Tumor mechanics and metabolic dysfunction

Free Radical Biology and Medicine - Tập 79 - Trang 269-280 - 2015
Jason C. Tung1, J. Matthew Barnes1, Shraddha R. Desai2, Christopher Sistrunk2, Matthew W. Conklin3, Pepper Schedin4, Kevin W. Eliceiri5, Patricia J. Keely3, Victoria L. Seewaldt2, Valerie M. Weaver1,6,7,8,9
1Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California at San Francisco, San Francisco, CA 94143, USA
2Department of Medicine, Duke University, Durham, NC 27710 USA
3Department of Biomedical Engineering, University of Wisconsin Carbone Comprehensive Cancer Center, Wisconsin Institute for Medical Research, University of Wisconsin at Madison, Madison, WI 53706, USA
4Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University. Portland, OR 97239, USA
5Laboratory for Optical and Computational Instrumentation, Laboratory for Cell and Molecular Biology, University of Wisconsin at Madison, Madison, WI 53706, USA
6Department of Anatomy, University of California, at San Francisco, San Francisco, CA 94143 USA
7Department of Bioengineering and Therapeutic Sciences, University of California at San Francisco, San Francisco, CA 94143, USA
8Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, CA 94143, USA
9Helen Diller Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94143, USA

Tài liệu tham khảo

Ai, 2007, [The relationship of expression of GLUT1, HIF-1alpha and the uptake of FDG in non-small cell lung cancer], Zhongguo Fei Ai Za Zhi, 10, 508 Alimonti, 2010, Subtle variations in Pten dose determine cancer susceptibility, Nat. Genet., 42, 454, 10.1038/ng.556 Bae, 1997, Epidermal growth factor (EGF)-induced generation of hydrogen peroxide: role in EGF receptor-mediated tyrosine phosphorylation, J. Biol. Chem., 272, 217, 10.1074/jbc.272.1.217 Barker, 2011, LOXL2-mediated matrix remodeling in metastasis and mammary gland involution, Cancer Res., 71, 1561, 10.1158/0008-5472.CAN-10-2868 Bell, 2007, The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production, J. Cell Biol., 177, 1029, 10.1083/jcb.200609074 Bensaad, 2006, TIGAR, a p53-inducible regulator of glycolysis and apoptosis, Cell, 126, 107, 10.1016/j.cell.2006.05.036 Bershadsky, 2003, Adhesion-dependent cell mechanosensitivity, Annu. Rev. Cell Dev. Biol., 19, 677, 10.1146/annurev.cellbio.19.111301.153011 Bird, 2005, Metabolic mapping of MCF10A human breast cells via multiphoton fluorescence lifetime imaging of the coenzyme NADH, Cancer Res., 65, 8766, 10.1158/0008-5472.CAN-04-3922 Biswas, 2012, Non-glucose metabolism in cancer cells—is it all in the fat?, Cancer Metastasis Rev., 31, 689, 10.1007/s10555-012-9384-6 Bowker, 2006, Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin: response to Farooki and Schneider, Diabetes Care, 29, 1990, 10.2337/dc06-0997 Butcher, 2009, A tense situation: forcing tumour progression, Nat. Rev. Cancer, 9, 108, 10.1038/nrc2544 Buzzai, 2005, The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid beta-oxidation, Oncogene, 24, 4165, 10.1038/sj.onc.1208622 Cairns, 2011, Regulation of cancer cell metabolism, Nat. Rev. Cancer, 11, 85, 10.1038/nrc2981 Castano, 2011, The tumor macroenvironment and systemic regulation of breast cancer progression, Int. J. Dev. Biol., 55, 889, 10.1387/ijdb.113366zc Chatterjee, 2012, Membrane depolarization is the trigger for PI3K/Akt activation and leads to the generation of ROS, Am. J. Physiol. Heart Circ. Physiol, 302, H105, 10.1152/ajpheart.00298.2011 Chaumeil, 2014, Hyperpolarized [1-13C]glutamate: a metabolic imaging biomarker of IDH1 mutational status in glioma, Cancer Res., 74, 4247, 10.1158/0008-5472.CAN-14-0680 Chiarugi, 2003, Reactive oxygen species as essential mediators of cell adhesion: the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion, J. Cell