Radiation and drug resistance are significant challenges in the treatment of locally advanced, recurrent and metastatic breast cancer that contribute to mortality. Clinically, radiotherapy requires oxygen to generate cytotoxic free radicals that cause DNA damage and allow that damage to become fixed in the genome rather than repaired. However, approximately 40% of all breast cancers have hypoxic tumor microenvironments that render cancer cells significantly more resistant to irradiation. Hypoxic stimuli trigger changes in the cell death/survival pathway that lead to increased cellular radiation resistance. As a result, the development of noninvasive strategies to assess tumor hypoxia in breast cancer has recently received considerable attention. Exosomes are secreted nanovesicles that have roles in paracrine signaling during breast tumor progression, including tumor-stromal interactions, activation of proliferative pathways and immunosuppression. The recent development of protocols to isolate and purify exosomes, as well as advances in mass spectrometry-based proteomics have facilitated the comprehensive analysis of exosome content and function. Using these tools, studies have demonstrated that the proteome profiles of tumor-derived exosomes are indicative of the oxygenation status of patient tumors. They have also demonstrated that exosome signaling pathways are potentially targetable drivers of hypoxia-dependent intercellular signaling during tumorigenesis. This article provides an overview of how proteomic tools can be effectively used to characterize exosomes and elucidate fundamental signaling pathways and survival mechanisms underlying hypoxia-mediated radiation resistance in breast cancer.
References
[1]
Slamon, D.; Eiermann, W.; Robert, N.; Pienkowski, T.; Martin, M.; Press, M.; Mackey, J.; Glaspy, J.; Chan, A.; Pawlicki, M.; et al. Adjuvant trastuzumab in HER2-positive breast cancer. N. Engl. J. Med. 2011, 365, 1273–1283, doi:10.1056/NEJMoa0910383.
[2]
Vaupel, P.; Briest, S.; Hockel, M. Hypoxia in breast cancer: Pathogenesis, characterization and biological/therapeutic implications. Wien. Med. Wochenschr. 2002, 152, 334–342.
[3]
Vaupel, P.; Mayer, A. Hypoxia in cancer: Significance and impact on clinical outcome. Cancer Metastasis Rev. 2007, 26, 225–239, doi:10.1007/s10555-007-9055-1.
[4]
Kucharzewska, P.; Christianson, H.C.; Welch, J.E.; Svensson, K.J.; Fredlund, E.; Ringner, M.; Morgelin, M.; Bourseau-Guilmain, E.; Bengzon, J.; Belting, M. Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc. Natl. Acad. Sci.USA 2013, 110, 7312–7317, doi:10.1073/pnas.1220998110.
[5]
Garnier, D.; Jabado, N.; Rak, J. Extracellular vesicles as prospective carriers of oncogenic protein signatures in adult and paediatric brain tumours. Proteomics 2012, 13, 1595–1607, doi:10.1002/pmic.201200360.
[6]
Bellingham, S.A.; Guo, B.B.; Coleman, B.M.; Hill, A.F. Exosomes: Vehicles for the transfer of toxic proteins associated with neurodegenerative diseases? Front. Physiol. 2012, 3, e124.
[7]
Yang, M.; Chen, J.; Su, F.; Yu, B.; Lin, L.; Liu, Y.; Huang, J.D.; Song, E. Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol. Cancer 2011, 10, e117.
[8]
Park, J.E.; Tan, H.S.; Datta, A.; Lai, R.C.; Zhang, H.; Meng, W.; Lim, S.K.; Sze, S.K. Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Mol. Cell. Proteomics 2011, 9, 1085–1099.
[9]
Subra, C.; Grand, D.; Laulagnier, K.; Stella, A.; Lambeau, G.; Paillasse, M.; de Medina, P.; Monsarrat, B.; Perret, B.; Silvente-Poirot, S.; et al. Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. J. Lipid Res. 2010, 51, 2105–2120, doi:10.1194/jlr.M003657.
[10]
Taylor, D.D.; Gercel-Taylor, C. Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects. Br. J. Cancer 2005, 92, 305–311.
[11]
Azmi, A.S.; Bao, B.; Sarkar, F.H. Exosomes in cancer development, metastasis, and drug resistance: A comprehensive review. Cancer Metastasis Rev. 2013, doi:10.1007/s10555-013-9441-9.
