Photo of Diane R. Bielenberg,  PhD

Diane R. Bielenberg, PhD

Boston Children's Hospital

Boston Children's Hospital
Phone: (617) 919-2428
Fax: (617) 730-0231


diane.bielenberg@childrens.harvard.edu

Diane R. Bielenberg, PhD

Boston Children's Hospital

EDUCATIONAL TITLES

  • Assistant Professor, Surgery, Harvard Medical School
  • Assistant Professor, Vascular Biology Program, Boston Children's Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

Metastasis is the most common cause of death in cancer patients. There are two main routes by which tumor cells disseminate, through blood vessels (hematogenous spread) and through lymphatic vessels (lymphogenous spread). Angiogenesis, the acquisition of new blood vessels, is an important step in tumor progression. Tumors that cannot switch to the angiogenic phenotype remain small dormant lesions. Therefore, drugs aimed at inhibiting angiogenesis are actively being investigated. Therapies targeted against lymphangiogenesis, the growth of new lymphatic vessels, are beginning to be explored. An ideal inhibitor may be one that is anti-angiogenic as well as anti-lymphangiogenic, thereby suppressing both routes of metastasis. Members of the vascular endothelial growth factor (VEGF) family, including VEGF-A and VEGF-C, stimulate the growth of blood vessels and lymphatic vessels. A common receptor expressed on both adult blood vessels and lymphatic vessels is neuropilin 2 (NRP2). Neuropilins are cell surface receptors for members of the VEGF family as well as for members of the semphorin family of axonal guidance mediators. Recently we have demonstrated that one member of the class 3 semaphorins, Semaphorin 3F (SEMA3F), can inhibit human melanoma metastasis. Melanoma is the most lethal skin cancer with most deaths occurring from distant metastases. Phenotypically, SEMA3F-overexpressing tumors are hypo-vascular, encapsulated, and resemble benign nevi. In vitro, SEMA3F inhibits tumor cell adhesion to fibronectin by inhibiting beta 1 integrin levels, inhibits tumor cell motility, and inhibits tumor cell invasion through matrigel. In vivo, mock-transfected tumors are circumscribed with many large, open-lumened lymphatic vessels and contain intratumoral lymphatic vessels as well, while tumors overexpressing SEMA3F do not contain lymphatic vessels or have dilated surrounding lymphatics. SEMA3F may inhibit angiogenesis and lymphangiogenesis by a novel mechanism, which is the repulsion of vascular and lymphatic endothelial cells (EC) expressing NRP2 similar to the way SEMA3F repels neurons. Together these results indicate that SEMA3F is a potent metastasis inhibitor that targets both tumor and stromal cells and raise the possibility of SEMA3F having therapeutic potential.

Publications

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  • 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; 29:662-70. PubMed
  • 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. PubMed
  • 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; 124:425-36. PubMed
  • 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; 14:387. PubMed
  • 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; 110:13528-33. PubMed
  • 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. 2013; 3:578-89. PubMed
  • Bielenberg DR, D'Amore PA. All vessels are not created equal. Am J Pathol 2013; 182:1087-91. PubMed
  • 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; 288:2210-22. PubMed
  • 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; 3:3151. PubMed
  • 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 2012. PubMed
  • 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; 4:743-60. PubMed
  • 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; 177:1459-69. PubMed
  • 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; 5:e13428. PubMed
  • 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; 15:6763-70. PubMed
  • 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; 106:3913-8. PubMed
  • Bielenberg DR. Metastasis: two assays explore the two roads traveled. Nat Methods 2008; 5:384-5. PubMed
  • 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; 76:15-22. PubMed
  • Bielenberg DR, Klagsbrun M. Targeting endothelial and tumor cells with semaphorins. Cancer Metastasis Rev 2007; 26:421-31. PubMed
  • Zwaans BM, Bielenberg DR. Potential therapeutic strategies for lymphatic metastasis. Microvasc Res 2007; 74:145-58. PubMed
  • Bielenberg DR, Pettaway CA, Takashima S, Klagsbrun M. Neuropilins in neoplasms: expression, regulation, and function. Exp Cell Res 2006; 312:584-93. PubMed
  • Mamluk R, Klagsbrun M, Detmar M, Bielenberg DR. Soluble neuropilin targeted to the skin inhibits vascular permeability. Angiogenesis 2005; 8:217-27. PubMed
  • 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; 114:1260-71. PubMed
  • 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; 97:2573-8. PubMed
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