelial and tumor cells with semaphorins. Cancer Metastasis Rev. 2007 Dec; 26(3-4):421-31.
  27. Kaipainen A, Kieran MW, Huang S, Butterfield C, Bielenberg D, Mostoslavsky G, Mulligan R, Folkman J, Panigrahy D. PPARalpha deficiency in inflammatory cells suppresses tumor growth. PLoS One. 2007; 2(2):e260.
  28. Estrada CR, Salanga M, Bielenberg DR, Harrell WB, Zurakowski D, Zhu X, Palmer MR, Freeman MR, Adam RM. Behavioral profiling of human transitional cell carcinoma ex vivo. Cancer Res. 2006 Mar 15; 66(6):3078-86.
  29. Amin DN, Hida K, Bielenberg DR, Klagsbrun M. 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.
  30. Bielenberg DR, Pettaway CA, Takashima S, Klagsbrun M. Neuropilins in neoplasms: expression, regulation, and function. Exp Cell Res. 2006 Mar 10; 312(5):584-93.
  31. Kurschat P, Bielenberg D, Rossignol-Tallandier M, Stahl A, Klagsbrun M. 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 3; 281(5):2721-9.
  32. Mamluk R, Klagsbrun M, Detmar M, Bielenberg DR. Soluble neuropilin targeted to the skin inhibits vascular permeability. Angiogenesis. 2005; 8(3):217-27.
  33. Bielenberg DR, Hida Y, Shimizu A, Kaipainen A, Kreuter M, Kim CC, Klagsbrun M. Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest. 2004 Nov; 114(9):1260-71.
  34. Parikh AA, Fan F, Liu WB, Ahmad SA, Stoeltzing O, Reinmuth N, Bielenberg D, Bucana CD, Klagsbrun M, Ellis LM. Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of angiogenesis. Am J Pathol. 2004 Jun; 164(6):2139-51.
  35. McCarty MF, Bielenberg DR, Nilsson MB, Gershenwald JE, Barnhill RL, Ahearne P, Bucana CD, Fidler IJ. Epidermal hyperplasia overlying human melanoma correlates with tumour depth and angiogenesis. Melanoma Res. 2003 Aug; 13(4):379-87.
  36. Kreuter M, Bielenberg D, Hida Y, Hida K, Klagsbrun M. Role of neuropilins and semaphorins in angiogenesis and cancer. Ann Hematol. 2002; 81 Suppl 2:S74.
  37. McCarty MF, Bielenberg D, Donawho C, Bucana CD, Fidler IJ. 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.
  38. Fidler IJ, Singh RK, Yoneda J, Kumar R, Xu L, Dong Z, Bielenberg DR, McCarty M, Ellis LM. Critical determinants of neoplastic angiogenesis. Cancer J. 2000 May; 6 Suppl 3:S225-36.
  39. Gagnon ML, Bielenberg DR, Gechtman Z, Miao HQ, Takashima S, Soker S, Klagsbrun M. 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.
  40. Bielenberg DR, McCarty MF, Bucana CD, Yuspa SH, Morgan D, Arbeit JM, Ellis LM, Cleary KR, Fidler IJ. Expression of interferon-beta is associated with growth arrest of murine and human epidermal cells. J Invest Dermatol. 1999 May; 112(5):802-9.
  41. Bielenberg DR, Bucana CD, Sanchez R, Mulliken JB, Folkman J, Fidler IJ. 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.
  42. Dong Z, Greene G, Pettaway C, Dinney CP, Eue I, Lu W, Bucana CD, Balbay MD, Bielenberg D, Fidler IJ. 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.
  43. Bielenberg DR, Bucana CD, Sanchez R, Donawho CK, Kripke ML, Fidler IJ. Molecular regulation of UVB-induced cutaneous angiogenesis. J Invest Dermatol. 1998 Nov; 111(5):864-72.
  44. Bielenberg DR, Fidler IJ, Bucana CD. Constitutive expression of interferon beta in differentiated epithelial cells exposed to environmental stimuli. Cancer Biother Radiopharm. 1998 Oct; 13(5):375-82.