[12]
EL Andaloussi, S.; Mager, I.; Breakefield, X.O.; Wood, M.J. Extracellular vesicles: Biology and emerging therapeutic opportunities. Nat. Rev. Drug Discov. 2013, 12, 347–357, doi:10.1038/nrd3978.
[13]
Simona, F.; Laura, S.; Simona, T.; Riccardo, A. Contribution of proteomics to understanding the role of tumor-derived exosomes in cancer progression: State of the art and new perspectives. Proteomics 2013, 13, 1581–1594, doi:10.1002/pmic.201200398.
[14]
Martins, V.R.; Dias, M.S.; Hainaut, P. Tumor-cell-derived microvesicles as carriers of molecular information in cancer. Curr. Opin. Oncol. 2013, 25, 66–75, doi:10.1097/CCO.0b013e32835b7c81.
[15]
Yu, X.; Harris, S.L.; Levine, A.J. The regulation of exosome secretion: A novel function of the p53 protein. Cancer Res. 2006, 66, 4795–4801, doi:10.1158/0008-5472.CAN-05-4579.
[16]
Lehmann, B.D.; Paine, M.S.; Brooks, A.M.; McCubrey, J.A.; Renegar, R.H.; Wang, R.; Terrian, D.M. Senescence-associated exosome release from human prostate cancer cells. Cancer Res. 2008, 68, 7864–7871, doi:10.1158/0008-5472.CAN-07-6538.
[17]
Lespagnol, A.; Duflaut, D.; Beekman, C.; Blanc, L.; Fiucci, G.; Marine, J.C.; Vidal, M.; Amson, R.; Telerman, A. Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice. Cell Death Differ. 2008, 15, 1723–1733, doi:10.1038/cdd.2008.104.
Savina, A.; Fader, C.M.; Damiani, M.T.; Colombo, M.I. Rab11 promotes docking and fusion of multivesicular bodies in a calcium-dependent manner. Traffic 2005, 6, 131–143, doi:10.1111/j.1600-0854.2004.00257.x.
[20]
Parolini, I.; Federici, C.; Raggi, C.; Lugini, L.; Palleschi, S.; de Milito, A.; Coscia, C.; Iessi, E.; Logozzi, M.; Molinari, A.; et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J. Biol. Chem. 2009, 284, 34211–34222, doi:10.1074/jbc.M109.041152.
[21]
Svensson, K.J.; Kucharzewska, P.; Christianson, H.C.; Skold, S.; Lofstedt, T.; Johansson, M.C.; Morgelin, M.; Bengzon, J.; Ruf, W.; Belting, M. Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells. Proc. Natl. Acad. Sci. USA 2011, 108, 13147–13152, doi:10.1073/pnas.1104261108.
[22]
Orriss, I.R.; Knight, G.E.; Utting, J.C.; Taylor, S.E.; Burnstock, G.; Arnett, T.R. Hypoxia stimulates vesicular ATP release from rat osteoblasts. J. Cell. Physiol. 2009, 220, 155–162, doi:10.1002/jcp.21745.
[23]
Wysoczynski, M.; Ratajczak, M.Z. Lung cancer secreted microvesicles: Underappreciated modulators of microenvironment in expanding tumors. Int. J. Cancer 2009, 125, 1595–1603, doi:10.1002/ijc.24479.
[24]
King, H.W.; Michael, M.Z.; Gleadle, J.M. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer 2012, 12, e421, doi:10.1186/1471-2407-12-421.
[25]
Simpson, R.J.; Jensen, S.S.; Lim, J.W. Proteomic profiling of exosomes: Current perspectives. Proteomics 2008, 8, 4083–4099, doi:10.1002/pmic.200800109.
Ward, C.; Langdon, S.P.; Mullen, P.; Harris, A.L.; Harrison, D.J.; Supuran, C.T.; Kunkler, I.H. New strategies for targeting the hypoxic tumour microenvironment in breast cancer. Cancer Treat. Rev. 2013, 39, 171–179, doi:10.1016/j.ctrv.2012.08.004.
