High Interstitial Fluid Pressure - an Obstacle in Cancer Therapy
Abstract
Many solid tumours show an increased interstitial fluid pressure (IFP), which forms a barrier to transcapillary transport. This barrier is an obstacle in tumour treatment, as it results in inefficient uptake of therapeutic agents. There are a number of factors that contribute to increased IFP in the tumour, such as vessel abnormalities, fibrosis and contraction of the interstitial matrix. Lowering the tumour IFP with specific signal-transduction antagonists might be a useful approach to improving anticancer drug efficacy.
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From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [3]
Cancer hypoxia and the induced adaptation mechanisms are major causes of therapy resistance.
“Cancer hypoxia and the induced adaptation mechanisms are two of the major causes of therapy resistance.”
From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [3]
Cites
Dvorak, H. F., Brown, L. F., Detmar, M. J., & Dvořàk, A. M. (1995) · Europe PMC (PubMed Central) · Cited by 3,103 · see citing works
Pericyte Loss and Microaneurysm Formation in PDGF-B-Deficient Mice
Lindahl, P., Johansson, B. R., Levéen, P., & Betsholtz, C. (1997) · Science · doi:10.1126/science.277.5323.242 · Cited by 2,226 · see citing works
Willett, C. G., Boucher, Y., di Tomaso, E., Duda, D. G., Munn, L. L., Tong, R. T., Chung, D. C., Sahani, D. V., Kalva, S. P., Kozin, S. V., et al. (2004) · Nature Medicine · doi:10.1038/nm988 · Cited by 1,966 · see citing works
The myofibroblast in wound healing and fibrocontractive diseases
Gabbiani, G. (2003) · The Journal of Pathology · doi:10.1002/path.1427 · Cited by 1,630 · see citing works
Transport of molecules in the tumor interstitium: a review.
Jain, R. K. (1987) · PubMed · Cited by 1,357 · see citing works
Angiopoietin-1 protects the adult vasculature against plasma leakage
Thurston, G., Rudge, J. S., Ioffe, E., Zhou, H., Ross, L. H., Croll, S. D., Glazer, N. L., Holash, J. A., McDonald, D. M., & Yancopoulos, G. D. (2000) · Nature Medicine · doi:10.1038/74725 · Cited by 1,284 · see citing works
Tong, R. T., Boucher, Y., Kozin, S. V., Winkler, F., Hicklin, D. J., & Jain, R. K. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0074 · Cited by 1,189 · see citing works
Barriers to Drug Delivery in Solid Tumors
Jain, R. K. (1994) · Scientific American · doi:10.1038/scientificamerican0794-58 · Cited by 1,074 · see citing works
Abnormalities in Pericytes on Blood Vessels and Endothelial Sprouts in Tumors
Morikawa, S., Bałuk, P., Kaidoh, T., Haskell, A., Jain, R. K., & McDonald, D. M. (2002) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64920-6 · Cited by 987 · see citing works
Lymphatic Metastasis in the Absence of Functional Intratumor Lymphatics
Padera, T. P., Kadambi, A., di Tomaso, E., Carreira, C. M., Brown, E. B., Boucher, Y., Choi, N. C., Mathisen, D. J., Wain, J. R., Mark, E. J., et al. (2002) · Science · doi:10.1126/science.1071420 · Cited by 964 · see citing works
Interstitial-lymphatic mechanisms in the control of extracellular fluid volume
Aukland, K., & Reed, R. K. (1993) · Physiological Reviews · doi:10.1152/physrev.1993.73.1.1 · Cited by 938 · see citing works
Transport of molecules across tumor vasculature
Jain, R. K. (1987) · Cancer and Metastasis Reviews · doi:10.1007/bf00047468 · Cited by 869 · see citing works
Cancer cells compress intratumour vessels
Padera, T. P., Stoll, B. R., Tooredman, J. B., Capen, D., Tomaso, E. D., & Jain, R. K. (2004) · Nature · doi:10.1038/427695a · Cited by 857 · see citing works
Delivery of molecular and cellular medicine to solid tumors
Jain, R. K. (2012) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2012.09.011 · Cited by 775 · see citing works
Inai, T., Mancuso, M. R., Hashizume, H., Baffert, F., Haskell, A., Bałuk, P., Hu‐Lowe, D. D., Shalinsky, D. R., Thurston, G., Yancopoulos, G. D., et al. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63273-7 · Cited by 759 · see citing works
(1990) · PubMed · Cited by 757 · see citing works
Molecular mechanisms of lymphangiogenesis in health and disease
Alitalo, K. K., & Carmeliet, P. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00051-x · Cited by 737 · see citing works
Lee, C. G., Heijn, M., di Tomaso, E., Griffon, G., Ancukiewicz, M., Koike, C., Park, K. R., Ferrara, N., Jain, R. K., Suit, H. D., et al. (2000) · PubMed · Cited by 674 · see citing works
Transport of macromolecules across microvascular walls: the two-pore theory
Rippe, B., & Haraldsson, B. S. (1994) · Physiological Reviews · doi:10.1152/physrev.1994.74.1.163 · Cited by 564 · see citing works
Montesano, R., & Orci, L. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.13.4894 · Cited by 560 · see citing works
Jain, R. K. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(00)00131-9 · Cited by 529 · see citing works
Abnormalities of Basement Membrane on Blood Vessels and Endothelial Sprouts in Tumors
Baluk, P., Morikawa, S., Haskell, A., Mancuso, M., & McDonald, D. M. (2003) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63540-7 · Cited by 528 · see citing works
Boucher, Y., & Jain, R. K. (1992) · PubMed · Cited by 510 · see citing works
Abramsson, A., Lindblom, P., & Betsholtz, C. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200318549 · Cited by 479 · see citing works
Abramsson, A., Lindblom, P., & Betsholtz, C. (2003) · Journal of Clinical Investigation · doi:10.1172/jci18549 · Cited by 478 · see citing works
(2000) · PubMed · Cited by 475 · see citing works
Pietras, K., Östman, A., SJÖQUIST, M., Buchdunger, E., Reed, R. K., Heldin, C., & Rubin, K. (2001) · PubMed · Cited by 449 · see citing works
Self-citationInhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy.