Biol., 161, 933, 10.1083/jcb.200211118 Cittadini, 2012, Metformin prevents the development of chronic heart failure in the SHHF rat model, Diabetes, 61, 944, 10.2337/db11-1132 Conklin, 2011, Aligned collagen is a prognostic signature for survival in human breast carcinoma, Am. J. Pathol., 178, 1221, 10.1016/j.ajpath.2010.11.076 Conklin, 2009, Fluorescence lifetime imaging of endogenous fluorophores in histopathology sections reveals differences between normal and tumor epithelium in carcinoma in situ of the breast, Cell. Biochem. Biophys., 53, 145, 10.1007/s12013-009-9046-7 Croft, 2004, Conditional ROCK activation in vivo induces tumor cell dissemination and angiogenesis, Cancer Res., 64, 8994, 10.1158/0008-5472.CAN-04-2052 De Beule, 2007, A hyperspectral fluorescence lifetime probe for skin cancer diagnosis, Rev. Sci. Instrum, 78, 123101, 10.1063/1.2818785 Dong, 2013, Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer, Cancer Cell, 23, 316, 10.1016/j.ccr.2013.01.022 Dowling, 2011, Understanding the benefit of metformin use in cancer treatment, BMC Med., 9, 33, 10.1186/1741-7015-9-33 Egeblad, 2010, Dynamic interplay between the collagen scaffold and tumor evolution, Curr. Opin. Cell Biol., 22, 697, 10.1016/j.ceb.2010.08.015 Elkin, 2007, Mechanical heterogeneity of the rat hippocampus measured by atomic force microscope indentation, J. Neurotrauma, 24, 812, 10.1089/neu.2006.0169 Erler, 2006, Lysyl oxidase mediates hypoxic control of metastasis, Cancer Res., 66, 10238, 10.1158/0008-5472.CAN-06-3197 Evans, 2005, Metformin and reduced risk of cancer in diabetic patients, BMJ, 330, 1304, 10.1136/bmj.38415.708634.F7 Fang, 2010, The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway, Cell, 143, 711, 10.1016/j.cell.2010.10.010 Flier, 1987, Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes, Science, 235, 1492, 10.1126/science.3103217 Forsberg, 2014, Cross talk between cellular redox status, metabolism, and p53 in neural stem cell biology, Neuroscientist, 20, 326, 10.1177/1073858413514634 Fournier, 2009, Interaction of E-cadherin and PTEN regulates morphogenesis and growth arrest in human mammary epithelial cells, Cancer Res., 69, 4545, 10.1158/0008-5472.CAN-08-1694 Gallagher, 2008, 13C MR spectroscopy measurements of glutaminase activity in human hepatocellular carcinoma cells using hyperpolarized 13C-labeled glutamine, Magn. Reson. Med., 60, 253, 10.1002/mrm.21650 Galletly, 2008, Fluorescence lifetime imaging distinguishes basal cell carcinoma from surrounding uninvolved skin, Br. J. Dermatol., 159, 152, 10.1111/j.1365-2133.2008.08577.x Galluzzi, 2013, Metabolic targets for cancer therapy, Nat. Rev. Drug Discovery, 12, 829, 10.1038/nrd4145 Gambhir, 2001, A tabulated summary of the FDG PET literature, J. Nucl. Med., 42, 1S Geiger, 2009, Environmental sensing through focal adhesions, Nat. Rev. Mol. Cell Biol., 10, 21, 10.1038/nrm2593 Georges, 2007, Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis, Am. J. Physiol. Gastrointest. Liver Physiol., 293, G1147, 10.1152/ajpgi.00032.2007 Gershtein, 2007, Phosphatidylinositol 3-kinase/AKT signalling pathway components in human breast cancer: clinicopathological correlations, Anticancer Res., 27, 1777 Gershtein, 2000, Expression of phosphatidylinositol-3 kinase in lung cancer, Bull. Exp. Biol. Med., 130, 1166, 10.1007/BF02682016 Giancotti, 1999, Integrin signaling, Science, 285, 1028, 10.1126/science.285.5430.1028 Giannoni, 2005, Intracellular reactive oxygen species activate Src tyrosine kinase during cell adhesion and anchorage-dependent cell growth, Mol. Cell. Biol., 25, 6391, 10.1128/MCB.25.15.6391-6403.2005 Gonzalez-Angulo, 2011, PI3K pathway mutations and PTEN levels in primary and metastatic breast cancer, Mol. Cancer Ther, 10, 1093, 