[28]
Gatenby, R.A.; Smallbone, K.; Maini, P.K.; Rose, F.; Averill, J.; Nagle, R.B.; Worrall, L.; Gillies, R.J. Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer. Br. J. Cancer 2007, 97, 646–653, doi:10.1038/sj.bjc.6603922.
[29]
Bristow, R.G.; Hill, R.P. Hypoxia and metabolism: Hypoxia, DNA repair and genetic instability. Nat. Rev. Cancer 2008, 8, 180–192, doi:10.1038/nrc2344.
[30]
Thomlinson, R.H.; Gray, L.H. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br. J. Cancer 1955, 9, 539–549, doi:10.1038/bjc.1955.55.
[31]
Bindra, R.S.; Crosby, M.E.; Glazer, P.M. Regulation of DNA repair in hypoxic cancer cells. Cancer Metastasis Rev. 2007, 26, 249–260, doi:10.1007/s10555-007-9061-3.
[32]
Yoshimura, M.; Itasaka, S.; Harada, H.; Hiraoka, M. Microenvironment and radiation therapy. Biomed. Res. Int. 2013, 2013, e685308.
[33]
Harada, H. How can we overcome tumor hypoxia in radiation therapy? J. Radiat. Res. 2011, 52, 545–556, doi:10.1269/jrr.11056.
[34]
Brown, J.M. Exploiting the hypoxic cancer cell: Mechanisms and therapeutic strategies. Mol. Med. Today 2000, 6, 157–162, doi:10.1016/S1357-4310(00)01677-4.
[35]
Brown, J.M.; Wilson, W.R. Exploiting tumour hypoxia in cancer treatment. Nat. Rev. Cancer 2004, 4, 437–447, doi:10.1038/nrc1367.
[36]
Ren, Y.; Hao, P.; Dutta, B.; Cheow, E.S.; Sim, K.H.; Gan, C.S.; Lim, S.K.; Sze, S.K. Hypoxia modulates A431 cellular pathways association to tumor radioresistance and enhanced migration revealed by comprehensive proteomic and functional studies. Mol. Cell. Proteomics 2013, 12, 485–498, doi:10.1074/mcp.M112.018325.
[37]
Sirbu, B.M.; Cortez, D. DNA damage response: Three levels of DNA repair regulation. Cold Spring Harb. Perspect. Biol. 2013, doi:10.1101/cshperspect.a012724.
[38]
Lin, H.H.; Li, X.; Chen, J.L.; Sun, X.; Cooper, F.N.; Chen, Y.R.; Zhang, W.; Chung, Y.; Li, A.; Cheng, C.T.; et al. Identification of an AAA ATPase VPS4B-dependent pathway that modulates epidermal growth factor receptor abundance and signaling during hypoxia. Mol. Cell. Biol. 2012, 32, 1124–1138, doi:10.1128/MCB.06053-11.
[39]
Liu, J.; Zhang, J.; Wang, X.; Li, Y.; Chen, Y.; Li, K.; Zhang, J.; Yao, L.; Guo, G. HIF-1 and NDRG2 contribute to hypoxia-induced radioresistance of cervical cancer Hela cells. Exp. Cell. Res. 2010, 316, 1985–1993, doi:10.1016/j.yexcr.2010.02.028.
[40]
Moeller, B.J.; Dewhirst, M.W. HIF-1 and tumour radiosensitivity. Br. J. Cancer 2006, 95, 1–5, doi:10.1038/sj.bjc.6603201.
[41]
Kaidar-Person, O.; Lai, C.; Kuten, A.; Belkacemi, Y. “The Infinite Maze” of breast cancer, signaling pathways and radioresistance. Breast 2013, 22, 411–418, doi:10.1016/j.breast.2013.04.003.
[42]
Grosso, S.; Doyen, J.; Parks, S.K.; Bertero, T.; Paye, A.; Cardinaud, B.; Gounon, P.; Lacas-Gervais, S.; Noel, A.; Pouyssegur, J.; et al. MiR-210 promotes a hypoxic phenotype and increases radioresistance in human lung cancer cell lines. Cell Death Dis. 2013, 4, e544, doi:10.1038/cddis.2013.71.
