Reengineering the Physical Microenvironment of Tumors to Improve Drug Delivery and Efficacy: From Mathematical Modeling to Bench to Bedside

Jain, 2013, Normalizing tumor microenvironment to treat cancer: Bench to bedside to biomarkers, J. Clin. Oncol., 31, 2205, 10.1200/JCO.2012.46.3653 Carmeliet, 2000, Angiogenesis in cancer and other diseases, Nature, 407, 249, 10.1038/35025220 Jain, 2007, Angiogenesis in brain tumours, Nat. Rev. Neurosci., 8, 610, 10.1038/nrn2175 Carmeliet, 2011, Molecular mechanisms and clinical applications of angiogenesis, Nature, 473, 298, 10.1038/nature10144 Gazit, 1997, Fractal characteristics of tumor vascular architecture during tumor growth and regression, Microcirculation, 4, 395, 10.3109/10739689709146803 Vakoc, 2009, Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging, Nat. Med., 15, 1219, 10.1038/nm.1971 Hobbs, 1998, Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment, Proc. Natl. Acad. Sci. U. S. A., 95, 4607, 10.1073/pnas.95.8.4607 Hashizume, 2000, Openings between defective endothelial cells explain tumor vessel leakiness, Am. J. Pathol., 156, 1363, 10.1016/S0002-9440(10)65006-7 Stylianopoulos, 2012, Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors, Proc. Natl. Acad. Sci. U. S. A., 109, 15101, 10.1073/pnas.1213353109 Padera, 2004, Pathology: cancer cells compress intratumour vessels, Nature, 427, 695, 10.1038/427695a Griffon-Etienne, 1999, Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors: clinical implications, Cancer Res., 59, 3776 Stylianopoulos, 2013, Coevolution of solid stress and interstitial fluid pressure in tumors during progression: Implications for vascular collapse, Cancer Res., 73, 3833, 10.1158/0008-5472.CAN-12-4521 Erkan, 2012, The impact of the activated stroma on pancreatic ductal adenocarcinoma biology and therapy resistance, Curr. Mol. Med., 12, 288, 10.2174/156652412799218921 Helmlinger, 1997, Solid stress inhibits the growth of multicellular tumor spheroids, Nat. Biotechnol., 15, 778, 10.1038/nbt0897-778 Cheng, 2009, Micro-environmental mechanical stress controls tumor spheroid size and morphology by suppressing proliferation and inducing apoptosis in cancer cells, PLoS One, 4, 10.1371/journal.pone.0004632 Tse, 2012, Mechanical compression drives cancer cells toward invasive phenotype, Proc. Natl. Acad. Sci. U. S. A., 109, 911, 10.1073/pnas.1118910109 Jain, 1987, Transport of molecules across tumor vasculature, Cancer Metastasis Rev., 6, 559, 10.1007/BF00047468 Baxter, 1989, Transport of fluid and macromolecules in tumors. I. Role of interstitial pressure and convection, Microvasc. Res., 37, 77, 10.1016/0026-2862(89)90074-5 Baxter, 1990, Transport of fluid and macromolecules in tumors. II. Role of heterogeneous perfusion and lymphatics, Microvasc. Res., 40, 246, 10.1016/0026-2862(90)90023-K Jain, 2007, Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model, Cancer Res., 67, 2729, 10.1158/0008-5472.CAN-06-4102 Jain, 1988, Determinants of tumor blood flow: a review, Cancer Res., 48, 2641 Stylianopoulos, 2013, Combining two strategies to improve perfusion and drug delivery in solid tumors, Proc. Natl. Acad. Sci. U. S. A., 110, 18632, 10.1073/pnas.1318415110 Jain, 2014, Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia, Cancer Cell, 26, 605, 10.1016/j.ccell.2014.10.006 Wilson, 2011, Targeting hypoxia in cancer therapy, Nat. Rev. Cancer, 11, 393, 10.1038/nrc3064 Young, 1950, The significance of the tissue pressure of normal testicular and of neoplastic (Brown-Pearce carcinoma) tissue in the rabbit, J. Pathol., 62, 313, 10.1002/path.1700620303 Peters, 1980, Microcirculatory studies in rat mammary carcinoma. I. Transparent chamber method, development of microvasculature, and pressures in tumor vessels, J. Natl. Cancer Inst., 65, 631 Nugent, 1984, Extravascular diffusion in normal and neoplastic tissues, Cancer Res., 44, 238 Gerlowski, 1986, Microvascular permeability of normal and neoplastic tissues, Microvasc. Res., 31, 288, 10.1016/0026-2862(86)90018-X Chary, 1989, Direct measurement of interstitial convection and diffusion of albumin