Current State-of-The-Art and Future Directions in Systems Biology
Systems Biology offers the promise of decoding genetic information, optimizing pharmaceutical design, and aiding in the development of precision medicine. These advances require the bimodal approach of deriving information from experimental data and integrating such information via computational modeling. However, choosing an appropriate experimental assay and computational model is paramount to the accuracy and relevancy of the output. Here, we delve into the fundamental concept of several commonly used modeling approaches, their advantages and limitations, as well as potential applications. We review and compare experimental assays used in systems biology, based on the throughput, simplicity and possibility for quantification. In addition, we review current experimental models used in conjunction with assays to provide parameters and/or validation for computational modeling. Lastly, we present applications of systems biology in medicine: case studies, clinical opportunities, and future directions of systems biology
E. C. Butcher, E. L. Berg, and E. J. Kunkel, “Systems biology in drug discovery,” Nat. Biotechnol., vol. 22, no. 10, pp. 1253–1259, Oct. 2004.
F. Mac Gabhann and A. S. Popel, “Systems biology of vascular endothelial growth factors,” Microcirculation, vol. 15, no. 8, pp. 715–738, Nov. 2008.
F. Mac Gabhann, B. H. Annex, and A. S. Popel, “Gene therapy from the perspective of systems biology,” Curr. Opin. Mol. Ther., vol. 12, no. 5, pp. 570–7, Oct. 2010.
J. Walpole, J. a Papin, and S. M. Peirce, “Multiscale computational models of complex biological systems,” Annu. Rev. Biomed. Eng., vol. 15, pp. 137–54, Jan. 2013.
S.-H. Kim, J. Turnbull, and S. Guimond, “Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor,” J. Endocrinol., vol. 209, no. 2, pp. 139–51, May 2011.
P. D. Yurchenco, “Basement membranes: cell scaffoldings and signaling platforms,” Cold Spring Harb. Perspect. Biol., vol. 3, no. 2, p. a004911–, Feb. 2011.
W. C. Aird, “Spatial and temporal dynamics of the endothelium,” J. Thromb. Haemost, vol. 3, no. 7, pp. 1392–1406, Jul. 2005.
L. You, “Toward computational systems biology,” Cell Biochem Biophys, vol. 40, no. 2, pp. 167–184, 2004.
C.-L. Ko, E. Voit, and F.-S. Wang, “Estimating parameters for generalized mass action models with connectivity information,” BMC Bioinformatics, vol. 10, no. 1, p. 140, 2009.
I. C. Chou and E. O. Voit, “Recent developments in parameter estimation and structure identification of biochemical and genomic systems,” Math. Biosci., vol. 219, no. 2, pp. 57–83, 2009.
K. Beven, “A manifesto for the equifinality thesis,” J. Hydrol., vol. 320, no. 1–2, pp. 18–36, 2006.
C. Hutton, Z. Kapelan, L. Vamvakeridou-Lyroudia, and D. Savić, “Dealing with Uncertainty in Water Distribution System Models: A Framework for Real-Time Modeling and Data Assimilation,” J. Water Resour. Plan. Manag., vol. 140, no. 2, pp. 169–183, 2012.
N. Jamshidi and B. Ø. Palsson, “Mass Action Stoichiometric Simulation Models: Incorporating Kinetics and Regulation into Stoichiometric Models,” Biophys. J., vol. 98, no. 2, pp. 175–185, 2010.
D. T. Gillespie, “Exact stochastic simulation of coupled chemical reactions,” J. Phys. Chem., vol. 93555, no. 1, pp. 2340–2361, 1977.
F. Mac Gabhann and A. S. Popel, “Model of competitive binding of vascular endothelial growth factor and placental growth factor to VEGF receptors on endothelial cells.,” Am. J. Physiol. Heart Circ. Physiol., vol. 286, no. 1, pp. H153–64, Jan. 2004.
A. Frigessi, M. a van de Wiel, M. Holden, D. H. Svendsrud, I. K. Glad, and H. Lyng, “Genome-wide estimation of transcript concentrations from spotted cDNA microarray data.,” Nucleic Acids Res., vol. 33, no. 17, p. e143, Jan. 2005.
D. J. Wilkinson, “Bayesian methods in bioinformatics and computational systems biology,” Brief. Bioinform, vol. 8, no. 2, pp. 109–116, Mar. 2007.