[43]
Potiron, V.A.; Abderrhamani, R.; Giang, E.; Chiavassa, S.; di Tomaso, E.; Maira, S.M.; Paris, F.; Supiot, S. Radiosensitization of prostate cancer cells by the dual PI3K/mTOR inhibitor BEZ235 under normoxic and hypoxic conditions. Radiother. Oncol. 2013, 106, 138–146, doi:10.1016/j.radonc.2012.11.014.
[44]
Tamara Marie-Egyptienne, D.; Lohse, I.; Hill, R.P. Cancer stem cells, the epithelial to mesenchymal transition (EMT) and radioresistance: Potential role of hypoxia. Cancer Lett. 2012. in press.
[45]
Eldh, M.; Ekstrom, K.; Valadi, H.; Sjostrand, M.; Olsson, B.; Jernas, M.; Lotvall, J. Exosomes communicate protective messages during oxidative stress; possible role of exosomal shuttle RNA. PLoS One 2010, 5, e15353.
[46]
Vlassov, A.V.; Magdaleno, S.; Setterquist, R.; Conrad, R. Exosomes: Current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim. Biophys. Acta 2012, 1820, 940–948.
[47]
Thery, C.; Zitvogel, L.; Amigorena, S. Exosomes: Composition, biogenesis and function. Nat. Rev. Immunol. 2002, 2, 569–579.
[48]
Conde-Vancells, J.; Rodriguez-Suarez, E.; Embade, N.; Gil, D.; Matthiesen, R.; Valle, M.; Elortza, F.; Lu, S.C.; Mato, J.M.; Falcon-Perez, J.M. Characterization and comprehensive proteome profiling of exosomes secreted by hepatocytes. J. Proteome Res. 2008, 7, 5157–5166, doi:10.1021/pr8004887.
[49]
Wubbolts, R.; Leckie, R.S.; Veenhuizen, P.T.; Schwarzmann, G.; Mobius, W.; Hoernschemeyer, J.; Slot, J.W.; Geuze, H.J.; Stoorvogel, W. Proteomic and biochemical analyses of human B cell-derived exosomes. J. Biol. Chem. 2003, 278, 10963–10972, doi:10.1074/jbc.M207550200.
[50]
Balaj, L.; Lessard, R.; Dai, L.; Cho, Y.J.; Pomeroy, S.L.; Breakefield, X.O.; Skog, J. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat. Commun. 2011, 2, e180, doi:10.1038/ncomms1180.
[51]
Gibbings, D.J.; Ciaudo, C.; Erhardt, M.; Voinnet, O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat. Cell Biol. 2009, 11, 1143–1149, doi:10.1038/ncb1929.
[52]
Lee, Y.S.; Shibata, Y.; Malhotra, A.; Dutta, A. A novel class of small RNAs: tRNA-derived RNA fragments (tRFs). Genes Dev. 2009, 23, 2639–2649, doi:10.1101/gad.1837609.
[53]
Haussecker, D.; Huang, Y.; Lau, A.; Parameswaran, P.; Fire, A.Z.; Kay, M.A. Human tRNA-derived small RNAs in the global regulation of RNA silencing. RNA 2010, 16, 673–695, doi:10.1261/rna.2000810.
[54]
Thomas, S.N.; Wan, Y.; Liao, Z.; Hanson, P.I.; Yang, A.J. Stable isotope labeling with amino acids in cell culture based mass spectrometry approach to detect transient protein interactions using substrate trapping. Anal. Chem. 2011, 83, 5511–5518, doi:10.1021/ac200950k.
[55]
Liao, Z.; Thomas, S.N.; Wan, Y.; Lin, H.H.; Ann, D.K.; Yang, A.J. An internal standard-assisted synthesis and degradation proteomic approach reveals the potential linkage between VPS4B depletion and activation of fatty acid beta-oxidation in breast cancer cells. Int. J. Proteomics 2013, 2013, e291415.
[56]
Battke, C.; Ruiss, R.; Welsch, U.; Wimberger, P.; Lang, S.; Jochum, S.; Zeidler, R. Tumour exosomes inhibit binding of tumour-reactive antibodies to tumour cells and reduce ADCC. Cancer Immunol. Immunother. 2011, 60, 639–648, doi:10.1007/s00262-011-0979-5.