Pietras, K., Rubin, K., Sjöblom, T., Buchdunger, E., Sjöquist, M., Heldin, C., & Östman, A. (2002) · PubMed · Cited by 432 · see citing works
Self-citationChary, S. R., & Jain, R. K. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.14.5385 · Cited by 412 · see citing works
The next frontier of molecular medicine: Delivery of therapeutics
Jain, R. K. (1998) · Nature Medicine · doi:10.1038/nm0698-655 · Cited by 411 · see citing works
Guo, P., Hu, B., Gu, W., Xu, L., Wang, D., Huang, H.-J. S., Cavenee, W. K., & Cheng, S. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63905-3 · Cited by 367 · see citing works
(1999) · PubMed · Cited by 348 · see citing works
Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11
Wildiers, H. P. M. W., Guetens, G., Boeck, G. D., Verbeken, E. K., Landuyt, B., Landuyt, W., de Bruijn, E. A., & van Oosterom, A. T. (2003) · British Journal of Cancer · doi:10.1038/sj.bjc.6601005 · Cited by 333 · see citing works
Wennström, S., Siegbahn, A., Yokote, K., Arvidsson, A., Heldin, C., Mori, S., & Claesson, L. (1994) · PubMed · Cited by 305 · see citing works
Self-citation(2000) · PubMed · Cited by 295 · see citing works
β1 Integrin-mediated collagen gel contraction is stimulated by PDGF
Gullberg, D., Tingström, A., Thuresson, A., Olsson, L., Terracio, L., Borg, T. K., & Rubin, K. (1990) · Experimental Cell Research · doi:10.1016/0014-4827(90)90305-t · Cited by 270 · see citing works
Self-citation(2001) · PubMed · Cited by 257 · see citing works
(1992) · PubMed · Cited by 252 · see citing works
Eikenes, L., Bruland, Ø. S., Brekken, C., & Davies, C. D. L. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-1472 · Cited by 251 · see citing works
(1992) · PubMed · Cited by 247 · see citing works
Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration
Curnis, F., Sacchi, A., & Corti, A. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15223 · Cited by 238 · see citing works
Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration
Curnis, F., Sacchi, A., & Corti, A. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215223 · Cited by 228 · see citing works
Clark, R. A. F., Folkvord, J. M., Hart, C. E., Murray, M. J., & McPherson, J. M. (1989) · Journal of Clinical Investigation · doi:10.1172/jci114227 · Cited by 221 · see citing works
(1991) · PubMed · Cited by 220 · see citing works
Furuhashi, M., Sjöblom, T., Abramsson, A., Ellingsen, J., Micke, P., Li, H., Folestad, E. B., Eriksson, U., Heuchel, R. L., Betsholtz, C., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-1489 · Cited by 204 · see citing works
Self-citationEnhancement of fluid filtration across tumor vessels: Implication for delivery of macromolecules
Netti, P. A., Hamberg, L. M., Babich, J. W., Kierstead, D., Graham, W. A., Hunter, G. J. S., Wolf, G. L., Fischman, A. J., Boucher, Y., & Jain, R. K. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.6.3137 · Cited by 203 · see citing works
Interstitial fluid pressure in breast cancer, benign breast conditions, and breast parenchyma
Nathanson, S. D., & Nelson, L. (1994) · Annals of Surgical Oncology · doi:10.1007/bf03187139 · Cited by 197 · see citing works
Young, J. S., Llumsden, C. E., & Stalker, A. (1950) · The Journal of Pathology and Bacteriology · doi:10.1002/path.1700620303 · Cited by 191 · see citing works
Heuchel, R. L., Berg, A., Tallquist, M. D., Åhlén, K., Reed, R. K., Rubin, K., Claesson, L., Heldin, C., & Soriano, P. M. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.20.11410 · Cited by 188 · see citing works
Self-citationRoh, H., Boucher, Y., Kalnicki, S., Buchsbaum, R., Bloomer, W. D., & Jain, R. K. (1991) · PubMed · Cited by 180 · see citing works
Analysis of Mural Cell Recruitment to Tumor Vessels
Abramsson, A., Berlin, O., Papayan, H., Paulin, D., Shani, M., & Betsholtz, C. (2002) · Circulation · doi:10.1161/hc0102.101437 · Cited by 178 · see citing works
(1993) · PubMed · Cited by 166 · see citing works
Steinberg, B. M., Smith, K., Colozzo, M. T., & Pollack, R. (1980) · The Journal of Cell Biology · doi:10.1083/jcb.87.1.304 · Cited by 156 · see citing works
Higashi, Y., Kanekura, T., & Kanzaki, T. (2000) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(20000601)86:5 · Cited by 155 · see citing works
Self-citationWiig, H., Rubin, K., & Reed, R. K. (2003) · Acta Anaesthesiologica Scandinavica · doi:10.1034/j.1399-6576.2003.00050.x · Cited by 151 · see citing works
Self-citationSTI571 enhances the therapeutic index of epothilone B by a tumor-selective increase of drug uptake.
