Harold F. Dvorak, M.D.
Professor of Pathology
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN-227C
Boston, MA 02215
Office Phone: 617-667-8529
Office Fax: 617-667-2913
Residency training in Pathology at MGH; two years as a post-doc at NIH; 16 years as Staff Pathologist, MGH; 27 years as Chair of Pathology at BIH and then BIDMC; now doing full time research in vascular biology.
Research Interests: Vascular Permeability & Angiogenesis
Basic Research - Tumors induce a heterogeneous neovascular response that includes angiogenesis, arteriogenesis, venogenesis and lymphangiogenesis; we have been able to mimic this response using an adenoviral vector expressing VEGF-A (Ad-VEGF-A164). Whether induced by tumors or by Ad-VEGF-A164, angiogenesis leads to the formation of at least four types of morphologically and functionally distinct blood vessels from preexisting venules: mother vessels (MV) form initially and subsequently differentiate into capillaries, glomeruloid microvascular proliferations (GMP) and vascular malformations (VM). Feeder arteries (FA), draining veins (DV) and giant lymphatics develop simultaneously from preexisting arteries, veins and lymphatics. Ad-VEGF-A164 offers the advantage that it induces the formation of each vessel type in large numbers, with predictable kinetics, and without the complicating presence of tumor cells. My major research interests are as follows: 1. Elucidate the mechanisms by which VEGF-secreting tumors induce the formation of new blood vessels and lymphatics. 2. Define the characteristics of these newly formed vessels. 3. Determine their response to anti-angiogenic therapy. 4. Identify new molecules on tumor vascular endothelium that may serve as therapeutic targets. 5. Elucidate the mechanisms of vascular permeability to macromolecules and cells.
New and Noteworthy Publications:
Nagy, J.A., Benjamin, L., Zeng, H., Dvorak, A.M., and Dvorak, H.F.. (2008) Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis 11, p109. This paper distinguishes among the three types of vascular permeability to circulating macromolecultes, basal vascular permeability (BVP), and the increased permeability induced by VEGF and other vascular permeability factors: the acute vascular permeability (AVH) of acute inflammation and the chronic vascular hyperpermeability (CVH) that is found in tumors, wound healing and chronic inflammatory diseases. Venules are the site of AVH and the pathway is to a large extent trans-endothelial cell via the vesiculo-vacuolar organelle (VVO). CVH is largely mediated by MV and glomeruloid microvascular proliferations (GMP).
Chang, S.H., Kanasaki, K., Gocheva, V., Blum, G., Harper, J., Moses, M.A., Shih, S.C., Nagy, J.A., Joyce, J., Bogyo, M., et al. (2009) VEGF-A induces angiogenesis by perturbing the cathepsin-cysteine protease inhibitor balance in venules, causing basement membrane degradation and mother vessel formation. Cancer Res 69, p4537. This paper demonstrates how increased pericyte cathepsins and reduced pericyte and endothelial cell cysteine protease inhibitors result in venular basement membrande degradation and the formation of mother vessels (MV), the first new blood vessel type to form in tumor- and Ad-VEGF-A164-induced angiogenesis.
Nagy, J.A., Chang, S.H., Shih, S.C., Dvorak, A.M., and Dvorak, H.F.. (2010) Heterogeneity of the tumor vasculature. Seminars in thrombosis and hemostasis 36, p321. This paper describes the several types of new blood vessels induced by tumors and by an adenovirus expressing VEGF-A164, the mechanisms by which they form, and the consequences of their formation.
Zukauskas, A., Merley, A., Li, D., Ang, L.H., Sciuto, T.E., Salman, S., Dvorak, A.M., Dvorak, H.F., and Jaminet, S.C.. (2011) TM4SF1: a tetraspanin-like protein necessary for nanopodia formation and endothelial cell migration. Angiogenesis 14, p345. TM4SF1 is a tetraspanin-like membrane protein that is highly and selectively expressed by cultured endothelial cells (EC) and, in vivo, by EC lining tumor blood vessels. It is necessary for the formation of unusually long (up to 50 mm), thin, F-actin-poor EC cell projections that we term ‘nanopodia’. Like genuine tetraspanins, TM4SF1 serves as a molecular organizer that interacts with membrane and cytoskeletal proteins and uniquely initiates the formation of nanopodia and facilitates cell polarization and migration.
Sitohy, B., Nagy, J.A., Jaminet, S.C., and Dvorak, H.F.. (2011) Tumor-Surrogate Blood Vessel Subtypes Exhibit Differential Susceptibility to Anti-VEGF Therapy. Cancer research 71, p7021. Antivascular therapy directed against VEGF/VEGFR is effective when given at early stages of tumor vessel growth but less so when administered later. Tumor blood vessels are heterogeneous, so vessel sub-populations may differ in their requirements for tumor cell–secreted VEGF and in their susceptibility to anti-VEGF/VEGFR therapy. WE show here that of the six types of new blood vessels found in tumors, only two, both “early” vessels, are sensitive to anti-VEGF therapy; in contrast, vessels that form later over time, and those likely to predominate in human cancers which are present months-years prior to discovery, are not susceptible and, though generated originally by VEGF-A, have become VEGF-A-independent.