[57]
Ciravolo, V.; Huber, V.; Ghedini, G.C.; Venturelli, E.; Bianchi, F.; Campiglio, M.; Morelli, D.; Villa, A.; Della Mina, P.; Menard, S.; et al. Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy. J. Cell. Physiol. 2012, 227, 658–667, doi:10.1002/jcp.22773.
[58]
Thery, C.; Amigorena, S.; Raposo, G.; Clayton, A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr. Protoc. Cell Biol. 2006, doi:10.1002/0471143030.cb0322s30.
[59]
Thery, C.; Boussac, M.; Veron, P.; Ricciardi-Castagnoli, P.; Raposo, G.; Garin, J.; Amigorena, S. Proteomic analysis of dendritic cell-derived exosomes: A secreted subcellular compartment distinct from apoptotic vesicles. J. Immunol. 2001, 166, 7309–7318.
[60]
Thery, C.; Regnault, A.; Garin, J.; Wolfers, J.; Zitvogel, L.; Ricciardi-Castagnoli, P.; Raposo, G.; Amigorena, S. Molecular characterization of dendritic cell-derived exosomes. J. Cell Biol. 1999, 147, 599–610, doi:10.1083/jcb.147.3.599.
[61]
Cheruvanky, A.; Zhou, H.; Pisitkun, T.; Kopp, J.B.; Knepper, M.A.; Yuen, P.S.; Star, R.A. Rapid isolation of urinary exosomal biomarkers using a nanomembrane ultrafiltration concentrator. Am. J. Physiol. Renal Physiol. 2007, 292, F1657–F1661, doi:10.1152/ajprenal.00434.2006.
[62]
de Bock, K.; Mazzone, M.; Carmeliet, P. Antiangiogenic therapy, hypoxia, and metastasis: Risky liaisons, or not? Nat. Rev. Clin. Oncol. 2011, 8, 393–404, doi:10.1038/nrclinonc.2011.83.
[63]
Marleau, A.M.; Chen, C.S.; Joyce, J.A.; Tullis, R.H. Exosome removal as a therapeutic adjuvant in cancer. J. Transl. Med. 2012, 10, e134, doi:10.1186/1479-5876-10-134.
[64]
Koga, K.; Matsumoto, K.; Akiyoshi, T.; Kubo, M.; Yamanaka, N.; Tasaki, A.; Nakashima, H.; Nakamura, M.; Kuroki, S.; Tanaka, M.; et al. Purification, characterization and biological significance of tumor-derived exosomes. Anticancer Res. 2005, 25, 3703–3707.
[65]
Nahta, R.; Yu, D.; Hung, M.C.; Hortobagyi, G.N.; Esteva, F.J. Mechanisms of disease: Understanding resistance to HER2-targeted therapy in human breast cancer. Nat. Clin. Pract. Oncol. 2006, 3, 269–280, doi:10.1038/ncponc0509.
[66]
Abdel-Razeq, H.; Marei, L. Current neoadjuvant treatment options for HER2-positive breast cancer. Biologics 2011, 5, 87–94.
[67]
von Minckwitz, G.; Loibl, S.; Untch, M. What is the current standard of care for anti-HER2 neoadjuvant therapy in breast cancer? Oncology 2012, 26, 20–26.
[68]
Aung, T.; Chapuy, B.; Vogel, D.; Wenzel, D.; Oppermann, M.; Lahmann, M.; Weinhage, T.; Menck, K.; Hupfeld, T.; Koch, R.; et al. Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3. Proc. Natl. Acad. Sci. USA 2011, 108, 15336–15341, doi:10.1073/pnas.1102855108.
[69]
Safaei, R.; Larson, B.J.; Cheng, T.C.; Gibson, M.A.; Otani, S.; Naerdemann, W.; Howell, S.B. Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells. Mol. Cancer Ther. 2005, 4, 1595–1604, doi:10.1158/1535-7163.MCT-05-0102.
[70]
Chen, K.G.; Valencia, J.C.; Lai, B.; Zhang, G.; Paterson, J.K.; Rouzaud, F.; Berens, W.; Wincovitch, S.M.; Garfield, S.H.; Leapman, R.D.; et al. Melanosomal sequestration of cytotoxic drugs contributes to the intractability of malignant melanomas. Proc. Natl. Acad. Sci. USA 2006, 103, 9903–9907, doi:10.1073/pnas.0600213103.