Pietras, K., Stumm, M., Hubert, M., Buchdunger, E., Rubin, K., Heldin, C., McSheehy, P. M. J., Wartmann, M., & Östman, A. (2003) · PubMed · Cited by 141 · see citing works
Self-citationA novel physiological function for platelet‐derived growth factor‐BB in rat dermis.
Rodt, S. Å., Åhlén, K., Berg, A., Rubin, K., & Reed, R. K. (1996) · The Journal of Physiology · doi:10.1113/jphysiol.1996.sp021584 · Cited by 136 · see citing works
Self-citationBlockade of beta 1-integrins in skin causes edema through lowering of interstitial fluid pressure.
Reed, R. K., Rubin, K., Wiig, H., & Rodt, S. Å. (1992) · Circulation Research · doi:10.1161/01.res.71.4.978 · Cited by 119 · see citing works
Self-citationLowering of tumor interstitial fluid pressure specifically augments efficacy of chemotherapy
Salnikov, A. V., Iversen, V. V., Koisti, M. J., Sundberg, C., Johansson, L. O. M., Stuhr, L. E. B., Sjöquist, M., Ahlström, H. K., Reed, R. K., & Rubin, K. (2003) · The FASEB Journal · doi:10.1096/fj.02-1201fje · Cited by 116 · see citing works
Self-citationKristensen, C. A., Nozue, M., Boucher, Y., & Jain, R. (1996) · British Journal of Cancer · doi:10.1038/bjc.1996.397 · Cited by 113 · see citing works
Nicotinamide can lower tumor interstitial fluid pressure: mechanistic and therapeutic implications.
Lee, I., Boucher, Y., & Jain, R. K. (1992) · PubMed · Cited by 105 · see citing works
Acute postburn edema: role of strongly negative interstitial fluid pressure
Lund, T., Wiig, H., & Reed, R. K. (1988) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1988.255.5.h1069 · Cited by 98 · see citing works
Meyer, F. A. (1983) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(83)90242-8 · Cited by 95 · see citing works
Dexamethasone reduces the interstitial fluid pressure in a human colon adenocarcinoma xenograft.
Kristjansen, P. E. G., Boucher, Y., & Jain, R. K. (1993) · PubMed · Cited by 75 · see citing works
Boucher, Y., Lee, I., & Jain, R. K. (1995) · Microvascular Research · doi:10.1006/mvre.1995.1051 · Cited by 62 · see citing works
Increasing tumor uptake of anticancer drugs with imatinib
Pietras, K. (2004) · Seminars in Oncology · doi:10.1053/j.seminoncol.2004.03.036 · Cited by 61 · see citing works
Self-citationControl of interstitial fluid pressure: Role of [beta ]-integrins
Reed, R. K., Berg, A., Gjerde, E.-A. B., & Rubin, K. (2001) · Seminars in Nephrology · doi:10.1053/snep.2001.21646 · Cited by 61 · see citing works
Self-citationBrekken, C., & Davies, C. D. L. (1998) · Cancer Letters · doi:10.1016/s0304-3835(98)00202-x · Cited by 54 · see citing works
Lammerts, E., Roswall, P., Sundberg, C., Gotwals, P. J., Koteliansky, V., Reed, R. K., Heldin, N., & Rubin, K. (2002) · International Journal of Cancer · doi:10.1002/ijc.10722 · Cited by 53 · see citing works
Self-citationAcute postburn edema: Role of strongly negative interstitial fluid pressure
Lund, T., Wiig, H., & Reed, R. K. (1989) · Journal of Critical Care · doi:10.1016/0883-9441(89)90039-7 · Cited by 53 · see citing works
Brekken, C., Hjelstuen, M., Bruland, Ø. S., & Davies, C. D. L. (2000) · PubMed · Cited by 53 · see citing works
DiResta, G. R., Lee, J., Larson, S. M., & Arbit, E. (1993) · Microvascular Research · doi:10.1006/mvre.1993.1044 · Cited by 51 · see citing works
Brekken, C., Bruland, Ø. S., & Davies, C. D. L. (2001) · PubMed · Cited by 50 · see citing works
Berg, A., Ekwall, A. H., Rubin, K., Stjernschantz, J., & Reed, R. K. (1998) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1998.274.2.h663 · Cited by 49 · see citing works
Self-citationControl of Ca2+ wave propagation in mouse pancreatic acinar cells
Pfeiffer, F., Sternfeld, L., Schmid, A., & Schulz, I. (1998) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1998.274.3.c663 · Cited by 47 · see citing works
Emerich, D. F., Dean, R. L., Snodgrass, P., Lafreniere, D., Agostino, M., Wiens, T., Xiong, H., Hasler, B. P., Marsh, J. P., Pink, M. M., et al. (2001) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)38780-4 · Cited by 42 · see citing works
Grundström, G., Mosher, D. F., Sakai, T., & Rubin, K. (2003) · Experimental Cell Research · doi:10.1016/j.yexcr.2003.07.010 · Cited by 31 · see citing works
Self-citationCytochalasin D induces edema formation and lowering of interstitial fluid pressure in rat dermis
Berg, A., Rubin, K., & Reed, R. K. (2001) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2001.281.1.h7 · Cited by 30 · see citing works