L. B. Edelman, J. A. Eddy, and N. D. Price, “In silico models of cancer,” Wiley Interdiscip. Rev. Syst. Biol. Med., vol. 2, no. 4, pp. 438–459, 2010.
L. Jakobsson, C. A. Franco, K. Bentley, R. T. Collins, B. Ponsioen, I. M. Aspalter, I. Rosewell, M. Busse, G. Thurston, A. Medvinsky, S. Schulte-Merker, and H. Gerhardt, “Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting,” Nat Cell Biol, vol. 12, no. 10, pp. 943–953, 2010.
A. Bailey, B. Thorne, and S. Peirce, “Multi-cell Agent-based Simulation of the Microvasculature to Study the Dynamics of Circulating Inflammatory Cell Trafficking,” Ann. Biomed. Eng., vol. 35, no. 6, pp. 916–936, 2007.
B. L. Long, R. Rekhi, A. Abrego, J. Jung, and A. A. Qutub, “Cells as state machines: Cell behavior patterns arise during capillary formation as a function of BDNF and VEGF,” J. Theor. Biol., vol. 326, pp. 43–57, 2013.
K.-A. Norton, M. Wininger, G. Bhanot, S. Ganesan, N. Barnard, and T. Shinbrot, “A 2D mechanistic model of breast ductal carcinoma in situ (DCIS) morphology and progression,” J. Theor. Biol., vol. 263, no. 4, pp. 393–406, 2010.
G. Cedersund and J. Roll, “Systems biology: model based evaluation and comparison of potential explanations for given biological data,” FEBS J., vol. 276, no. 4, pp. 903–922, Feb. 2009.
A. Chakrabarty, G. T. Buzzard, and A. E. Rundell, “Model-based design of experiments for cellular processes,” Wiley Interdiscip. Rev. Syst. Biol. Med., vol. 5, no. 2, pp. 181–203, 2013.
E. Walter and L. Pronzato, “Qualitative and quantitative experiment design for phenomenological models—A survey,” Automatica, vol. 26, no. 2, pp. 195–213, 1990.
Schneider MV, “Defining systems biology: a brief overview of the term and field,” Methods Mol Biol, vol. 1021, pp. 1–11, 2013.
S. D. Finley, M. O. Engel-Stefanini, P. I. Imoukhuede, and A. S. Popel, “Pharmacokinetics and pharmacodynamics of VEGF-neutralizing antibodies,” BMC Systems Biology, vol. 5. p. 193, 2011.
M. Schena, D. Shalont, R. Heller, A. Chai, P. Brown, and R. W. Davis, “Parallel human genome analysis : Microarray-based expression monitoring of 1000 genes,” vol. 93, no. October, pp. 10614–10619, 1996.
M. Bakkali, “A bird’s-eye view on the modern genetics workflow and its potential applicability to the locust problem.,” C. R. Biol., vol. 336, no. 8, pp. 375–383, Aug. 2013.
A. Ståhlberg, P. Aman, L. Strömbom, N. Zoric, A. Diez, O. Nilsson, M. Kubista, and B. Ridell, “Comparison of reverse transcription quantitative real-time PCR, flow cytometry, and immunohistochemistry for detection of monoclonality in lymphomas.,” ISRN Oncol., vol. 2014, p. 796210, Jan. 2014.
R. R. Swiger and J. D. Tucker, “Fluorescence in situ hybridization,” Env. Mol Mutagen, vol. 254, no. 1 996, pp. 245–254, 1996.
D. J. Eastburn, A. Sciambi, and A. R. Abate, “Ultrahigh-throughput Mammalian single-cell reverse-transcriptase polymerase chain reaction in microfluidic drops,” Anal. Chem., vol. 85, no. 16, pp. 8016–8021, Aug. 2013.
D. L. Stokes, I. Ubarretxena-Belandia, T. Gonen, and A. Engel, “High-throughput methods for electron crystallography,” Methods Mol. Biol. (Clifton, NJ), vol. 955, pp. 273–296, 2013.
P. Picotti, O. Rinner, R. Stallmach, F. Dautel, T. Farrah, B. Domon, H. Wenschuh, and R. Aebersold, “High-throughput generation of selected reaction-monitoring assays for proteins and proteomes.,” Nat. Methods, vol. 7, no. 1, pp. 43–6, Jan. 2010.