in normal and neoplastic tissues by fluorescence photobleaching, Proc. Natl. Acad. Sci. U. S. A., 86, 5385, 10.1073/pnas.86.14.5385 Jain, 1988, Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure, Cancer Res., 48, 7022 Leunig, 1992, Interstitial fluid pressure in solid tumors following hyperthermia: possible correlation with therapeutic response, Cancer Res., 52, 487 Skalak, 1996, Compatibility and the genesis of residual stress by volumetric growth, J. Math. Biol., 34, 889, 10.1007/BF01834825 Netti, 2000, Role of extracellular matrix assembly in interstitial transport in solid tumors, Cancer Res., 60, 2497 Jain, 2001, Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy, Nat. Med., 7, 987, 10.1038/nm0901-987 Brown, 2003, Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation, Nat. Med., 9, 796, 10.1038/nm879 Nia, 2016, Solid stress and elastic energy as measures of tumour mechanopathology, Nat. Biomed. Eng., 1, 10.1038/s41551-016-0004 Voutouri, 2016, Hyaluronan-derived swelling of solid tumors, the contribution of collagen and cancer cells, and Implications for Cancer Therapy, Neoplasia, 18, 732, 10.1016/j.neo.2016.10.001 Martin, 2016, Reengineering the tumor microenvironment to alleviate hypoxia and overcome cancer heterogeneity, Cold Spring Harb. Perspect. Med., 6 Jain, 2014, The role of mechanical forces in tumor growth and therapy, Annu. Rev. Biomed. Eng., 16, 321, 10.1146/annurev-bioeng-071813-105259 Stylianopoulos, 2017, The solid mechanics of cancer and strategies for improved therapy, J. Biomech. Eng. Trans. Asme, 139, 10.1115/1.4034991 Rahbari, 2016, Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases, Sci. Transl. Med., 8, 10.1126/scitranslmed.aaf5219 Voutouri, 2014, Role of constitutive behavior and tumor-host mechanical interactions in the state of stress and growth of solid tumors, PLoS One, 9, 10.1371/journal.pone.0104717 Olive, 2009, Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer, Science, 324, 1457, 10.1126/science.1171362 Northey, 2017, Tissue force programs cell fate and tumor aggression, Cancer Discov., 7, 1224, 10.1158/2159-8290.CD-16-0733 Voutouri, 2018, Accumulation of mechanical forces in tumors is related to hyaluronan content and tissue stiffness, PLoS One, 10.1371/journal.pone.0193801 Chuong, 1986, On residual stresses in arteries, J. Biomech. Eng., 108, 189, 10.1115/1.3138600 Koike, 2002, Solid stress facilitates spheroid formation: potential involvement of hyaluronan, Br. J. Cancer, 86, 947, 10.1038/sj.bjc.6600158 Kalli, 2018, Solid stress facilitates fibroblasts activation to promote pancreatic cancer cell migration, Ann. Biomed. Eng., 10.1007/s10439-018-1997-7 Kaufman, 2005, Glioma expansion in collagen I matrices: analyzing collagen concentration-dependent growth and motility patterns, Biophys. J., 89, 635, 10.1529/biophysj.105.061994 Delarue, 2014, Compressive stress inhibits proliferation in tumor spheroids through a volume limitation, Biophys. J., 107, 1821, 10.1016/j.bpj.2014.08.031 Wipff, 2009, Myofibroblasts work best under stress, J. Bodyw. Mov. Ther., 13, 121, 10.1016/j.jbmt.2008.04.031 Samani, 2007, Elastic moduli of normal and pathological human breast tissues: an inversion-technique-based investigation of 169 samples, Phys. Med. Biol., 52, 1565, 10.1088/0031-9155/52/6/002 Angeli, 2016, Biphasic modeling of brain tumor biomechanics and response to radiation treatment, J. Biomech., 49, 1524, 10.1016/j.jbiomech.2016.03.029 Huang, 2016, Elastic hydrogel as a sensor for detection of mechanical stress generated by single cells grown in three-dimensional environment, Biomaterials, 98, 103, 10.1016/j.biomaterials.2016.04.024 Roose, 2003, Solid stress generated by spheroid growth estimated using a linear poroelasticity model, Microvasc. Res., 66, 204, 10.1016/S0026-2862(03)00057-8 Desmaison, 2013, Mechanical stress impairs mitosis progression in multi-cellular tumor spheroids, PLoS One, 8, 10.1371/journal.pone.0080447 Alessandri, 2013, Cellular capsules as a tool for multicellular spheroid production and for investigating the mechanics of tumor progression in