10.1158/1535-7163.MCT-10-1089 Goo, 2012, PTEN/Akt signaling controls mitochondrial respiratory capacity through 4E-BP1, PLoS One, 7, e45806, 10.1371/journal.pone.0045806 Guan, 2010, Integrin signaling through FAK in the regulation of mammary stem cells and breast cancer, IUBMB Life, 62, 268 Gwinn, 2008, AMPK phosphorylation of raptor mediates a metabolic checkpoint, Mol. Cell, 30, 214, 10.1016/j.molcel.2008.03.003 Hadad, 2010, Gene signature of metformin actions on primary breast cancer within a window of opportunity randomized clinical trial, J. Clin. Oncol., 28, 560, 10.1200/jco.2010.28.15_suppl.560 Hamill, 2001, Molecular basis of mechanotransduction in living cells, Physiol. Rev., 81, 685, 10.1152/physrev.2001.81.2.685 Han, 2009, Correlation of 18F-FDG PET activity with expressions of survivin, Ki67, and CD34 in non-small-cell lung cancer, Nucl. Med. Commun., 30, 831, 10.1097/MNM.0b013e32832dcfc4 Hanahan, 2011, Hallmarks of cancer: the next generation, Cell, 144, 646, 10.1016/j.cell.2011.02.013 Hollander, 2011, PTEN loss in the continuum of common cancers, rare syndromes and mouse models, Nat. Rev. Cancer, 11, 289, 10.1038/nrc3037 Hosono, 2010, Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial, Cancer Prev. Res. (Philadelphia), 3, 1077, 10.1158/1940-6207.CAPR-10-0186 Hu, 2012, The regulation of multiple p53 stress responses is mediated through MDM2, Genes Cancer, 3, 199, 10.1177/1947601912454734 Ibarra-Drendall, 2011, Metabolic syndrome and breast cancer risk: is there a role for metformin?, Curr. Breast Cancer Rep, 3, 142, 10.1007/s12609-011-0050-8 Ibarra-Drendall, 2012, Pilot and feasibility study: prospective proteomic profiling of mammary epithelial cells from high-risk women provides evidence of activation of pro-survival pathways, Breast Cancer Res. Treat., 132, 487, 10.1007/s10549-011-1609-9 Ilan, 2006, Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis, Int. J. Biochem. Cell Biol., 38, 2018, 10.1016/j.biocel.2006.06.004 Ingber, 2008, Tensegrity-based mechanosensing from macro to micro, Prog. Biophys. Mol. Biol., 97, 163, 10.1016/j.pbiomolbio.2008.02.005 Ingman, 2006, Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland, Dev. Dyn., 235, 3222, 10.1002/dvdy.20972 Isakovic, 2007, Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis, Cell. Mol. Life Sci., 64, 1290, 10.1007/s00018-007-7080-4 Jadvar, 2009, 18F-FDG uptake in lung, breast, and colon cancers: molecular biology correlates and disease characterization, J. Nucl. Med., 50, 1820, 10.2967/jnumed.108.054098 Janmey, 1998, The cytoskeleton and cell signaling: component localization and mechanical coupling, Physiol. Rev., 78, 763, 10.1152/physrev.1998.78.3.763 Jiralerspong, 2008, The effects of metformin on pathologic complete response (pCR) rates in diabetic breast cancer (BC) patients receiving neoadjuvant systemic therapy (NST), J. Clin. Oncol., 26, 528, 10.1200/jco.2008.26.15_suppl.528 Johnson, 2007, Demystifying the effects of a three-dimensional microenvironment in tissue morphogenesis, Methods Cell Biol., 83, 547, 10.1016/S0091-679X(07)83023-8 Kaira, 2013, Biological correlation of 18F-FDG uptake on PET in pulmonary neuroendocrine tumors, Anticancer Res., 33, 4219 Kallergi, 2007, Activation of FAK/PI3K/Rac1 signaling controls actin reorganization and inhibits cell motility in human cancer cells, Cell. Physiol. Biochem., 20, 977, 10.1159/000110458 Kasznicki, 2014, Metformin in cancer prevention and therapy, Ann. Transl. Med, 2, 57 Katsumi, 2004, Integrins in mechanotransduction, J. Biol. Chem., 279, 12001, 10.1074/jbc.R300038200 Kauppila, 1998, Aberrant type I and type III collagen gene expression in human breast cancer in vivo, J. Pathol., 186, 262, 10.1002/(SICI)1096-9896(1998110)186:3<262::AID-PATH191>3.0.CO;2-3 