C. Krisp, M. J. McKay, D. A. Wolters, and M. P. Molloy, “Multidimensional protein identification technology-selected reaction monitoring improving detection and quantification for protein biomarker studies,” Anal. Chem., vol. 84, no. 3, pp. 1592–1600, Feb. 2012.
E. A. Kislinger T, Gramolini AO, Maclennan DH, “Multidimensional protein identification technology (MudPIT): technical overview of a profiling method optimized for the comprehensive proteomic investigation of normal and diseased heart tissue,” J Am Soc Mass Spectrom, vol. 16, pp. 1207–20, 2005.
J. P. Nolan, D. Condello, E. Duggan, M. Naivar, and D. Novo, “Visible and near infrared fluorescence spectral flow cytometry,” Cytometry. A, vol. 83, no. 3, pp. 253–64, Mar. 2013.
E. Engvall and P. Perlmann, “Enzyme-linked immunosorbent assay (ELISA). Quantitative assay of immunoglobulin G.,” Immunochemistry, vol. 8, no. 9, pp. 871–4, Sep. 1971.
E. P. Trieu, J. K. Gross, and I. N. Targoff, “Protein Blotting and Detection,” vol. 536, pp. 259–275, 2009.
A. a. De Graaf, A. P. Freidig, B. De Roos, N. Jamshidi, M. Heinemann, J. a C. Rullmann, K. D. Hall, M. Adiels, and B. Van Ommen, “Nutritional systems biology modeling: From molecular mechanisms to physiology,” PLoS Comput. Biol., vol. 5, no. 11, p. e1000554, Nov. 2009.
Y.-C. Chen, S. V. Rajagopala, T. Stellberger, and P. Uetz, “Exhaustive benchmarking of the yeast two-hybrid system.,” Nat. Methods, vol. 7, no. 9, pp. 667–8; author reply 668, Sep. 2010.
C. a S. Banks, S. E. Kong, and M. P. Washburn, “Affinity purification of protein complexes for analysis by multidimensional protein identification technology,” Protein Expr. Purif., vol. 86, no. 2, pp. 105–19, Dec. 2012.
L. Comai, “for the Detection of Kinase – Substrate Interactions,” Methods Mol Biol, vol. 218, pp. 277–284, 2003.
Y. Sun, C. Rombola, V. Jyothikumar, and A. Periasamy, “Förster resonance energy transfer microscopy and spectroscopy for localizing protein-protein interactions in living cells,” Cytometry. A, vol. 83, no. 9, pp. 780–793, Sep. 2013.
P. Johnström, J. L. Bird, and A. P. Davenport, “Receptor Binding Techniques,” Methods Mol Biol, vol. 897, pp. 205–220, 2012.
D. Rank, P. Baybayan, B. Bettman, A. Bibillo, K. Bjornson, B. Chaudhuri, F. Christians, R. Cicero, S. Clark, R. Dalal, J. Dixon, M. Foquet, A. Gaertner, P. Hardenbol, C. Heiner, K. Hester, D. Holden, G. Kearns, X. Kong, R. Kuse, Y. Lacroix, S. Lin, P. Lundquist, C. Ma, P. Marks, M. Maxham, D. Murphy, I. Park, T. Pham, M. Phillips, J. Roy, R. Sebra, G. Shen, J. Sorenson, A. Tomaney, K. Travers, M. Trulson, J. Vieceli, J. Wegener, D. Wu, A. Yang, D. Zaccarin, P. Zhao, F. Zhong, J. Korlach, and S. Turner, “Single Polymerase Molecules,” no. January, pp. 133–138, 2009.
S. Ekins, Y. Nikolsky, and T. Nikolskaya, “Techniques: application of systems biology to absorption, distribution, metabolism, excretion and toxicity,” Trends Pharmacol. Sci., vol. 26, no. 4, pp. 202–209, Apr. 2005.
C. S. H. Tan and R. Linding, “Experimental and computational tools useful for (re)construction of dynamic kinase-substrate networks,” Proteomics, vol. 9, no. 23, pp. 5233–5242, Dec. 2009.
J. a Hewel, J. Liu, K. Onishi, V. Fong, S. Chandran, J. B. Olsen, O. Pogoutse, M. Schutkowski, H. Wenschuh, D. F. H. Winkler, L. Eckler, P. W. Zandstra, and A. Emili, “Synthetic peptide arrays for pathway-level protein monitoring by liquid chromatography-tandem mass spectrometry.,” Mol. Cell. Proteomics, vol. 9, no. 11, pp. 2460–2473, Nov. 2010.
