Fukumura, Dai, MD, PhD

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Angiogenesis and Microcirculation in Physiological and Pathophysiological Settings

The long-term goal of my research is to uncover the fundamental nature of vascular biology in both physiological and pathophysiological settings, and to utilize this knowledge for detection and treatment of diseases. Together with outstanding collaborators, I have been developing and utilizing state of the art imaging techniques and animal models which led to the discoveries summarize below.

Role of NO in tumor angiogenesis, lymphangiogenesis, microcirculation and radiation therapy

Nitric oxide (NO) is a highly reactive mediator with a variety of physiological and pathological functions. NO increases and/or maintains tumor blood flow, decreases leukocyte-endothelial interactions, and increases vascular permeability and thus, may facilitate tumor growth. Furthermore, NO mediates angiogenesis and vessel maturation predominantly through endothelial NO synthase. We also found that NO mediates lymph-angiogenesis and metastasis as well as function of lymphatic vessels. We recently uncovered that restoration of perivascular NO gradients improves structure and function of both blood and lymphatic vessels, and response to radiation.

Role of tumor-host interactions in angiogenesis, tumor growth and metastasis

Using genetically engineered mouse and tumor models as well as in vivo imaging techniques, we found for the first time that nontransformed stromal cells –including activated fibroblasts, bone marrow derived cells – are a major inducer of tumor angiogenesis and mediate the formation of abnormal microenvironment. Furthermore, various anti-angiogenic or molecularly targeting treatments result in the activation of host stromal cells leading to treatment resistance. Our recent data indicate that stromal cells in the primary tumor travel with tumor cells and facilitate survival and growth of metastatic tumors. Controlling tumor-host interaction is an promising approach to facilitate tumor treatment. For example,, the blockade of vascular endothelial growth factor signaling can transiently normalize tumor vasculature and potentiate anti-tumor cytotoxic therapies.

Probing tumor microenvironment using nanotechnology

We have been studying the tumor microenvironment and transport properties using nano-probes. We found that relatively large nanoparticles – size of current nanomedicine – can take advantage of enhanced permeability and retention effect for transvascular transport but are unable to penetrate into tumor tissues. We also found superior transvascular transport of rod-shape over spherical nanoparticles. Furthermore, we discovered that neutral charge is the best for interstitial transport. These findings led us to develop multistage nanotherapeutics that shrink upon the entry to the tumor microenvironment in order to facilitate interstitial transport.

Role of obesity in angiogenesis, tumor growth and treatments.

First, we established in vivo system to investigate blood vessel formation during adipogenesis. Using genetic inhibition of PPAR? and pharmacological inhibition of VEGFR2 signaling we found provocative reciprocal regulation of adipogenesis and angiogenesis, suggesting a novel strategy to treat obesity related diseases including cancer. We then established a physiologically based mathematical model and found that leptin pathway plays a key role in maintenance of body mass and its disruption destroys the body weight balance. We are currently studying the underling mechanisms of obesity-induced aggravation of breast cancer through both preclinical studies and clinical trials of breast cancer patients.

Engineering blood vessels

A major limitation of tissue engineering is the lack of functional blood and lymph vessels. First, we established a model to monitor tissue engineered blood vessels in vivo using MPLSM. We found that mesenchymal precursor cells accelerate remodeling of 3-D endothelial cell structure to functional blood vessels, differentiate into peri-vascular cells, and stabilize engineered vessel network for up to a year. Using this tissue engineered blood vessel model,.we then, showed that human ES cell, cord blood and peripheral blood -derived endothelial cells form functional blood vessels in vivo and that human bone marrow derived mesenchymal stem cells serve as perivascular precursor cells, mature and stabilize blood vessels. Detail observation of vessel anastomosis in these tissue-engineered blood vessels revealed a novel mechanism – wrapping-and-tapping of host vessels. More recently, we have established robust protocols deriving endothelial cells and mesenchymal precursor cells from induced pluripotent stem (iPS) cells and successfully generated blood vessels these iPS-derived cells

Selected Publications (from total of 220)