Self-citationHyaluronan content in experimental carcinoma is not correlated to interstitial fluid pressure
Jacobson, A., Salnikov, A. V., Lammerts, E., Roswall, P., Sundberg, C., Heldin, P., Rubin, K., & Heldin, N. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)00872-6 · Cited by 12 · see citing works
Self-citation
Flagged first, then by citations
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Sorted by citations
Principles of nanoparticle design for overcoming biological barriers to drug delivery
Blanco, E., Shen, H., & Ferrari, M. (2015) · Nature Biotechnology · doi:10.1038/nbt.3330 · Cited by 7,002 · see citing works
Analysis of nanoparticle delivery to tumours
Wilhelm, S., Tavares, A. J., Dai, Q., Ohta, S., Audet, J., Dvorak, H. F., & Chan, W. C. W. (2016) · Nature Reviews Materials · doi:10.1038/natrevmats.2016.14 · Cited by 5,218 · see citing works
The biology and function of fibroblasts in cancer
Kalluri, R. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.73 · Cited by 4,366 · see citing works
Angiogenesis in life, disease and medicine
Carmeliet, P. (2005) · Nature · doi:10.1038/nature04478 · Cited by 3,494 · see citing works
Danhier, F., Féron, O., & Véronique Préat, A. (2010) · Journal of Controlled Release · doi:10.1016/j.jconrel.2010.08.027 · Cited by 2,827 · see citing works
Drug penetration in solid tumours
Minchinton, A. I., & Tannock, I. F. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1893 · Cited by 2,805 · see citing works
Extracellular matrix structure
Theocharis, A. D., Skandalis, S. S., Gialeli, C., & Karamanos, N. K. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.11.001 · Cited by 2,598 · see citing works
Role of platelet-derived growth factors in physiology and medicinePreprint
Andræ, J., Gallini, R., & Betsholtz, C. (2008) · Genes & Development · doi:10.1101/gad.1653708 · Cited by 2,444 · see citing works
Provenzano, P. P., Cuevas, C., Chang, A. E., Goel, V. K., Von Hoff, D. D., & Hingorani, S. R. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.01.007 · Cited by 2,195 · see citing works
Engineered Nanoparticles for Drug Delivery in Cancer Therapy
Sun, T., Zhang, Y. S., Pang, B., Hyun, D. C., Yang, M., & Xia, Y. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201403036 · Cited by 2,164 · see citing works
Drug Resistance and the Solid Tumor Microenvironment
Tredan, O., Galmarini, C. M., Patel, K., & Tannock, I. F. (2007) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djm135 · Cited by 2,116 · see citing works
Macrophages and Therapeutic Resistance in Cancer
Ruffell, B., & Coussens, L. M. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.02.015 · Cited by 1,474 · see citing works
Targeting the TGFβ signalling pathway in disease
Akhurst, R. J., & Hata, A. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3810 · Cited by 1,466 · see citing works
Tumor angiogenesis and vascular normalization: alternative therapeutic targets
Viallard, C., & Larrivée, B. (2017) · Angiogenesis · doi:10.1007/s10456-017-9562-9 · Cited by 1,435 · see citing works
Drug targeting to tumors: Principles, pitfalls and (pre-) clinical progress
Lammers, T., Kiessling, F., Hennink, W. E., & Storm, G. (2012) · Journal of Controlled Release · doi:10.1016/j.jconrel.2011.09.063 · Cited by 1,324 · see citing works
Danhier, F. (2016) · Journal of Controlled Release · doi:10.1016/j.jconrel.2016.11.015 · Cited by 1,288 · see citing works
Barua, S., & Mitragotri, S. (2014) · Nano Today · doi:10.1016/j.nantod.2014.04.008 · Cited by 1,270 · see citing works
Clinical and therapeutic relevance of cancer-associated fibroblasts
Chen, Y., McAndrews, K. M., & Kalluri, R. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00546-5 · Cited by 1,230 · see citing works
Tissue-Penetrating Delivery of Compounds and Nanoparticles into Tumors
Sugahara, K. N., Teesalu, T., Karmali, P. P., Kotamraju, V. R., Agemy, L., Girard, O. M., Hanahan, D., Mattrey, R. F., & Ruoslahti, E. I. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.10.013 · Cited by 1,140 · see citing works
Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer
Jacobetz, M. A., Chan, D. S., Neesse, A., Bapiro, T. E., Cook, N., Frese, K. K., Feig, C., Nakagawa, T., Caldwell, M. E., Zecchini, H. I., et al. (2013) · Gut · doi:10.1136/gutjnl-2012-302529 · Cited by 1,120 · see citing works
Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions
Felfoul, O., Mohammadi, M., Taherkhani, S., de Lanauze, D., Xu, Y. Z., Loghin, D., Essa, S., Jančík, S., Houle, D., Lafleur, M., et al. (2016) · Nature Nanotechnology · doi:10.1038/nnano.2016.137 · Cited by 1,111 · see citing works