Stokes DL, “High-throughput methods for electron crystallography,” Methods Mol Biol, vol. 955, pp. 273–96, 2013.
D. B. Kell, M. Brown, H. M. Davey, W. B. Dunn, I. Spasic, and S. G. Oliver, “Metabolic footprinting and systems biology: the medium is the message.,” Nat. Rev. Microbiol., vol. 3, no. 7, pp. 557–565, Jul. 2005.
D. Faratian, J. Christiansen, M. Gustavson, C. Jones, C. Scott, I. Um, and D. J. Harrison, “Heterogeneity mapping of protein expression in tumors using quantitative immunofluorescence.,” J. Vis. Exp., no. 56, p. e3334, Jan. 2011.
A. M. Smith, H. Duan, A. M. Mohs, and S. Nie, “NIH Public Access,” Adv Drug Deliv Rev, vol. 60, no. 11, pp. 1226–1240, 2009.
F. T. Lee-Montiel and P. I. Imoukhuede, “Engineering quantum dot calibration standards for quantitative fluorescent profiling,” Journal of Materials Chemistry B, no. -. The Royal Society of Chemistry, p. -, 2013.
P.I. Imoukhuede and A.S. Popel, “Quantification and cell-to-cell variation of vascular endothelial growth factor receptors,” Exp. Cell Res., vol. 317, no. 7, pp. 955–965, 2011.
P. I. Imoukhuede and A. S. Popel, “Expression of VEGF receptors on endothelial cells in mouse skeletal muscle,” PLoS One, vol. 7, no. 9, p. e44791, Jan. 2012.
I. PI, D. AO, A. BH, and P. AS, “Endothelial cell-by-cell profiling reveals temporal dynamics of VEGFR1 and VEGFR2 membrane-localization following murine hindlimb ischemia,” Am J Physiol Hear. Circ Physiol, vol. 304, no. 8, pp. H1085–93, 2013.
P. I. Imoukhuede and A. S. Popel, “Quantitative fluorescent profiling of VEGFRs reveals tumor cell and endothelial cell heterogeneity in breast cancer xenografts,” Cancer Med., Jan. 2014.
I. G. Khalil and C. Hill, “Systems biology for cancer,” pp. 44–48, 2005.
H. Yu, I. Meyvantsson, I. a Shkel, and D. J. Beebe, “Diffusion dependent cell behavior in microenvironments,” Lab Chip, vol. 5, no. 10, pp. 1089–95, Oct. 2005.
R. B. Rutherford and R. Ross, “Platelet factors stimulate fibroblasts and smooth muscle cells quiescent in plasma serum to proliferate,” J Cell Biol, vol. 69, no. 14, pp. 196–203, 1976.
C. J. Jackson and M. Nguyen, “Human microvascular endothelial cells differ from macrovascular endothelial cells in their expression of matrix metalloproteinases.,” Int J Biochem Cell Biol, vol. 29, no. 10, pp. 1167–77, Oct. 1997.
B. A. Bryan and P. A. D’Amore, “Pericyte isolation and use in endothelial/pericyte coculture models”, Methods Enzymol., vol. 443, pp. 315–31, Jan. 2008.
J. Jedelská, B. Strehlow, U. Bakowsky, A. Aigner, S. Höbel, M. Bette, M. Roessler, N. Franke, A. Teymoortash, J. A. Werner, B. Eivazi, and R. Mandic, “The chorioallantoic membrane assay is a promising ex vivo model system for the study of vascular anomalies”, In Vivo, vol. 27, no. 6, pp. 701–5, 2013.
I. Arnaoutova and H. K. Kleinman, “In vitro angiogenesis: endothelial cell tube formation on gelled basement membrane extract”, Nat. Protoc., vol. 5, no. 4, pp. 628–35, Apr. 2010.
Z. Shao, M. Friedlander, C. G. Hurst, Z. Cui, D. T. Pei, L. P. Evans, A. M. Juan, H. Tahir, F. Duhamel, J. Chen, P. Sapieha, S. Chemtob, J.-S. Joyal, and L. E. H. Smith, “Choroid sprouting assay: an ex vivo model of microvascular angiogenesis”, PLoS One, vol. 8, no. 7, p. e69552, Jan. 2013.
C. a Staton, M. W. R. Reed, and N. J. Brown, “A critical analysis of current in vitro and in vivo angiogenesis assays”, Int. J. Exp. Pathol., vol. 90, no. 3, pp. 195–221, Jun. 2009.