vitro, Proc. Natl. Acad. Sci. U. S. A., 110, 14843, 10.1073/pnas.1309482110 Paszek, 2005, Tensional homeostasis and the malignant phenotype, Cancer Cell, 8, 241, 10.1016/j.ccr.2005.08.010 Samuel, 2011, Actomyosin-mediated cellular tension drives increased tissue stiffness and beta-catenin activation to induce epidermal hyperplasia and tumor growth, Cancer Cell, 19, 776, 10.1016/j.ccr.2011.05.008 Laklai, 2016, Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression, Nat. Med., 22, 497, 10.1038/nm.4082 Friedland, 2009, Mechanically activated integrin switch controls alpha5beta1 function, Science, 323, 642, 10.1126/science.1168441 Levental, 2009, Matrix crosslinking forces tumor progression by enhancing integrin signaling, Cell, 139, 891, 10.1016/j.cell.2009.10.027 Rubashkin, 2014, Force engages vinculin and promotes tumor progression by enhancing PI3K activation of phosphatidylinositol (3,4,5)-triphosphate, Cancer Res., 74, 4597, 10.1158/0008-5472.CAN-13-3698 Shi, 2003, A novel mode for integrin-mediated signaling: tethering is required for phosphorylation of FAK Y397, Mol. Biol. Cell, 14, 4306, 10.1091/mbc.e03-01-0046 Lawson, 2014, The on-off relationship of Rho and Rac during integrin-mediated adhesion and cell migration, Small GTPases, 5, 10.4161/sgtp.27958 Gkretsi, 2017, Identification of Ras suppressor-1 (RSU-1) as a potential breast cancer metastasis biomarker using a three-dimensional in vitro approach, Oncotarget, 8, 27364, 10.18632/oncotarget.16062 Chaffer, 2016, EMT, cell plasticity and metastasis, Cancer Metastasis Rev., 35, 645, 10.1007/s10555-016-9648-7 Guen, 2017, EMT programs promote basal mammary stem cell and tumor-initiating cell stemness by inducing primary ciliogenesis and Hedgehog signaling, Proc. Natl. Acad. Sci. U. S. A., 114, E10532, 10.1073/pnas.1711534114 Mpekris, 2017, Sonic-hedgehog pathway inhibition normalizes desmoplastic tumor microenvironment to improve chemo- and nanotherapy, J. Control. Release, 261, 105, 10.1016/j.jconrel.2017.06.022 Diop-Frimpong, 2011, Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors, Proc. Natl. Acad. Sci. U. S. A., 108, 2909, 10.1073/pnas.1018892108 Chauhan, 2013, Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumor blood vessels, Nat. Commun., 4, 10.1038/ncomms3516 Baxter, 1988, Vascular permeability and interstitial diffusion in superfused tissues: a two-dimensional model, Microvasc. Res., 36, 108, 10.1016/0026-2862(88)90043-X Jain, 2005, Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy, Science, 307, 58, 10.1126/science.1104819 Sevick, 1989, Viscous resistance to blood flow in solid tumors: effect of hematocrit on intratumor blood viscosity, Cancer Res., 49, 3513 Sun, 2007, Non-uniform plasma leakage affects local hematocrit and blood flow: implications for inflammation and tumor perfusion, Ann. Biomed. Eng., 35, 2121, 10.1007/s10439-007-9377-8 Netti, 1996, Effect of transvascular fluid exchange on pressure-flow relationship in tumors: a proposed mechanism for tumor blood flow heterogeneity, Microvasc. Res., 52, 27, 10.1006/mvre.1996.0041 Pries, 2010, The shunt problem: control of functional shunting in normal and tumour vasculature, Nat. Rev. Cancer, 10, 587, 10.1038/nrc2895 Sevick, 1989, Geometric resistance to blood flow in solid tumors perfused ex vivo: effects of tumor size and perfusion pressure, Cancer Res., 49, 3506 Less, 1997, Geometric resistance and microvascular network architecture of human colorectal carcinoma, Microcirculation, 4, 25, 10.3109/10739689709148315 Yuan, 1994, Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows, Cancer Res., 54, 4564 Deen, 1987, Hindered transport of large molecules in liquid-filled pores, AIChE J., 33, 1409, 10.1002/aic.690330902 Stylianopoulos, 2013, Cationic nanoparticles have superior transvascular flux into solid tumors: Insights from a mathematical model, Ann. Biomed. Eng., 41, 68, 10.1007/s10439-012-0630-4 Boucher, 1990, Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy, Cancer Res., 50, 4478 Boucher, 1992, Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse, Cancer Res., 52, 5110 Stohrer, 