Li W, Liu Y, Yang W, Han X, Li S, Liu H, Gerweck LE, Fukumura D, Loeffler JS, Yang BB, Jain RK, Huang P
MicroRNA-378 enhances radiation response in ectopic and orthotopic implantation models of glioblastoma.
J Neurooncol. 2017;:ePub - PMID: 29081036
Askoxylakis V, Badeaux M, Roberge S, Batista A, Kirkpatrick N, Snuderl M, Amoozgar Z, Seano G, Ferraro GB, Chatterjee S, Xu L, Fukumura D, Duda DG, Jain RK
A cerebellar window for intravital imaging of normal and disease states in mice.
Nat Protoc. 2017;12(11):2251-2262 - PMID: 28981123
Jung K, Heishi T, Incio J, Huang Y, Beech EY, Pinter M, Ho WW, Kawaguchi K, Rahbari NN, Chung E, Kim JK, Clark JW, Willett CG, Yun SH, Luster AD, Padera TP, Jain RK, Fukumura D
Targeting CXCR4-dependent immunosuppressive Ly6C(low) monocytes improves antiangiogenic therapy in colorectal cancer.
Proc Natl Acad Sci U S A. 2017;114(39):10455-10460 - PMID: 28900008 - PMCID: PMC5625928
Jung K, Heishi T, Khan OF, Kowalski PS, Incio J, Rahbari NN, Chung E, Clark JW, Willett CG, Luster AD, Yun SH, Langer R, Anderson DG, Padera TP, Jain RK, Fukumura D
Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy.
J Clin Invest. 2017;127(8):3039-3051 - PMID: 28691930 - PMCID: PMC5531423
Kodack DP, Askoxylakis V, Ferraro GB, Sheng Q, Badeaux M, Goel S, Qi X, Shankaraiah R, Cao ZA, Ramjiawan RR, Bezwada D, Patel B, Song Y, Costa C, Naxerova K, Wong CSF, Kloepper J, Das R, Tam A, Tanboon J, Duda DG, Miller CR, Siegel MB, Anders CK, Sanders M, Estrada MV, Schlegel R, Arteaga CL, Brachtel E, Huang A, Fukumura D, Engelman JA, Jain RK
The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation.
Sci Transl Med. 2017;9(391):ePub - PMID: 28539475
Rowlands CJ, Park D, Bruns OT, Piatkevich KD, Fukumura D, Jain RK, Bawendi MG, Boyden ES, So PT
Wide-field three-photon excitation in biological samples.
Light Sci Appl. 2017;6:e16255 - PMID: 29152380 - PMCID: PMC5687557
Bruns OT, Bischof TS, Harris DK, Franke D, Shi Y, Riedemann L, Bartelt A, Jaworski FB, Carr JA, Rowlands CJ, Wilson MWB, Chen O, Wei H, Hwang GW, Montana DM, Coropceanu I, Achorn OB, Kloepper J, Heeren J, So PTC, Fukumura D, Jensen KF, Jain RK, Bawendi MG
Next-generation in vivo optical imaging with short-wave infrared quantum dots.
Nat Biomed Eng. 2017;1:ePub - PMID: 29119058 - PMCID: PMC5673283
Martin JD, Fukumura D, Duda DG, Boucher Y, Jain RK
Corrigendum: Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity.
Cold Spring Harb Perspect Med. 2016;6(12):ePub - PMID: 27908927 - PMCID: PMC5131752
Nia HT, Liu H, Seano G, Datta M, Jones D, Rahbari N, Incio J, Chauhan VP, Jung K, Martin JD, Askoxylakis V, Padera TP, Fukumura D, Boucher Y, Hornicek FJ, Grodzinsky AJ, Baish JW, Munn LL, Jain RK
Solid stress and elastic energy as measures of tumour mechanopathology.
Nat Biomed Eng. 2016;1:ePub - PMID: 28966873 - PMCID: PMC5621647
Rahbari NN, Kedrin D, Incio J, Liu H, Ho WW, Nia HT, Edrich CM, Jung K, Daubriac J, Chen I, Heishi T, Martin JD, Huang Y, Maimon N, Reissfelder C, Weitz J, Boucher Y, Clark JW, Grodzinsky AJ, Duda DG, Jain RK, Fukumura D
Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases.
Sci Transl Med. 2016;8(360):360ra135 - PMID: 27733559 - PMCID: PMC5457741
Martin JD, Fukumura D, Duda DG, Boucher Y, Jain RK
Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity.
Cold Spring Harb Perspect Med. 2016;:ePub - PMID: 27663981 - PMCID: PMC5131751
Meijer EF, Baish JW, Padera TP, Fukumura D
Measuring Vascular Permeability In Vivo.
Methods Mol Biol. 2016;1458:71-85 - PMID: 27581015 - PMCID: PMC5435480
Incio J, Liu H, Suboj P, Chin SM, Chen IX, Pinter M, Ng MR, Nia HT, Grahovac J, Kao S, Babykutty S, Huang Y, Jung K, Rahbari NN, Han X, Chauhan VP, Martin JD, Kahn J, Huang P, Desphande V, Michaelson J, Michelakos TP, Ferrone CR, Soares R, Boucher Y, Fukumura D, Jain RK
Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy.
Cancer Discov. 2016;6(8):852-69 - PMID: 27246539 - PMCID: PMC4972679
Patil MD, Bhaumik J, Babykutty S, Banerjee UC, Fukumura D
Arginine dependence of tumor cells: targeting a chink in cancer's armor.
Oncogene. 2016;35(38):4957-72 - PMID: 27109103 - PMCID: PMC5457742
Kloepper J, Riedemann L, Amoozgar Z, Seano G, Susek K, Yu V, Dalvie N, Amelung RL, Datta M, Song JW, Askoxylakis V, Taylor JW, Lu-Emerson C, Batista A, Kirkpatrick ND, Jung K, Snuderl M, Muzikansky A, Stubenrauch KG, Krieter O, Wakimoto H, Xu L, Munn LL, Duda DG, Fukumura D, Batchelor TT, Jain RK
Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival.
Proc Natl Acad Sci U S A. 2016;113(16):4476-81 - PMID: 27044098 - PMCID: PMC4843473
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