S. J. Maerkl, “Next generation microfluidic platforms for high-throughput protein biochemistry”, Curr. Opin. Biotechnol., vol. 22, no. 1, pp. 59–65, Feb. 2011.
C. L. Stokes and D. a Lauffenburger, “Analysis of the roles of microvessel endothelial cell random motility and chemotaxis in angiogenesis”, J. Theor. Biol., vol. 152, no. 3, pp. 377–403, Oct. 1991.
Z. Qu, A. Garfinkel, J. N. Weiss, and M. Nivala, “Multi-scale modeling in biology: how to bridge the gaps between scales?”, Prog. Biophys. Mol. Biol., vol. 107, no. 1, pp. 21–31, Oct. 2011.
L. A. Chylek, E. C. Stites, R. G. Posner, and W. S. Hlavacek, “Systems Biology”, pp. 273–300, 2013.
W. W. Chen, B. Schoeberl, P. J. Jasper, M. Niepel, U. B. Nielsen, D. a Lauffenburger, and P. K. Sorger, “Input-output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data”, Mol. Syst. Biol., vol. 5, no. 239, p. 239, Jan. 2009.
M. W. Covert, N. Xiao, T. J. Chen, and J. R. Karr, “Integrating metabolic, transcriptional regulatory and signal transduction models in Escherichia coli”, Bioinformatics, vol. 24, no. 18, pp. 2044–50, Sep. 2008.
K. Bettenbrock, S. Fischer, A. Kremling, K. Jahreis, T. Sauter, and E.-D. Gilles, “A quantitative approach to catabolite repression in Escherichia coli”, J. Biol. Chem., vol. 281, no. 5, pp. 2578–84, Mar. 2006.
H. N. Hayenga, B. C. Thorne, S. M. Peirce, and J. D. Humphrey, “Ensuring congruency in multiscale modeling: towards linking agent based and continuum biomechanical models of arterial adaptation”, Ann. Biomed. Eng., vol. 39, no. 11, pp. 2669–82, Nov. 2011.
B. He, R. Baird, R. Butera, A. Datta, S. George, B. Hecht, A. Hero, G. Lazzi, L. RC, J. Liang, M. Neuman, P. GCY, P. EJ, M. Ramasubramanian, W. MD, J. Wikswo, G. Yang, and Y. Zhang, “Grand challenges in interfacing engineering with life sciences and medicine”, IEEE T Bio-Med Eng, vol. 60, pp. 589–598, 2013.
C. S. Greene, J. Tan, M. Ung, J. H. Moore, and C. Cheng, “Big Data Bioinformatics”, J. Cell. Physiol., p. n/a–n/a, 2014.
M. Gerstein, “Genomics: ENCODE leads the way on big data”, Nature, vol. 489, no. 7415, p. 208, 2012.
S. F. Martin, H. Falkenberg, T. F. Dyrlund, G. A. Khoudoli, C. J. Mageean, and R. Linding, “PROTEINCHALLENGE: Crowd sourcing in proteomics analysis and software development”, J. Proteomics, vol. 88, pp. 41–46, 2013.
A. J. Lusis, A. D. Attie, and K. Reue, “Metabolic syndrome: from epidemiology to systems biology”, Nat. Rev. Genet., vol. 9, no. 11, pp. 819–30, Nov. 2008.
Q. Meng, V.-P. Mäkinen, H. Luk, and X. Yang, “Systems Biology Approaches and Applications in Obesity, Diabetes, and Cardiovascular Diseases”, Curr. Cardiovasc. Risk Rep., vol. 7, no. 1, pp. 73–83, Mar. 2013.
S. Pasinetti, Giulio M, Hiller-Sturmhofel, “Systems biology in the study of neurological disease: focus on Alzheimer’s disease”, Putting Systems Biology Approaches into Practice, 2008.
G. Juhász, I. Földi, and B. Penke, “Systems biology of Alzheimer’s disease: how diverse molecular changes result in memory impairment in AD”, Neurochem. Int., vol. 58, no. 7, pp. 739–50, Jun. 2011.
S. Pepke, T. Kinzer-Ursem, S. Mihalas, and M. B. Kennedy, “A dynamic model of interactions of Ca2+, calmodulin, and catalytic subunits of Ca2+/calmodulin-dependent protein kinase II”, PLoS Comput. Biol., vol. 6, no. 2, p. e1000675, Mar. 2010.