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Zhao, Z., Ukidve, A., Kim, J., & Mitragotri, S. (2020) · Cell · doi:10.1016/j.cell.2020.02.001 · Cited by 1,114 · see citing works
Integrin-mediated mechanotransduction
Sun, Z., Guo, S., & Fässler, R. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201609037 · Cited by 1,079 · see citing works
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Sun, Q., Zhou, Z., Qiu, N., & Shen, Y. (2017) · Advanced Materials · doi:10.1002/adma.201606628 · Cited by 1,063 · see citing works
Ernsting, M. J., Murakami, M., Roy, A., & Li, S. (2013) · Journal of Controlled Release · doi:10.1016/j.jconrel.2013.09.013 · Cited by 1,018 · see citing works
Smart nanocarrier-based drug delivery systems for cancer therapy and toxicity studies: A review
Hossen, S., Hossain, M. K., Basher, M. K., Mia, M. N. H., Rahman, M. T., & Uddin, M. J. (2019) · Journal of Advanced Research · doi:10.1016/j.jare.2018.06.005 · Cited by 998 · see citing works
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Derynck, R., Turley, S. J., & Akhurst, R. J. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0403-1 · Cited by 944 · see citing works
Dai, Y., Xu, C., Sun, X., & Chen, X. S. (2017) · Chemical Society Reviews · doi:10.1039/c6cs00592f · Cited by 931 · see citing works
Modelling cancer in microfluidic human organs-on-chips
Sontheimer-Phelps, A., Hassell, B. A., & Ingber, D. E. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-018-0104-6 · Cited by 906 · see citing works
Dynamic interplay between the collagen scaffold and tumor evolution
Egeblad, M., Rasch, M. G., & Weaver, V. M. (2010) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2010.08.015 · Cited by 898 · see citing works
Wolinsky, J. B., Colson, Y. L., & Grinstaff, M. W. (2011) · Journal of Controlled Release · doi:10.1016/j.jconrel.2011.11.031 · Cited by 848 · see citing works
Targeting of drugs and nanoparticles to tumors
Ruoslahti, E. I., Bhatia, S. N., & Sailor, M. J. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.200910104 · Cited by 833 · see citing works
Functional and Biomimetic Materials for Engineering of the Three-Dimensional Cell Microenvironment
Huang, G., Li, F., Zhao, X., Ma, Y., Li, Y., Lin, M., Jin, G., Lu, T. J., Genin, G. M., & Xu, F. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00094 · Cited by 825 · see citing works
Enzyme-activatable polymer–drug conjugate augments tumour penetration and treatment efficacy
Zhou, Q., Shao, S., Wang, J., Xu, C., Xiang, J., Piao, Y., Zhou, Z., Yu, Q., Tang, J., Liu, X., et al. (2019) · Nature Nanotechnology · doi:10.1038/s41565-019-0485-z · Cited by 822 · see citing works
Microenvironmental regulation of therapeutic response in cancer
Klemm, F., & Joyce, J. A. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.11.006 · Cited by 769 · see citing works
Fang, J., Islam, W., & Maeda, H. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.06.005 · Cited by 757 · see citing works
Lipid-Based Drug Delivery Systems in Cancer Therapy: What Is Available and What Is Yet to Come
Yingchoncharoen, P., Kalinowski, D. S., & Richardson, D. R. (2016) · Pharmacological Reviews · doi:10.1124/pr.115.012070 · Cited by 744 · see citing works
In search of definitions: Cancer‐associated fibroblasts and their markers
Nurmik, M., Ullmann, P., Rodriguez, F., Haan, S., & Letellier, E. (2020) · International Journal of Cancer · doi:10.1002/ijc.32193 · Cited by 739 · see citing works
Wiig, H., & Swartz, M. A. (2012) · Physiological Reviews · doi:10.1152/physrev.00037.2011 · Cited by 726 · see citing works
Conquering the Hypoxia Limitation for Photodynamic Therapy
Wan, Y., Fu, L., Li, C., Lin, J., & Huang, P. (2021) · Advanced Materials · doi:10.1002/adma.202103978 · Cited by 705 · see citing works
Mechanisms of Multidrug Resistance in Cancer
Gillet, J., & Gottesman, M. M. (2009) · Methods in molecular biology · doi:10.1007/978-1-60761-416-6_4 · Cited by 696 · see citing works
Nanogels: An overview of properties, biomedical applications and obstacles to clinical translation
Soni, K. S., Desale, S. S., & Bronich, T. K. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.11.009 · Cited by 700 · see citing works
Li, Z., Lai, X., Fu, S., Ren, L. F., Cai, H., Zhang, H., Gu, Z., Ma, X., & Luo, K. (2022) · Advanced Science · doi:10.1002/advs.202201734 · Cited by 688 · see citing works