  45. Fidler IJ, Kumar R, Bielenberg DR, Ellis LM. Molecular determinants of angiogenesis in cancer metastasis. Cancer J Sci Am. 1998 May; 4 Suppl 1:S58-66.
  46. Dong Z, Juang SH, Kumar R, Eue I, Xie K, Bielenberg D, Lu W, Bucana C, Yang X, Fidler IJ. 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.
  47. Dinney CP, Bielenberg DR, Perrotte P, Reich R, Eve BY, Bucana CD, Fidler IJ. 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.
  48. Xie K, Bielenberg D, Huang S, Xu L, Salas T, Juang SH, Dong Z, Fidler IJ. 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.
  49. Xie K, Wang Y, Huang S, Xu L, Bielenberg D, Salas T, McConkey DJ, Jiang W, Fidler IJ. Nitric oxide-mediated apoptosis of K-1735 melanoma cells is associated with downregulation of Bcl-2. Oncogene. 1997 Aug 14; 15(7):771-9.
  50. Glinsky GV, Mossine VV, Price JE, Bielenberg D, Glinsky VV, Ananthaswamy HN, Feather MS. 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.
  51. Radinsky R, Risin S, Fan D, Dong Z, Bielenberg D, Bucana CD, Fidler IJ. 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.
  52. Zhang Z, Wang H, Ikeda S, Fahey F, Bielenberg D, Smits P, Hauschka PV. 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.
  53. Bielenberg DR, D'Amore PA. Judah Folkman's contribution to the inhibition of angiogenesis. Lymphat Res Biol. 2008; 6(3-4):203-7.
  54. Yang J, Bielenberg DR, Rodig SJ, Doiron R, Clifton MC, Kung AL, Strong RK, Zurakowski D, Moses MA. Lipocalin 2 promotes breast cancer progression. Proc Natl Acad Sci U S A. 2009 Mar 10; 106(10):3913-8.
  55. Roy R, Rodig S, Bielenberg D, Zurakowski D, Moses MA. 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.
  56. Shimizu A, Nakayama H, Wang P, König C, Akino T, Sandlund J, Coma S, Italiano JE, Mammoto A, Bielenberg DR, Klagsbrun M. 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.
  57. Panigrahy D, Edin ML, Lee CR, Huang S, Bielenberg DR, Butterfield CE, Barnés CM, Mammoto A, Mammoto T, Luria A, Benny O, Chaponis DM, Dudley AC, Greene ER, Vergilio JA, Pietramaggiori G, Scherer-Pietramaggiori SS, Short SM, Seth M, Lih FB, Tomer KB, Yang J, Schwendener RA, Hammock BD, Falck JR, Manthati VL, Ingber DE, Kaipainen A, D'Amore PA, Kieran MW, Zeldin DC. Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice. J Clin Invest. 2012 Jan; 122(1):178-91.
  58. Zwaans BM, Bielenberg DR. Potential therapeutic strategies for lymphatic metastasis. Microvasc Res. 2007 Sep-Nov; 74(2-3):145-58.
  59. Banyard J, Chung I, Wilson AM, Vetter G, Le Béchec A, Bielenberg DR, Zetter BR. Regulation of epithelial plasticity by miR-424 and miR-200 in a new prostate cancer metastasis model. Sci Rep. 2013 Nov 06; 3:3151.
  60. Adini I, Ghosh K, Adini A, Chi ZL, Yoshimura T, Benny O, Connor KM, Rogers MS, Bazinet L, Birsner AE, Bielenberg DR, D'Amato RJ. Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment. J Clin Invest. 2014 Jan; 124(1):425-36.
  61. Adini I, Adini A, Bazinet L, Watnick RS, Bielenberg DR, D'Amato RJ. Melanocyte pigmentation inversely correlates with MCP-1 production and angiogenesis-inducing potential. FASEB J. 2015 Feb; 29(2):662-70.
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