P. K. Kreeger and D. a Lauffenburger, “Cancer systems biology: a network modeling perspective”, Carcinogenesis, vol. 31, no. 1, pp. 2–8, Jan. 2010.
M. R. Birtwistle, M. Hatakeyama, N. Yumoto, B. a Ogunnaike, J. B. Hoek, and B. N. Kholodenko, “Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses”, Mol. Syst. Biol., vol. 3, no. 144, p. 144, Jan. 2007.
S. Sanga, H. B. Frieboes, X. Zheng, R. Gatenby, E. L. Bearer, and V. Cristini, “Predictive oncology: a review of multidisciplinary, multiscale in silico modeling linking phenotype, morphology and growth”, Neuroimage, vol. 37 Suppl 1, pp. S120–34, Jan. 2007.
A. M. Gonzalez-Angulo, B. T. J. Hennessy, and G. B. Mills, “Future of personalized medicine in oncology: a systems biology approach”, J. Clin. Oncol., vol. 28, no. 16, pp. 2777–83, Jun. 2010.
R. A. Weinberg, The biology of cancer. 2007.
A. J. Guidi, S. J. Schnitt, L. Fischer, K. Tognazzi, J. R. Harris, H. F. Dvorak, and L. F. Brown, “Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in patients with ductal carcinoma in situ of the breast”, Cancer, vol. 80, no. 10, pp. 1945–1953, Nov. 1997.
N. A. Saunders, F. Simpson, E. W. Thompson, M. M. Hill, L. Endo-Munoz, G. Leggatt, R. F. Minchin, and A. Guminski, “Role of intratumoural heterogeneity in cancer drug resistance: molecular and clinical perspectives”, EMBO Mol. Med., vol. 4, no. 8, pp. 675–684, Aug. 2012.
G. Bergers and D. Hanahan, “Modes of resistance to anti-angiogenic therapy”, Nat Rev Cancer, vol. 8, no. 8, pp. 592–603, 2008.
A. B. Sandler, “Clinical trials comparing carboplatin/paclitaxel with or without bevacizumab in patients with metastatic NSCLC”, Lung Cancer Updat., vol. 2, pp. 6–10, 2005.
H. Hurwitz, “Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer”, N Engl J Med, vol. 350, pp. 2335–2342, 2004.
B. P. Schneider and G. W. Sledge, “Drug insight: VEGF as a therapeutic target for breast cancer”, Nat. Clin. Pract. Oncol., vol. 4, no. 3, pp. 181–189, Mar. 2007.
R. Erber, A. Thurnher, A. D. Katsen, G. Groth, H. Kerger, H.-P. Hammes, M. D. Menger, A. Ullrich, and P. Vajkoczy, “Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms”, FASEB J., vol. 18, no. 2, pp. 338–340, Feb. 2004.
O. Casanovas, D. J. Hicklin, G. Bergers, and D. Hanahan, “Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors”, Cancer Cell, vol. 8, no. 4, pp. 299–309, Oct. 2005.
H. Iwata, S. Imamura, A. Hori, M. S. Hixon, H. Kimura, and H. Miki, “Biochemical characterization of TAK-593, a novel VEGFR/PDGFR inhibitor with a two-step slow binding mechanism”, Biochemistry, vol. 50, no. 5, pp. 738–751, Feb. 2011.
A. Schwandt, V. E. von Gruenigen, R. M. Wenham, H. Frasure, S. Eaton, N. Fusco, P. Fu, J. J. Wright, A. Dowlati, and S. Waggoner, “Randomized phase II trial of sorafenib alone or in combination with carboplatin/paclitaxel in women with recurrent platinum sensitive epithelial ovarian, peritoneal, or fallopian tube cancer”, Invest. New Drugs, Mar. 2014.
R. Mabry, D. G. Gilbertson, A. Frank, T. Vu, D. Ardourel, C. Ostrander, B. Stevens, S. Julien, S. Franke, B. Meengs, J. Brody, S. Presnell, N. B. Hamacher, M. Lantry, A. Wolf, T. Bukowski, R. Rosler, C. Yen, M. Anderson-Haley, K. Brasel, Q. Pan, H. Franklin, P. Thompson, M. Dodds, S. Underwood, S. Peterson, P. V Sivakumar, and M. Snavely, “A dual-targeting PDGFRbeta/VEGF-A molecule assembled from stable antibody fragments demonstrates anti-angiogenic activity in vitro and in vivo”, MAbs, vol. 2, no. 1, pp. 20–34, 2010.