The application of nanoparticles in cancer immunotherapy: Targeting tumor microenvironment
Yang, M., Li, J., Gu, P., & Fan, X. (2020) · Bioactive Materials · doi:10.1016/j.bioactmat.2020.12.010 · Cited by 680 · see citing works
Cellular mechanotransduction in health and diseases: from molecular mechanism to therapeutic targets
Di, X., Gao, X., Peng, L., Ai, J., Jin, X., Qi, S., Li, H., Wang, K., & Luo, D. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01501-9 · Cited by 660 · see citing works
Loeffler, M. (2006) · Journal of Clinical Investigation · doi:10.1172/jci26532 · Cited by 633 · see citing works
Recent advances of cocktail chemotherapy by combination drug delivery systems
Hu, Q., Sun, W., Wang, C., & Gu, Z. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.10.022 · Cited by 625 · see citing works
Therapeutic targeting of the tumor microenvironment
Joyce, J. A. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.05.024 · Cited by 580 · see citing works
Vascular normalization in Rgs5-deficient tumours promotes immune destruction
Hamzah, J., Jugold, M., Kiessling, F. M., Rigby, P. J., Manzur, M., Marti, H. H., Rabie, T., Kaden, S., Gröne, H., Hämmerling, G. J., et al. (2008) · Nature · doi:10.1038/nature06868 · Cited by 565 · see citing works
Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages
Guerriero, J. L., Sotayo, A., Ponichtera, H. E., Castrillon, J. A., Pourzia, A. L., Schad, S., Johnson, S. F., Carrasco, R. D., Lazo, S., Bronson, R. T., et al. (2017) · Nature · doi:10.1038/nature21409 · Cited by 558 · see citing works
Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity
Swartz, M. A., & Lund, A. W. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3186 · Cited by 544 · see citing works
Targeting the PDGF signaling pathway in tumor treatment
Heldin, C. (2013) · Cell Communication and Signaling · doi:10.1186/1478-811x-11-97 · Cited by 541 · see citing works
Self-citationImproving drug delivery to solid tumors: Priming the tumor microenvironment
Khawar, I. A., Kim, J. H., & Kuh, H.-J. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.12.018 · Cited by 533 · see citing works
Rubbia‐Brandt, L., Giostra, E., Brézault, C., Roth, A., Andrès, A., Audard, V., Sartoretti, P., Dousset, B. E., Majno, P. E., Soubrane, O., et al. (2006) · Annals of Oncology · doi:10.1093/annonc/mdl386 · Cited by 524 · see citing works
Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance
Khalaf, K., Hana, D., Chou, J. T.-T., Singh, C., Mackiewicz, A. A., & Kaczmarek, M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.656364 · Cited by 526 · see citing works
Interstitial flow influences direction of tumor cell migration through competing mechanisms
Polacheck, W. J., Charest, J. L., & Kamm, R. D. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1103581108 · Cited by 509 · see citing works
Rational combinations of targeted cancer therapies: background, advances and challenges
Jin, H., Wang, L., & Bernards, R. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00615-z · Cited by 503 · see citing works
Targeting the microenvironment in solid tumors
Belli, C., Trapani, D., Viale, G., D’Amico, P., Duso, B. A., Vigna, P. D., Orsi, F., & Curigliano, G. (2018) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2018.02.004 · Cited by 506 · see citing works
Liu, D., & Hornsby, P. J. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3452 · Cited by 499 · see citing works
TGF-β Signaling in Lung Health and Disease
Saito, A., Horie, M., & Nagase, T. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19082460 · Cited by 501 · see citing works
Nissen, N. I., Karsdal, M. A., & Willumsen, N. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1110-6 · Cited by 492 · see citing works
VEGF and angiopoietin signaling in tumor angiogenesis and metastasis
Saharinen, P., Eklund, L., Pulkki, K. H., Bono, P., & Alitalo, K. K. (2011) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2011.01.015 · Cited by 478 · see citing works
Extracellularly Activated Nanocarriers: A New Paradigm of Tumor Targeted Drug Delivery
Gullotti, E., & Yeo, Y. (2009) · Molecular Pharmaceutics · doi:10.1021/mp900090z · Cited by 471 · see citing works
Roles of p53, MYC and HIF-1 in regulating glycolysis–the seventh hallmark of cancer
Yeung, S. J., Pan, J., & Lee, M.-H. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8224-x · Cited by 514 · see citing works
Biodistribution, Clearance, and Long‐Term Fate of Clinically Relevant Nanomaterials