2000, Oncotic pressure in solid tumors is elevated, Cancer Res., 60, 4251 Tong, 2004, Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors, Cancer Res., 64, 3731, 10.1158/0008-5472.CAN-04-0074 Boucher, 1991, Interstitial hypertension in superficial metastatic melanomas in humans, Cancer Res., 51, 6691 Jain, 1997, Delivery of molecular and cellular medicine to solid tumors, Adv. Drug Deliv. Rev., 26, 71, 10.1016/S0169-409X(97)00027-6 Levick, 1987, Flow through interstitium and other fibrous matrices, Q. J. Exp. Physiol., 72, 409, 10.1113/expphysiol.1987.sp003085 Mok, 2007, Matrix metalloproteinases-1 and -8 improve the distribution and efficacy of an oncolytic virus, Cancer Res., 67, 10664, 10.1158/0008-5472.CAN-07-3107 Swabb, 1974, Diffusion and convection in normal and neoplastic tissues, Cancer Res., 34, 2814 Schmid-Schonbein, 1990, Microlymphatics and lymph flow, Physiol. Rev., 70, 987, 10.1152/physrev.1990.70.4.987 Mendoza, 2003, A model for mechanics of primary lymphatic valves, J. Biomech. Eng., 125, 407, 10.1115/1.1568128 Roddie, 1980, Lymphatic motility, Lymphology, 13, 166 Gashev, 2001, Physiology of human lymphatic contractility: a historical perspective, Lymphology, 34, 124 Bazigou, 2014, Primary and secondary lymphatic valve development: molecular, functional and mechanical insights, Microvasc. Res., 96, 38, 10.1016/j.mvr.2014.07.008 Vittet, 2014, Lymphatic collecting vessel maturation and valve morphogenesis, Microvasc. Res., 96, 31, 10.1016/j.mvr.2014.07.001 Kunert, 2015, Mechanobiological oscillators control lymph flow, Proc. Natl. Acad. Sci. U. S. A., 112, 10938, 10.1073/pnas.1508330112 Baish, 2016, Synchronization and random triggering of lymphatic vessel contractions, PLoS Comput. Biol., 12, 10.1371/journal.pcbi.1005231 Hagendoorn, 2006, Onset of abnormal blood and lymphatic vessel function and interstitial hypertension in early stages of carcinogenesis, Cancer Res., 66, 3360, 10.1158/0008-5472.CAN-05-2655 Leu, 2000, Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation, Cancer Res., 60, 4324 Liao, 2011, Impaired lymphatic contraction associated with immunosuppression, Proc. Natl. Acad. Sci. U. S. A., 108, 18784, 10.1073/pnas.1116152108 Dewhirst, 2017, Transport of drugs from blood vessels to tumour tissue, Nat. Rev. Cancer, 17, 738, 10.1038/nrc.2017.93 Baish, 2011, Scaling rules for diffusive drug delivery in tumor and normal tissues, Proc. Natl. Acad. Sci. U. S. A., 108, 1799, 10.1073/pnas.1018154108 Chauhan, 2011, Delivery of molecular and nanomedicine to tumors: Transport barriers and strategies, Annu. Rev. Chem. Biomol. Eng., 2, 281, 10.1146/annurev-chembioeng-061010-114300 Jain, 2010, Delivering nanomedicine to solid tumors, Nat. Rev. Clin. Oncol., 7, 653, 10.1038/nrclinonc.2010.139 Yuan, 1995, Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size, Cancer Res., 55, 3752 Pluen, 2001, Role of tumor-host interactions in interstitial diffusion of macromolecules: cranial vs. subcutaneous tumors, Proc. Natl. Acad. Sci. U. S. A., 98, 4628, 10.1073/pnas.081626898 Chauhan, 2012, Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner, Nat. Nanotechnol., 7, 383, 10.1038/nnano.2012.45 Stylianopoulos, 2010, Diffusion anisotropy in collagen gels and tumors: The effect of fiber network orientation, Biophys. J., 99, 3119, 10.1016/j.bpj.2010.08.065 Popovic, 2010, A nanoparticle size series for in vivo fluorescence imaging, Angew. Chem. Int. Ed. Engl., 49, 8649, 10.1002/anie.201003142 Fujimori, 1990, A modeling analysis of monoclonal antibody percolation through tumors: a binding-site barrier, J. Nucl. Med., 31, 1191 Baxter, 1991, Transport of fluid and macromolecules in tumors. III. Role of binding and metabolism, Microvasc. Res., 41, 5, 10.1016/0026-2862(91)90003-T Schmidt, 2009, A modeling analysis of the effects of molecular size and binding affinity on tumor targeting, Mol. Cancer Ther., 8, 2861, 10.1158/1535-7163.MCT-09-0195 Lammers, 2012, Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress, J. Control. Release, 161, 175, 10.1016/j.jconrel.2011.09.063 Yuan, 