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DELIVERY OF MOLECULAR MEDICINE TO TUMORS II: Transvascular Transport 1
Delivery of Molecular and Cellular Medicine to Tumors
Angiogenesis &
Microcirculation
(Lecture I)
Vascular Transport
(Lecture I)
Interstitial and Lymphatic Transport
(Lecture II)
Vascular
Normalization
(Lecture Il)
Harvard-MIT Division of Health Sciences and Technology
HST.525J: Tumor Pathophysiology and Transport Phenomena, Fall 2005
Course Director: Dr. Rakesh Jain Transvascular Transport
OVERVIEW
R.K. Jain, Transport of Molecules Across Tumor Vasculature. Cancer and Metastasis Reviews, 6: 559-594 (1987).
R.K. Jain, 1996 Landis Award Lecture: Delivery of Molecular and Cellular Medicine to Solid Tumors, Microcirculation, 4:1-23
(1997).
R.K. Jain and L.L. Munn, Leaky Vessels? Call Ang1! Nature Medicine, 6:131-32 (2000).
R.K. Jain, L.L. Munn, and D. Fukumura, Dissecting Tumor Pathophysiology using Intravital Microscopy, Nature Reviews
Cancer, 2: 266-276 (2002).
H.F. Dvorak, Vascular Permeability Factor/Vascular Endothelial Growth Factor: A Critical Cytokine in Tumor Angiogenesis and
a Potential Target for Diagnosis and Therapy Journal of Clinical Oncology, 4368-4380 (2002).
R.K. Jain, Molecular Regulation of Vessel Maturation, Nature Medicine,9:685-693 (2003).
R.K. Jain, Normalization of the tumor vasculature: An emerging concept in anti-angiogenic therapy, Science 307: 58-62
(2005). 2005
3
L.E. Gerlowski and R.K. Jain, "Microvascular Permeability of Normal and Neoplastic Tissues," Microvascular Research, 31:288-
305 (1986).
F. Yuan, M. Leunig, D. Berk and R.K. Jain, Microvascular Permeability of Albumin, Vascular Surface Area and Vascular Volume
Measured in Human Adenocarcinoma LS174T Using Dorsal Chamber in SCID Mice, Microvascular Research, 45:269-289
(1993).
F. Yuan, M. Leunig, S.K. Huang, D.A. Berk,D. Papahadjopoulos, and R.K. Jain, Microvascular Permeability and Interstitial
Penetration of Sterically Stabilized (Stealth) Liposomes in a Human Tumor Xenograft, Cancer Research, 54: 3352-3356 (1994).
F. Yuan, H.A. Salehi, Y. Boucher, U.S. Vasthare, R.F. Tuma, and R.K. Jain, Vascular Permeability and Microcirculation of
Gliomas and Mammary Carcinomas Transplanted in Rat and Mouse Cranial Windows, Cancer Research, 54:4564-4568 (1994).
F. Yuan, M. Dellian, D. Fukumura, M. Leunig, D.A. Berk, V.P. Torchilin, and R.K. Jain, Vascular Permeability in a Human Tumor
Xenograft: Molecular Size-Dependence and Cut-off Size, Cancer Research, 55:3752-3756 (1995).
F. Yuan, Y. Chen, M. Dellian, N. Safabakhsh, N. Ferrara, and R.K. Jain, Time-dependent Changes in Vascular Permeability and
Morphology in Established Human Tumor Xenografts Induced by an Anti-VEGF/VPF Antibody, PNAS, 93:14765-14770 (1996).
H.C. Lichtenbeld, F. Yuan, C.C. Michel, and R.K. Jain, Perfusion of Single Tumor Microvessels: Application to Vascular
Permeability Measurement, Microcirculation, 3: 349-357 (1996).