Bourquin, J., Milosevic, A. M., Hauser, D., Lehner, R., Blank, F., Petri‐Fink, A., & Rothen‐Rutishauser, B. (2018) · Advanced Materials · doi:10.1002/adma.201704307 · Cited by 470 · see citing works
Tumor penetrating peptides for improved drug delivery
Ruoslahti, E. I. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2016.03.008 · Cited by 461 · see citing works
Phototherapy in cancer treatment: strategies and challenges
Cai, Y., Chai, T., Nguyen, W., Liu, J., Xiao, E., Ran, X., Ran, Y., Du, D., Chen, W., & Chen, X. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02140-y · Cited by 453 · see citing works
Vascular Endothelial Growth Factor as an Anti-Angiogenic Target for Cancer Therapy
Niu, G., & Chen, X. S. (2010) · Current Drug Targets · doi:10.2174/138945010791591395 · Cited by 449 · see citing works
Effect of physicochemical and surface properties on in vivo fate of drug nanocarriers
Zhao, Z., Ukidve, A., Krishnan, V., & Mitragotri, S. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.01.002 · Cited by 449 · see citing works
The tumor microenvironment is a dominant force in multidrug resistance
Correia, A. L., & Bissell, M. J. (2012) · Drug Resistance Updates · doi:10.1016/j.drup.2012.01.006 · Cited by 443 · see citing works
Dickson, P. V., Hamner, J. B., Sims, T. L., Fraga, C. H., Ng, C. Y., Rajasekeran, S., Hagedorn, N. L., McCarville, M. B., Stewart, C. F., & Davidoff, A. M. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-0278 · Cited by 443 · see citing works
The tumor EPR effect for cancer drug delivery: Current status, limitations, and alternatives
Sun, R., Xiang, J., Zhou, Q., Piao, Y., Tang, J., Shao, S., Zhou, Z., Bae, Y. H., & Shen, Y. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114614 · Cited by 442 · see citing works
Chemophototherapy: An Emerging Treatment Option for Solid Tumors
Luo, D., Carter, K. A., Miranda, D., & Lovell, J. F. (2016) · Advanced Science · doi:10.1002/advs.201600106 · Cited by 436 · see citing works
El‐Sawy, H. S., Al-Abd, A. M., Ahmed, T. A., El‐Say, K. M., & Torchilin, V. P. (2018) · ACS Nano · doi:10.1021/acsnano.8b06104 · Cited by 435 · see citing works
Tian, H., Zhang, T., Qin, S., Huang, Z., Zhou, L., Shi, J., Nice, E. C., Xie, N., Huang, C., & Shen, Z. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01320-5 · Cited by 443 · see citing works
Microfluidic cell culture systems for drug research
Wu, M.-H., Huang, S.-B., & Lee, G.-B. (2010) · Lab on a Chip · doi:10.1039/b921695b · Cited by 432 · see citing works
Cardiac fibroblasts: friend or foe?
Baudino, T. A., Carver, W., Giles, W., & Borg, T. K. (2006) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00023.2006 · Cited by 427 · see citing works
Peptides as Targeting Elements and Tissue Penetration Devices for Nanoparticles
Ruoslahti, E. I. (2012) · Advanced Materials · doi:10.1002/adma.201200454 · Cited by 418 · see citing works
Magnesium silicide nanoparticles as a deoxygenation agent for cancer starvation therapy
Zhang, C., Ni, D., Liu, Y., Yao, H., Bu, W., & Shi, J. (2017) · Nature Nanotechnology · doi:10.1038/nnano.2016.280 · Cited by 413 · see citing works
Precise nanomedicine for intelligent therapy of cancer
Chen, H., Gu, Z., An, H., Chen, C., Chen, J., Cui, R., Chen, S., Chen, W., Chen, X., Chen, X. S., et al. (2018) · Science China Chemistry · doi:10.1007/s11426-018-9397-5 · Cited by 409 · see citing works
Biomaterials and emerging anticancer therapeutics: engineering the microenvironment
Gu, L., & Mooney, D. J. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2015.3 · Cited by 407 · see citing works
Mesoporous Silica Nanoparticles as Drug Delivery Vehicles in Cancer
Watermann, A., & Brieger, J. (2017) · Nanomaterials · doi:10.3390/nano7070189 · Cited by 404 · see citing works
Anti-Inflammatory Drugs as Anticancer Agents
Zappavigna, S., Cossu, A. M., Grimaldi, A., Bocchetti, M., Ferraro, G. A., Nicoletti, G. F., Filosa, R., & Caraglia, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072605 · Cited by 401 · see citing works
Solaß, W., Kerb, R., Mürdter, T. E., Giger-Pabst, U., Strumberg, D., Tempfer, C. M., Zieren, J., Schwab, M. G., & Reymond, M. A. (2013) · Annals of Surgical Oncology · doi:10.1245/s10434-013-3213-1 · Cited by 386 · see citing works
Differentiation plasticity regulated by TGF-β family proteins in development and disease
Derynck, R., & Akhurst, R. J. (2007) · Nature Cell Biology · doi:10.1038/ncb434 · Cited by 411 · see citing works