1994, Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft, Cancer Res., 54, 3352 Chauhan, 2011, Fluorescent nanorods and nanospheres for real-time in vivo probing of nanoparticle shape-dependent tumor penetration, Angew. Chem. Int. Ed. Engl., 50, 11417, 10.1002/anie.201104449 Dellian, 2000, Vascular permeability in a human tumour xenograft: molecular charge dependence, Br. J. Cancer, 82, 1513 Schmitt-Sody, 2003, Neovascular targeting therapy: paclitaxel encapsulated in cationic liposomes improves antitumoral efficacy, Clin. Cancer Res., 9, 2335 Krasnici, 2003, Effect of the surface charge of liposomes on their uptake by angiogenic tumor vessels, Int. J. Cancer, 105, 561, 10.1002/ijc.11108 Campbell, 2002, Cationic charge determines the distribution of liposomes between the vascular and extravascular compartments of tumors, Cancer Res., 62, 6831 Lieleg, 2009, Selective filtering of particles by the extracellular matrix: an electrostatic bandpass, Biophys. J., 97, 1569, 10.1016/j.bpj.2009.07.009 Stylianopoulos, 2010, Diffusion of particles in the extracellular matrix: The effect of repulsive electrostatic interactions, Biophys. J., 99, 1342, 10.1016/j.bpj.2010.06.016 Stylianopoulos, 2015, Towards optimal design of cancer nanomedicines: multi-stage nanoparticles for the treatment of solid tumors, Ann. Biomed. Eng., 43, 2291, 10.1007/s10439-015-1276-9 Stylianopoulos, 2015, Design considerations for nanotherapeutics in oncology, Nanomedicine, 11, 1893, 10.1016/j.nano.2015.07.015 Wong, 2011, Multistage nanoparticle delivery system for deep penetration into tumor tissue, Proc. Natl. Acad. Sci. U. S. A., 108, 2426, 10.1073/pnas.1018382108 Stylianopoulos, 2012, Multistage nanoparticles for improved delivery into tumor tissue, Methods Enzymol., 508, 109, 10.1016/B978-0-12-391860-4.00006-9 Guo, 2018, Nanoparticle elasticity directs tumor uptake, Nat. Commun., 9, 130, 10.1038/s41467-017-02588-9 Hammer, 1987, A dynamical model for receptor-mediated cell adhesion to surfaces, Biophys. J., 52, 475, 10.1016/S0006-3495(87)83236-8 Munn, 1995, Kinetics of adhesion molecule expression and spatial organization using targeted sampling fluorometry, Biotechniques, 19 Munn, 1996, Role of erythrocytes in leukocyte-endothelial interactions: mathematical model and experimental validation, Biophys. J., 71, 466, 10.1016/S0006-3495(96)79248-2 Jain, 1996, 1995 Whitaker Lecture: delivery of molecules, particles, and cells to solid tumors, Ann. Biomed. Eng., 24, 457, 10.1007/BF02648108 Huang, 2012, Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy, Proc. Natl. Acad. Sci. U. S. A., 109, 17561, 10.1073/pnas.1215397109 Huang, 2013, Vascular normalization as an emerging strategy to enhance cancer immunotherapy, Cancer Res., 73, 2943, 10.1158/0008-5472.CAN-12-4354 Fukumura, D. et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol. Published online on March 6, 2018; doi: 10.1038/nrclinonc.2018.29. Melder, 1995, Selectin- and integrin-mediated T-lymphocyte rolling and arrest on TNF-alpha-activated endothelium: augmentation by erythrocytes, Biophys. J., 69, 2131, 10.1016/S0006-3495(95)80087-1 Melder, 1993, Imaging of activated natural killer cells in mice by positron emission tomography: preferential uptake in tumors, Cancer Res., 53, 5867 Fukumura, 1995, Tumor necrosis factor alpha-induced leukocyte adhesion in normal and tumor vessels: effect of tumor type, transplantation site, and host strain, Cancer Res., 55, 4824 Melder, 1996, During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium, Nat. Med., 2, 992, 10.1038/nm0996-992 Ohkubo, 1991, Interleukin 2 induced leukocyte adhesion to the normal and tumor microvascular endothelium in vivo and its inhibition by dextran sulfate: implications for vascular leak syndrome, Cancer Res., 51, 1561 Sasaki, 1991, Preferential localization of human adherent lymphokine-activated killer cells in tumor microcirculation, J. Natl. Cancer Inst., 83, 433, 10.1093/jnci/83.6.433 Melder, 1995, Interaction of activated natural killer cells with normal and tumor vessels in cranial windows in mice, Microvasc. Res., 50, 35, 10.1006/mvre.1995.1036 