V. W. Rebecca, E. R. Wood, I. V Fedorenko, K. H. T. Paraiso, H. E. Haarberg, Y. Chen, Y. Xiang, A. Sarnaik, G. T. Gibney, V. K. Sondak, J. M. Koomen, and K. S. M. Smalley, “Evaluating Melanoma Drug Response and Therapeutic Escape with Quantitative Proteomics”, Mol. Cell. Proteomics, Apr. 2014.
E. A. Logsdon, S. D. Finley, A. S. Popel, and F. Mac Gabhann, “A systems biology view of blood vessel growth and remodelling”, J. Cell. Mol. Med., Nov. 2013.
F. Mac Gabhann and A. S. Popel, “Targeting neuropilin-1 to inhibit VEGF signaling in cancer: Comparison of therapeutic approaches”, PLoS Comput. Biol., vol. 2, no. 12, p. e180, Dec. 2006.
S. D. Finley and A. S. Popel, “Predicting the effects of anti-angiogenic agents targeting specific VEGF isoforms”, AAPS J., vol. 14, no. 3, pp. 500–9, Sep. 2012.
J. C. Weddell and P. I. Imoukhuede, “Quantitative characterization of cellular membrane-receptor heterogeneity through statistical and computational modeling”, PLoS One, vol. 9, no. 5, p. e97271, Jan. 2014.
H. F. Dvorak, V. M. Weaver, T. D. Tlsty, and G. Bergers, “Tumor microenvironment and progression”, J. Surg. Oncol., vol. 103, no. 6, pp. 468–474, May 2011.
P. Lu, V. M. Weaver, and Z. Werb, “The extracellular matrix: a dynamic niche in cancer progression”, J. Cell Biol., vol. 196, no. 4, pp. 395–406, Mar. 2012.
M. Egeblad, M. G. Rasch, and V. M. Weaver, “Dynamic interplay between the collagen scaffold and tumor evolution”, Curr. Opin. Cell Biol., vol. 22, no. 5, pp. 697–706, Oct. 2010.
O. Maller, C. C. DuFort, and V. M. Weaver, “YAP forces fibroblasts to feel the tension”, Nat. Cell Biol., vol. 15, no. 6, pp. 570–572, Jun. 2013.
G. Haralabopoulos, DS Grant, HK Klienman, PI Lelkes, SP Papaioanno, and M. Maragoudaki, “Inhibitors of basement membrane collagen synthesis prevent endothelial cell alignment in matrigel in vitro and angiogenesis in vivo”, Lab Inves, vol, 71,. pp. 575–582, 1994.
R. O. Hynes and A. Naba, “Overview of the matrisome--an inventory of extracellular matrix constituents and functions”, Cold Spring Harb. Perspect. Biol., vol. 4, no. 1, p. a004903, Jan. 2012.
M. Kanapathipillai, A. Mammoto, T. Mammoto, J. H. Kang, E. Jiang, K. Ghosh, N. Korin, A. Gibbs, R. Mannix, and D. E. Ingber, “Inhibition of mammary tumor growth using lysyl oxidase-targeting nanoparticles to modify extracellular matrix”, Nano Lett., vol. 12, no. 6, pp. 3213–3217, Jun. 2012.
H. Fang and Y. a Declerck, “Targeting the tumor microenvironment: from understanding pathways to effective clinical trials”, Cancer Res., vol. 73, no. 16, pp. 4965–4977, Aug. 2013.
R. Kalluri, “Basement membranes: structure, assembly and role in tumour angiogenesis”, Nat. Rev. Cancer, vol. 3, no. 6, pp. 422–433, Jun. 2003.
S. Huang, K. Shao, Y. Kuang, Y. Liu, J. Li, S. An, Y. Guo, H. Ma, X. He, and C. Jiang, “Tumor targeting and microenvironment-responsive nanoparticles for gene delivery”, Biomaterials, vol. 34, no. 21, pp. 5294–5302, Jul. 2013.
A. Toma, A. Mang, T. a Schuetz, S. Becker, and T. M. Buzug, “A novel method for simulating the extracellular matrix in models of tumour growth”, Comput. Math. Methods Med., vol. 2012, p. 109019, Jan. 2012.
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