Overchuk, M., & Zheng, G. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2017.10.024 · Cited by 383 · see citing works
Organ-on-a-chip platforms for studying drug delivery systems
Bhise, N. S., Ribas, J., Manoharan, V., Zhang, Y. S., Polini, A., Massa, S., Dokmeci, M. R., & Khademhosseini, A. (2014) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.05.004 · Cited by 381 · see citing works
Challenges in Development of Targeted Liposomal Therapeutics
Sawant, R. R., & Torchilin, V. P. (2012) · The AAPS Journal · doi:10.1208/s12248-012-9330-0 · Cited by 382 · see citing works
Nonviral cancer gene therapy: Delivery cascade and vector nanoproperty integration
Zhou, Z., Liu, X., Zhu, D., Wang, Y., Zhang, Z., Zhou, X., Qiu, N., Chen, X., & Shen, Y. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.07.021 · Cited by 380 · see citing works
Immunologic tumor microenvironment modulators for turning cold tumors hot
Khosravi, G. R., Mostafavi, S., Bastan, S., Ebrahimi, N., Gharibvand, R. S., & Eskandari, N. (2024) · 癌症:英文版 · doi:10.1002/cac2.12539 · Cited by 384 · see citing works
Hinz, B. (2009) · Current Rheumatology Reports · doi:10.1007/s11926-009-0017-1 · Cited by 373 · see citing works
Cairns, R. A., Papandreou, I., & Denko, N. C. (2006) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-06-0002 · Cited by 370 · see citing works
Rosmarinus officinalis L. (rosemary) as therapeutic and prophylactic agent
de Oliveira, J. R., Camargo, S. E. A., & de Oliveira, L. D. (2019) · Journal of Biomedical Science · doi:10.1186/s12929-019-0499-8 · Cited by 385 · see citing works
Miao, T., Wang, J., Zeng, Y., Liu, G., & Chen, X. S. (2018) · Advanced Science · doi:10.1002/advs.201700513 · Cited by 369 · see citing works
Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro
Ng, C. P., Hinz, B., & Swartz, M. A. (2005) · Journal of Cell Science · doi:10.1242/jcs.02605 · Cited by 360 · see citing works
Engineered polymers for advanced drug delivery
Kim, S., Kim, J., Jeon, O., Kwon, I. C., & Park, K. (2008) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2008.09.021 · Cited by 355 · see citing works
Sonodynamic Therapy: Concept, Mechanism and Application to Cancer Treatment
McHale, A. P., Callan, J. F., Nomikou, N., Fowley, C., & Callan, B. (2015) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-22536-4_22 · Cited by 351 · see citing works
Antitumor Effects of Chimeric Receptor Engineered Human T Cells Directed to Tumor Stroma
Kakarla, S., Chow, K. K. H., Mata, M., Shaffer, D. R., Song, X., Wu, M.-F., Liu, H., Wang, L. L., Rowley, D. R., Pfizenmaier, K., et al. (2013) · Molecular Therapy · doi:10.1038/mt.2013.110 · Cited by 347 · see citing works
The Use of Therapeutic Peptides to Target and to Kill Cancer Cells
Boohaker, R. J., Lee, M. W., Vishnubhotla, P., Perez, J. L. M., & Khaled, A. R. (2012) · Current Medicinal Chemistry · doi:10.2174/092986712801661004 · Cited by 342 · see citing works
Current Multistage Drug Delivery Systems Based on the Tumor Microenvironment
Chen, B., Dai, W., He, B., Zhang, H., Wang, X., Wang, Y., & Zhang, Q. (2017) · Theranostics · doi:10.7150/thno.16684 · Cited by 347 · see citing works
- Authors
- Heldin, C.-H., Rubin, K., Pietras, K., & Östman, A.
- Affiliations
- Ludwig Cancer Research (SE)
- Uppsala University (SE)
- University of California, San Francisco (US)
- Karolinska Institutet (SE)
- Corresponding author
- Heldin, Carl-Henrik
- Venue
- Nature reviews. Cancer
- Published
- 2004-10
- Volume
- 4
- Issue
- 10
- Pages
- 806-813
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- OpenAlex
- W2028156849
- Cited by
- 2,222
- References
- 78
- Citations by year
- 2026: 121 · 2025: 110 · 2024: 118 · 2023: 119 · 2022: 163 · 2021: 158 · 2020: 158 · 2019: 123 · 2018: 123 · 2017: 135 · 2016: 133 · 2015: 110 · 2014: 117 · 2013: 124 · 2012: 87
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancerfonden
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Keywords
- interstitial fluid pressure, solid tumors, tumor microenvironment, tumor fibrosis, anticancer drug delivery, tumor hypoxia
- MeSH terms
- Alprostadil, Animals, Antineoplastic Agents, Biological Transport, Bradykinin, Humans, Hyaluronoglucosaminidase, Hydrostatic Pressure, Neoplasms, Niacinamide, Platelet-Derived Growth Factor, Tumor Necrosis Factor-alpha, Signal Transduction, Transforming Growth Factor beta, Vascular Endothelial Growth Factor A, Extracellular Fluid, Mice
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