Sasaki, 1989, Low deformability of lymphokine-activated killer cells as a possible determinant of in vivo distribution, Cancer Res., 49, 3742 Melder, 1992, Kinetics of interleukin-2 induced changes in rigidity of human natural killer cells, Cell Biophys., 20, 161, 10.1007/BF02823656 Melder, 1994, Reduction of rigidity in human activated natural killer cells by thioglycollate treatment, J. Immunol. Methods, 175, 69, 10.1016/0022-1759(94)90332-8 Netti, 1999, Enhancement of fluid filtration across tumor vessels: implication for delivery of macromolecules, Proc. Natl. Acad. Sci. U. S. A., 96, 3137, 10.1073/pnas.96.6.3137 Winkler, 2004, Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases, Cancer Cell, 6, 553 Goel, 2011, Normalization of the vasculature for treatment of cancer and other diseases, Physiol. Rev., 91, 1071, 10.1152/physrev.00038.2010 Huang, 2013, Benefits of vascular normalization are dose and time dependent–letter, Cancer Res., 73, 7144, 10.1158/0008-5472.CAN-13-1989 Jiang, 2015, Remodeling tumor vasculature to enhance delivery of intermediate-sized nanoparticles, ACS Nano, 9, 8689, 10.1021/acsnano.5b02028 Dings, 2007, Scheduling of radiation with angiogenesis inhibitors anginex and Avastin improves therapeutic outcome via vessel normalization, Clin. Cancer Res., 13, 3395, 10.1158/1078-0432.CCR-06-2441 McGee, 2010, Improved intratumoral oxygenation through vascular normalization increases glioma sensitivity to ionizing radiation, Int. J. Radiat. Oncol. Biol. Phys., 76, 1537, 10.1016/j.ijrobp.2009.12.010 Batchelor, 2013, Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation, Proc. Natl. Acad. Sci. U. S. A., 110, 19059, 10.1073/pnas.1318022110 Batchelor, 2007, AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients, Cancer Cell, 11, 83, 10.1016/j.ccr.2006.11.021 Sorensen, 2012, Increased survival of glioblastoma patients who respond to anti-angiogenic therapy with elevated blood perfusion, Cancer Res., 72, 402, 10.1158/0008-5472.CAN-11-2464 Matsumoto, 2011, Antiangiogenic agent sunitinib transiently increases tumor oxygenation and suppresses cycling hypoxia, Cancer Res., 71, 6350, 10.1158/0008-5472.CAN-11-2025 Eichhorn, 2008, Contrast enhanced MRI and intravital fluorescence microscopy indicate improved tumor microcirculation in highly vascularized melanomas upon short-term anti-VEGFR treatment, Cancer. Biol. Ther., 7, 1006, 10.4161/cbt.7.7.5997 Qayum, 2009, Tumor vascular changes mediated by inhibition of oncogenic signaling, Cancer Res., 69, 6347, 10.1158/0008-5472.CAN-09-0657 Kashiwagi, 2008, Perivascular nitric oxide gradients normalize tumor vasculature, Nat. Med., 14, 255, 10.1038/nm1730 Goel, 2013, Effects of vascular-endothelial protein tyrosine phosphatase inhibition on breast cancer vasculature and metastatic progression, J. Natl. Cancer Inst., 105, 1188, 10.1093/jnci/djt164 Leite de Oliveira, 2012, Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity, Cancer Cell, 22, 263, 10.1016/j.ccr.2012.06.028 Mpekris, 2017, Role of vascular normalization in benefit from metronomic chemotherapy, Proc. Natl. Acad. Sci. U. S. A., 114, 1994, 10.1073/pnas.1700340114 De Palma, 2017, CD4+ T cell activation and vascular normalization: two sides of the same coin?, Immunity, 46, 773, 10.1016/j.immuni.2017.04.015 Kloepper, 2016, 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., 113, 4476, 10.1073/pnas.1525360113 Peterson, 2016, Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages, Proc. Natl. Acad. Sci. U. S. A., 113, 4470, 10.1073/pnas.1525349113 Willett, 2004, Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer, Nat. Med., 10, 145, 10.1038/nm988 Willett, 2009, Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study, J. Clin. Oncol., 27, 3020, 10.1200/JCO.2008.21.1771 Sorensen, 2009, A ‘vascular normalization index’ as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients, Cancer Res., 69, 5296, 10.1158/0008-5472.CAN-09-0814 Gerstner, 2012, Effects of cediranib, a VEGF signaling inhibitor, in combination with chemoradiation on tumor blood flow and survival in newly diagnosed glioblastoma, J. Clin. Oncol., 