M. Dellian, B.P. Witwer, H.A. Salehi, F. Yuan, and R.K. Jain, Quantitation and Physiological Characterization of bFGF and
VEGF/VPF Induced Vessels in Mice: Effect of Microenvironment on Angiogenesis, American Journal of Pathology, 149:59-71
(1996)
D. Fukumura, F. Yuan, M. Endo, and R.K. Jain, Role of Nitric Oxide in Tumor Microcirculation: Blood Flow, Vascular
Permeability, and Leukocyte-Endothelial Interactions, American Journal of Pathology, 150:713-725 (1997).
Vascular Permeability 2005
4
D. Fukumura, F. Yuan, W.L. Monsky, Y. Chen, and R.K. Jain, Effect of Host Microenvironment on the Microcirculation of Human Colon
Adenocarcinoma, American Journal of Pathology, 150:679-688 (1997).
S. Hobbs, W.L. Monsky, F. Yuan, W.G. Roberts, L. Griffith, V. P. Torchilin and R.K. Jain, Regulation of Transport Pathways in Tumor
Vessels: Role of Tumor Type and Microenvironment, PNAS, 95: 4607-4612 (1998).
R. K. Jain, N. Safabakhsh, A. Sckell, Y. Chin, P. Jiang, L. Benjamin, F. Yuan, and E. Keshet, Endothelial Cell Death, Angiogenesis
and Microvascular Function Following Castration in an Androgen-dependent Tumor: Role of Vascular Endothelial Growth Factor,
PNAS, 95: 10820-10825 (1998).
W.L. Monsky, D. Fukumura, T. Gohongi, M. Ancukiewcz, H.A. Weich, V.P, Torchilin, F. Yuan and R.K. Jain, Augmentation of
Transvascular Transport of Macromolecules and Nanoparticles in Tumors Using Vascular Endothelial Growth Factor, Cancer
Research, 59:4129-4135 (1999).
M. Dellian, F. Yuan, V. S. Trubetskoy, V.P. Torchilin and R.K. Jain, Vascular Permeability in a Human Tumor Xenograft: Molecular
Charge Dependence, British Journal of Cancer, 82: 1513-1518 (2000).
H. Hashizume, P. Baluk, S. Morikawa, J.W. McLean, G. Thurston, S. Roberge, R.K. Jain and D.M. McDonald, Openings Between
Defective Endothelial Cells Contribute to Tumor Vessel Leakiness, American Journal of Pathology, 156: 1363-1380 (2000).
Y.S. Chang, E. di Tomaso, D.M. McDonald. R. Jones, R.K. Jain and L.L. Munn. Mosaic Blood Vessels in Tumors: Frequency of
Cancer Cells in Contact with Flowing Blood, PNAS, 97: 14608-14613 (2000).
Y.S. Chang, L.L. Munn, M. V. Hillsley, R. O. Dull, T.W. Gardner, R.K. Jain and J.M. Tarbell, Effect of Vascular Endothelial Growth
Factor on Cultured Endothelial Cell Monolayer Transport Properties, Microvascular Research, 59: 265-277 (2000).
Y. Tsuzuki, D. Fukumura, B. Oosthuyse, C. Koike, P. Carmeliet and R.K. Jain. VEGF Modulation by Targeting HIF-1a®HRE® VEGF
Cascade Differentially Regulates Vascular Response and Growth Rate in Tumors, Cancer Research, 60: 6248-6252 (2000).
D. Fukumura, T. Gohongi, A Kadambi, J. Ang, C. Yun, D.G. Buerk, P.L. Huang and R.K. Jain, Predominant Role of Endothelial Nitric
Oxide Synthase in VEGF-induced Angiogenesis and Vascular Permeability, PNAS, 98: 2604-2609 (2001).
A. Kadambi, C.M. Carreira, C.-O. Yun, T.P. Padera, D.E.J.G.J. Dolmans, P. Carmeliet, D. Fukumura and R.K. Jain. Vascular
endothelial Growth Factor (VEGF)-C Differentially Affects Tumor Vascular Function and Leukocyte Recruitment: Role of VEGF-
Receptor 2 and Host .VEGF-A, Cancer Research, 61: 2404-2408 (2001).