[71]
Shedden, K.; Xie, X.T.; Chandaroy, P.; Chang, Y.T.; Rosania, G.R. Expulsion of small molecules in vesicles shed by cancer cells: Association with gene expression and chemosensitivity profiles. Cancer Res. 2003, 63, 4331–4337.
[72]
Choi, D.S.; Lee, J.M.; Park, G.W.; Lim, H.W.; Bang, J.Y.; Kim, Y.K.; Kwon, K.H.; Kwon, H.J.; Kim, K.P.; Gho, Y.S. Proteomic analysis of microvesicles derived from human colorectal cancer cells. J. Proteome Res. 2007, 6, 4646–4655, doi:10.1021/pr070192y.
[73]
Ji, H.; Greening, D.W.; Barnes, T.W.; Lim, J.W.; Tauro, B.J.; Rai, A.; Xu, R.; Adda, C.; Mathivanan, S.; Zhao, W.; et al. Proteome profiling of exosomes derived from human primary and metastatic colorectal cells reveal differential expression of key metastatic factors and signal transduction components. Proteomics 2013, 13, 1672–1686, doi:10.1002/pmic.201200562.
[74]
Wolfers, J.; Lozier, A.; Raposo, G.; Regnault, A.; Thery, C.; Masurier, C.; Flament, C.; Pouzieux, S.; Faure, F.; Tursz, T.; et al. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat. Med. 2001, 7, 297–303, doi:10.1038/85438.
[75]
Craven, R.A.; Totty, N.; Harnden, P.; Selby, P.J.; Banks, R.E. Laser capture microdissection and two-dimensional polyacrylamide gel electrophoresis: Evaluation of tissue preparation and sample limitations. Am. J. Pathol. 2002, 160, 815–822, doi:10.1016/S0002-9440(10)64904-8.
[76]
Marton, A.; Vizler, C.; Kusz, E.; Temesfoi, V.; Szathmary, Z.; Nagy, K.; Szegletes, Z.; Varo, G.; Siklos, L.; Katona, R.L.; et al. Melanoma cell-derived exosomes alter macrophage and dendritic cell functions in vitro. Immunol. Lett. 2012, 148, 34–38, doi:10.1016/j.imlet.2012.07.006.
[77]
Hegmans, J.P.; Bard, M.P.; Hemmes, A.; Luider, T.M.; Kleijmeer, M.J.; Prins, J.B.; Zitvogel, L.; Burgers, S.A.; Hoogsteden, H.C.; Lambrecht, B.N. Proteomic analysis of exosomes secreted by human mesothelioma cells. Am. J. Pathol. 2004, 164, 1807–1815, doi:10.1016/S0002-9440(10)63739-X.
[78]
Graner, M.W.; Alzate, O.; Dechkovskaia, A.M.; Keene, J.D.; Sampson, J.H.; Mitchell, D.A.; Bigner, D.D. Proteomic and immunologic analyses of brain tumor exosomes. FASEB J. 2009, 23, 1541–1557, doi:10.1096/fj.08-122184.
[79]
Caby, M.P.; Lankar, D.; Vincendeau-Scherrer, C.; Raposo, G.; Bonnerot, C. Exosomal-like vesicles are present in human blood plasma. Int. Immunol. 2005, 17, 879–887, doi:10.1093/intimm/dxh267.
[80]
Looze, C.; Yui, D.; Leung, L.; Ingham, M.; Kaler, M.; Yao, X.; Wu, W.W.; Shen, R.F.; Daniels, M.P.; Levine, S.J. Proteomic profiling of human plasma exosomes identifies PPARgamma as an exosome-associated protein. Biochem. Biophys. Res. Commun. 2009, 378, 433–438, doi:10.1016/j.bbrc.2008.11.050.
[81]
Sabapatha, A.; Gercel-Taylor, C.; Taylor, D.D. Specific isolation of placenta-derived exosomes from the circulation of pregnant women and their immunoregulatory consequences. Am. J. Reprod. Immunol. 2006, 56, 345–355, doi:10.1111/j.1600-0897.2006.00435.x.