30, 2009, 10.1200/jco.2012.30.15_suppl.2009 Gerstner, 2015, A phase I study of cediranib in combination with cilengitide in patients with recurrent glioblastoma, Neuro Oncol., 17, 1386, 10.1093/neuonc/nov085 Lu-Emerson, 2015, Lessons from anti-vascular endothelial growth factor and anti-vascular endothelial growth factor receptor trials in patients with glioblastoma, J. Clin. Oncol., 33, 1197, 10.1200/JCO.2014.55.9575 Papageorgis, 2017, Tranilast-induced stress alleviation in solid tumors improves the efficacy of chemo- and nanotherapeutics in a size-independent manner, Sci. Rep., 7, 10.1038/srep46140 McKee, 2006, Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector, Cancer Res., 66, 2509, 10.1158/0008-5472.CAN-05-2242 Ganesh, 2007, Relaxin-expressing, fiber chimeric oncolytic adenovirus prolongs survival of tumor-bearing mice, Cancer Res., 67, 4399, 10.1158/0008-5472.CAN-06-4260 Kim, 2006, Relaxin expression from tumor-targeting adenoviruses and its intratumoral spread, apoptosis induction, and efficacy, J. Natl. Cancer Inst., 98, 1482, 10.1093/jnci/djj397 Liu, 2017, Use of angiotensin system inhibitors is associated with immune activation and longer survival in nonmetastatic pancreatic ductal adenocarcinoma, Clin. Cancer Res., 23, 5959, 10.1158/1078-0432.CCR-17-0256 Pinter, 2017, Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy, Sci. Transl. Med., 9, 10.1126/scitranslmed.aan5616 Polydorou, 2017, Pirfenidone normalizes the tumor microenvironment to improve chemotherapy, Oncotarget, 8, 24506, 10.18632/oncotarget.15534 Provenzano, 2012, Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma, Cancer Cell, 21, 418, 10.1016/j.ccr.2012.01.007 Liu, 2012, TGF-beta blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma, Proc. Natl. Acad. Sci. U. S. A., 109, 16618, 10.1073/pnas.1117610109 Incio, 2015, Metformin reduces desmoplasia in pancreatic cancer by reprogramming stellate cells and tumor-associated macrophages, PLoS One, 10, 10.1371/journal.pone.0141392 Vennin, 2017, Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis, Sci. Transl. Med., 9, 10.1126/scitranslmed.aai8504 Miller, 2015, Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy, EMBO Mol. Med., 7, 1063, 10.15252/emmm.201404827 Jiang, 2016, Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy, Nat. Med., 22, 851, 10.1038/nm.4123 Sherman, 2014, Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy, Cell, 159, 80, 10.1016/j.cell.2014.08.007 Jain, 1977, Dynamics of drug transport in solid tumors: distributed parameter model, J. Bioeng., 1, 313 Weissbrod, 1978, Pharmacokinetics of methotrexate in leukemia cells: effect of dose and mode of injection, J. Pharmacokinet. Biopharm., 6, 487, 10.1007/BF01062105 Jain, 1979, Pharmacokinetics of methotrexate in solid tumors, J. Pharmacokinet. Biopharm., 7, 181, 10.1007/BF01059737 Townsend, 1982, In vivo pharmacokinetics of triazinate in L-1210 and W-256 cells, J. Pharm. Sci., 71, 1102, 10.1002/jps.2600711005 Gerlowski, 1983, Physiologically based pharmacokinetic modeling: principles and applications, J. Pharm. Sci., 72, 1103, 10.1002/jps.2600721003 Jain, 1978, Effect of inhomogeneities and finite boundaries on temperature distribution in a perfused medium with application to tumors, J. Biomech. Eng., 100, 235, 10.1115/1.3426216 Jain, 1979, Transient temperature distributions in an infinite perfused medium due to a time-dependent, spherical heat source, J. Biomech. Eng., 101, 82, 10.1115/1.3426229 Sien, 1979, Temperature distributions in normal and neoplastic tissues during hyperthermia: a lumped parameter model, J. Therm. Biol., 4, 157, 10.1016/0306-4565(79)90030-5 Jain, 1980, Analysis of transient temperature distribution in a perfused medium Due to a spherical heat source with application to heat transfer in tumors: homogeneous and infinite medium, Chem. Eng. Commun., 4, 95, 10.1080/00986448008935894 Chryanthopoulos, 1980, Thermal interactions between normal and neoplastic tissues in the rat, rabbit, swine, and dog during hyperthermia, Med. Phys., 7, 529, 10.1118/1.594668 Gullino, 1982, Temperature