R.O. Dull, J. Yuan, Y.S. Chang, J. Tarbell, R.K. Jain, and L.L. Munn, Kinetics of Placenta Growth Factor/Vascular Endothelial Growth
Factor Synergy in Endothelial Hydraulic Conductivity and Proliferation, Microvascular Research, 61: 203-210 (2001). 2005
5
E.B. Brown, R.B. Campbell, Y. Tsuzuki, L. Xu, P. Carmeliet, D. Fukumura, and R.K. Jain, In Vivo Measurement of Gene Expression,
Angiogenesis, and Physiological Function in Tumors Using Multiphoton Laser Scanning Microscopy, Nature Medicine, 7:864-868
(2001).
Y. Izumi, L. Xu, E. di Tomaso, D. Fukumura, and R.K. Jain, Herceptin Acts as an Anti-angiogenic Cocktail, Nature. 416:279-280
(2002).
S. Morikawa, P. Baluk, T. Kaidoh, A. Haskell, R.K. Jain and D.M. McDonald, Abnormalities in Pericytes on Blood Vessels and
Endothelial Sprouts in Tumors, Am. J. Pathology, 160:985-1000 (2002).
R.B. Campbell, D. Fukumura, E.B. Brown, L.M. Mazzola, Y. Izumi, R.K. Jain, V.P. Torchilin and L.L. Munn, Cationic Charge
Determines the Distribution of Liposomes between the Vascular and Extravascular Compartments of Tumors, Cancer Research. 62:
6831-6836 (2002).
R. T. Tong, Y. Boucher, S. V. Kozin, D. J. Hicklin, and R. K. Jain, Vascular normalization by VEGFR2 blockade induces a pressure
gradient across the vasculature and improves drug penetration in tumors, Cancer Research, 64:3731-3736 (2004).
F. Winkler, S. Kozin, R. Tong, S. Chae, M. Booth, I. Garkavstev, L. Xu, D. J. Hicklin, D. Fukumura, E. di Tomaso, L.L. Munn, R.K. Jain.
Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation,
Angiopoietin-1, and matrix metallproteinases, Cancer Cell 6: 553-562, 2004.
M. Stroh, J. P. Zimmer, V. Torchilin, M. G. Bawendi, D. Fukumura, & R.K. Jain. Quantum dots spectrally distinguish multiple species
within the tumor milieu in vivo, Nature Medicine 11:687-682, 2005.
E. di Tomaso, D. Capen, A. Haskell, J. Hart, D.M. McDonald, R.K. Jain, R.C. Jones and L.L. Munn, Mosaic tumor vessels: cellular
basis and ultrastructure of focal regions lacking endothelial markers, Cancer Research 65:5740-5749, 2005.
L. Xu, R. Tong, D. M. Cochran and R. K. Jain, Blocking PDGF-D/PDGFb signaling inhibits human renal cell carcinoma progression in
an orthotopic mouse model, Cancer Research 65:5711-5719, 2005.
S. Kashiwagi, Y. Takeshi Gohongi, Z. N. Demou, L. Xu, P. L. Huang, D. G. Buerk, L. L. Munn, R. K. Jain, and D. Fukumura, NO
mediates mural cell recruitment and vessel morphogenesis in murine melanomas and tissue-engineered blood vessels, Journal of
Clinical Investigation 115:1816-1827, 2005 .
Hydraulic Conductivity
E.M. Sevick and R.K. Jain, Measurement of Capillary Filtration Coefficient in a Solid Tumor. Cancer Research, 51:1352-1355 (1991).
M. Endo, R.K. Jain, B. Witwer and D. Brown, Water Channel (Aquaporin 1) Expression and Distribution in Mammary Carcinomas and
Glioblastomas, Microvascular Research, 58: 89-98 (1999). 2005
6
Interstitial Hypertension
Y. Boucher, L.T. Baxter and R.K. Jain, "Interstitial Pressure Gradients in Tissue-Isolated and Subcutaneous Tumors: Implications
for Therapy," Cancer Researc