[82]
Gonzales, P.A.; Pisitkun, T.; Hoffert, J.D.; Tchapyjnikov, D.; Star, R.A.; Kleta, R.; Wang, N.S.; Knepper, M.A. Large-scale proteomics and phosphoproteomics of urinary exosomes. J. Am. Soc. Nephrol. 2009, 20, 363–379, doi:10.1681/ASN.2008040406.
[83]
Nilsson, J.; Skog, J.; Nordstrand, A.; Baranov, V.; Mincheva-Nilsson, L.; Breakefield, X.O.; Widmark, A. Prostate cancer-derived urine exosomes: A novel approach to biomarkers for prostate cancer. Br. J. Cancer 2009, 100, 1603–1607, doi:10.1038/sj.bjc.6605058.
[84]
Gonzalez-Begne, M.; Lu, B.; Han, X.; Hagen, F.K.; Hand, A.R.; Melvin, J.E.; Yates, J.R. Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). J. Proteome Res. 2009, 8, 1304–1314, doi:10.1021/pr800658c.
[85]
Andre, F.; Schartz, N.E.; Movassagh, M.; Flament, C.; Pautier, P.; Morice, P.; Pomel, C.; Lhomme, C.; Escudier, B.; Le Chevalier, T.; et al. Malignant effusions and immunogenic tumour-derived exosomes. Lancet 2002, 360, 295–305, doi:10.1016/S0140-6736(02)09552-1.
[86]
Admyre, C.; Johansson, S.M.; Qazi, K.R.; Filen, J.J.; Lahesmaa, R.; Norman, M.; Neve, E.P.; Scheynius, A.; Gabrielsson, S. Exosomes with immune modulatory features are present in human breast milk. J. Immunol. 2007, 179, 1969–1978.
[87]
Ong, S.E.; Blagoev, B.; Kratchmarova, I.; Kristensen, D.B.; Steen, H.; Pandey, A.; Mann, M. Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics. Mol. Cell. Proteomics 2002, 1, 376–386, doi:10.1074/mcp.M200025-MCP200.
[88]
Liao, Z.; Wan, Y.; Thomas, S.N.; Yang, A.J. IsoQuant: A software tool for stable isotope labeling by amino acids in cell culture-based mass spectrometry quantitation. Anal. Chem. 2012, 84, 4535–4543, doi:10.1021/ac300510t.
[89]
Aebersold, R.; Mann, M. Mass spectrometry-based proteomics. Nature 2003, 422, 198–207, doi:10.1038/nature01511.
[90]
Picotti, P.; Aebersold, R. Selected reaction monitoring-based proteomics: Workflows, potential, pitfalls and future directions. Nat. Methods 2012, 9, 555–566, doi:10.1038/nmeth.2015.
[91]
Anderson, L.; Hunter, C.L. Quantitative mass spectrometric multiple reaction monitoring assays for major plasma proteins. Mol. Cell. Proteomics 2006, 5, 573–588.
[92]
Lange, V.; Picotti, P.; Domon, B.; Aebersold, R. Selected reaction monitoring for quantitative proteomics: A tutorial. Mol. Syst. Biol. 2008, 4, e222.
[93]
Yost, R.A.; Enke, C.G. Triple quadrupole mass spectrometry for direct mixture analysis and structure elucidation. Anal. Chem. 1979, 51, 1251–1264, doi:10.1021/ac50048a002.
[94]
Gillette, M.A.; Carr, S.A. Quantitative analysis of peptides and proteins in biomedicine by targeted mass spectrometry. Nat. Methods 2013, 10, 28–34, doi:10.1038/nmeth.2309.
[95]
Cox, J.; Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 2008, 26, 1367–1372, doi:10.1038/nbt.1511.
[96]
Vaudel, M.; Sickmann, A.; Martens, L. Current methods for global proteome identification. Expert Rev. Proteomics 2012, 9, 519–532, doi:10.1586/epr.12.51.
[97]
Eng, J.K.; Searle, B.C.; Clauser, K.R.; Tabb, D.L. A face in the crowd: Recognizing peptides through database search. Mol. Cell. Proteomics 2011, 10, R111.009522.
[98]
Matthiesen, R.; Carvalho, A.S. Methods and algorithms for relative quantitative proteomics by mass spectrometry. Methods Mol. Biol. 2010, 593, 187–204, doi:10.1007/978-1-60327-194-3_10.