gradients and local perfusion in a mammary carcinoma, J. Natl. Cancer Inst., 68, 519 Volpe, 1982, Temperature distributions and thermal response in humans. I. Simulations of various modes of whole-body hyperthermia in normal subjects, Med. Phys., 9, 506, 10.1118/1.595115 Volpe, 1983, Temperature distributions and thermal response in humans. II. Simulation of whole-body, regional and localized hyperthermia in cancer patients, AlChE Symp. Ser., 79, 116 Jain, 1984, Mass and heat transfer in tumors: applications in detection and treatment, Adv. Transp. Process., 3, 205 Baxter, 1991, Transport of fluid and macromolecules in tumors. IV. A microscopic model of the perivascular distribution, Microvasc. Res., 41, 252, 10.1016/0026-2862(91)90026-8 Netti, 1995, Time-dependent behavior of interstitial fluid pressure in solid tumors: implications for drug delivery, Cancer Res., 55, 5451 Baish, 1997, Transmural coupling of fluid flow in microcirculatory network and interstitium in tumors, Microvasc. Res., 53, 128, 10.1006/mvre.1996.2005 Swartz, 1999, Mechanics of interstitial-lymphatic fluid transport: theoretical foundation and experimental validation, J. Biomech., 32, 1297, 10.1016/S0021-9290(99)00125-6 Gazit, 1995, Scale-invariant behavior and vascular network formation in normal and tumor tissue, Phys. Rev. Lett., 75, 2428, 10.1103/PhysRevLett.75.2428 Baish, 1996, Role of tumor vascular architecture in nutrient and drug delivery: an invasion percolation-based network model, Microvasc. Res., 51, 327, 10.1006/mvre.1996.0031 Zhu, 1996, Physiologically based kinetic model of effector cell biodistribution in mammals: implications for adoptive immunotherapy, Cancer Res., 56, 3771 Zhu, 1997, Potential and limitations of radioimmunodetection and radioimmunotherapy with monoclonal antibodies, J. Nucl. Med., 38, 731 Melder, 2002, Systemic distribution and tumor localization of adoptively transferred lymphocytes in mice: comparison with physiologically based pharmacokinetic model, Neoplasia, 4, 3, 10.1038/sj.neo.7900209 Friedrich, 2002, Antibody-directed effector cell therapy of tumors: analysis and optimization using a physiologically based pharmacokinetic model, Neoplasia, 4, 449, 10.1038/sj.neo.7900260 Migliorini, 2002, Red blood cells augment leukocyte rolling in a virtual blood vessel, Biophys. J., 83, 1834, 10.1016/S0006-3495(02)73948-9 Sun, 2003, Red blood cells initiate leukocyte rolling in postcapillary expansions: a lattice Boltzmann analysis, Biophys. J., 85, 208, 10.1016/S0006-3495(03)74467-1 Netti, 2003, Coupled macromolecular transport and gel mechanics: Poroviscoelastic approach, AIChE J., 49, 1580, 10.1002/aic.690490621 Mpekris, 2015, Stress-mediated progression of solid tumors: effect of mechanical stress on tissue oxygenation, cancer cell proliferation, and drug delivery, Biomech. Model. Mechanobiol., 14, 1391, 10.1007/s10237-015-0682-0 Swartz, 2012, Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity, Nat. Rev. Cancer, 12, 210, 10.1038/nrc3186 Pries, 2014, Making microvascular networks work: angiogenesis, remodeling, and pruning, Physiology (Bethesda), 29, 446 Chin, 2016, Mechanotransduction in cancer, Curr. Opin. Chem. Eng., 11, 77, 10.1016/j.coche.2016.01.011 Mitchell, 2017, Engineering and physical sciences in oncology: challenges and opportunities, Nat. Rev. Cancer, 17, 659, 10.1038/nrc.2017.83 Pardoll, 2012, The blockade of immune checkpoints in cancer immunotherapy, Nat. Rev. Cancer, 12, 252, 10.1038/nrc3239 Killock, 2018, Immunotherapy: Gut bacteria modulate responses to PD-1 blockade, Nat. Rev. Clin. Oncol., 15, 6 Luksza, 2017, A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy, Nature, 551, 517, 10.1038/nature24473 Rombouts, 2016, Systematic review of resection rates and clinical outcomes after FOLFIRINOX-based treatment in patients with locally advanced pancreatic cancer, Ann. Surg. Oncol., 23, 4352, 10.1245/s10434-016-5373-2 Faris, 2013, FOLFIRINOX in locally advanced pancreatic cancer: the Massachusetts General Hospital Cancer Center experience, Oncologist, 18, 543, 10.1634/theoncologist.2012-0435