Hurley, J.H.; Odorizzi, G. Get on the exosome bus with ALIX. Nat. Cell Biol. 2012, 14, 654–655, doi:10.1038/ncb2530.
[101]
Old, W.M.; Meyer-Arendt, K.; Aveline-Wolf, L.; Pierce, K.G.; Mendoza, A.; Sevinsky, J.R.; Resing, K.A.; Ahn, N.G. Comparison of label-free methods for quantifying human proteins by shotgun proteomics. Mol. Cell. Proteomics 2005, 4, 1487–1502, doi:10.1074/mcp.M500084-MCP200.
[102]
Ross, P.L.; Huang, Y.N.; Marchese, J.N.; Williamson, B.; Parker, K.; Hattan, S.; Khainovski, N.; Pillai, S.; Dey, S.; Daniels, S.; et al. Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol. Cell. Proteomics 2004, 3, 1154–1169, doi:10.1074/mcp.M400129-MCP200.
[103]
Thompson, A.; Schafer, J.; Kuhn, K.; Kienle, S.; Schwarz, J.; Schmidt, G.; Neumann, T.; Johnstone, R.; Mohammed, A.K.; Hamon, C. Tandem mass tags: A novel quantification strategy for comparative analysis of complex protein mixtures by MS/MS. Anal. Chem. 2003, 75, 1895–1904, doi:10.1021/ac0262560.
[104]
Li, Z.; Adams, R.M.; Chourey, K.; Hurst, G.B.; Hettich, R.L.; Pan, C. Systematic comparison of label-free, metabolic labeling, and isobaric chemical labeling for quantitative proteomics on LTQ Orbitrap Velos. J. Proteome Res. 2012, 11, 1582–1590, doi:10.1021/pr200748h.
[105]
Chrysogelos, S.A.; Dickson, R.B. EGF receptor expression, regulation, and function in breast cancer. Breast Cancer Res. Treat. 1994, 29, 29–40, doi:10.1007/BF00666179.
[106]
Chrysogelos, S.A.; Yarden, R.I.; Lauber, A.H.; Murphy, J.M. Mechanisms of EGF receptor regulation in breast cancer cells. Breast Cancer Res. Treat. 1994, 31, 227–236, doi:10.1007/BF00666156.
[107]
Danielsen, A.J.; Maihle, N.J. The EGF/ErbB receptor family and apoptosis. Growth Factors 2002, 20, 1–15, doi:10.1080/08977190290022185.
[108]
Bucci, B.; D'Agnano, I.; Botti, C.; Mottolese, M.; Carico, E.; Zupi, G.; Vecchione, A. EGF-R expression in ductal breast cancer: Proliferation and prognostic implications. Anticancer Res. 1997, 17, 769–774.
[109]
Buchholz, T.A.; Tu, X.; Ang, K.K.; Esteva, F.J.; Kuerer, H.M.; Pusztai, L.; Cristofanilli, M.; Singletary, S.E.; Hortobagyi, G.N.; Sahin, A.A. Epidermal growth factor receptor expression correlates with poor survival in patients who have breast carcinoma treated with doxorubicin-based neoadjuvant chemotherapy. Cancer 2005, 104, 676–681, doi:10.1002/cncr.21217.
[110]
Navolanic, P.M.; Steelman, L.S.; McCubrey, J.A. EGFR family signaling and its association with breast cancer development and resistance to chemotherapy. Int. J. Oncol. 2003, 22, 237–252.
[111]
Peng, X.H.; Karna, P.; Cao, Z.; Jiang, B.H.; Zhou, M.; Yang, L. Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. J. Biol. Chem. 2006, 281, 25903–25914.
[112]
Tu, C.; Ortega-Cava, C.F.; Winograd, P.; Stanton, M.J.; Reddi, A.L.; Dodge, I.; Arya, R.; Dimri, M.; Clubb, R.J.; Naramura, M.; et al. Endosomal-sorting complexes required for transport (ESCRT) pathway-dependent endosomal traffic regulates the localization of active Src at focal adhesions. Proc. Natl. Acad. Sci. USA 2010, 107, 16107–16112, doi:10.1073/pnas.1009471107.