Kessenbrock, 2010, Matrix metalloproteinases: regulators of the tumor microenvironment, Cell, 141, 52, 10.1016/j.cell.2010.03.015 Khaled, 2006, Ultrasonic strain imaging and reconstructive elastography for biological tissue, Ultrasonics, 44, e199, 10.1016/j.ultras.2006.06.007 Kim, 2007, Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1, Mol. Cell. Biol., 27, 7381, 10.1128/MCB.00440-07 Kim, 2014, Expression of metabolism-related proteins in triple-negative breast cancer, Int. J. Clin. Exp. Pathol., 7, 301 Kohn, 1996, Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation, J. Biol. Chem., 271, 31372, 10.1074/jbc.271.49.31372 Kokkinos, 2007, Vimentin and epithelial–mesenchymal transition in human breast cancer—observations in vitro and in vivo, Cells Tissues Organs, 185, 191, 10.1159/000101320 Kurhanewicz, 2011, Analysis of cancer metabolism by imaging hyperpolarized nuclei: prospects for translation to clinical research, Neoplasia, 13, 81, 10.1593/neo.101102 Kwon, 2004, Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors, Proc. Natl. Acad. Sci. USA, 101, 16419, 10.1073/pnas.0407396101 Laplante, 2012, mTOR signaling in growth control and disease, Cell, 149, 274, 10.1016/j.cell.2012.03.017 Le, 2009, Validation of lysyl oxidase as a prognostic marker for metastasis and survival in head and neck squamous cell carcinoma: Radiation Therapy Oncology Group trial 90-03, J. Clin. Oncol., 27, 4281, 10.1200/JCO.2008.20.6003 Lee, 2012, Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial–mesenchymal transition, Mol. Biol. Cell, 23, 4097, 10.1091/mbc.E12-02-0166 Leevers, 1999, Signalling through phosphoinositide 3-kinases: the lipids take centre stage, Curr. Opin. Cell Biol., 11, 219, 10.1016/S0955-0674(99)80029-5 Lele, 2007, Tools to study cell mechanics and mechanotransduction, Methods Cell Biol., 83, 443 Lelievre, 1998, Tissue phenotype depends on reciprocal interactions between the extracellular matrix and the structural organization of the nucleus, Proc. Natl. Acad. Sci. USA, 95, 14711, 10.1073/pnas.95.25.14711 Leppert, 2006, Multiphoton excitation of autofluorescence for microscopy of glioma tissue, Neurosurgery, 58, 759, 10.1227/01.NEU.0000204885.45644.22 Levental, 2009, Matrix crosslinking forces tumor progression by enhancing integrin signaling, Cell, 139, 891, 10.1016/j.cell.2009.10.027 Liu, 2009, Metformin induces unique biological and molecular responses in triple negative breast cancer cells, Cell Cycle, 8, 2031, 10.4161/cc.8.13.8814 Liu, 2004, Polarity and proliferation are controlled by distinct signaling pathways downstream of PI3-kinase in breast epithelial tumor cells, J. Cell Biol., 164, 603, 10.1083/jcb.200306090 Lopez, 2011, In situ force mapping of mammary gland transformation, Integr. Biol. (Cambridge), 3, 910, 10.1039/c1ib00043h Lu, 2012, The extracellular matrix: a dynamic niche in cancer progression, J. Cell Biol., 196, 395, 10.1083/jcb.201102147 Maehama, 1998, The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate, J. Biol. Chem., 273, 13375, 10.1074/jbc.273.22.13375 Maller, 2013, Collagen architecture in pregnancy-induced protection from breast cancer, J. Cell Sci., 126, 4108, 10.1242/jcs.121590 Manning, 2007, AKT/PKB signaling: navigating downstream, Cell, 129, 1261, 10.1016/j.cell.2007.06.009 Masin, 2014, GLUT3 is induced during epithelial–mesenchymal transition and promotes tumor cell proliferation in non-small cell lung cancer, Cancer Metab, 2, 11, 10.1186/2049-3002-2-11 Matoba, 2006, p53 regulates mitochondrial respiration, Science, 312, 1650, 10.1126/science.1126863 Mbeunkui, 2009, Cancer and the tumor microenvironment: a review of an essential relationship, Cancer Chemother. Pharmacol., 63, 571, 10.1007/s00280-008-0881-9 McKnight, 2007, Correlation of magnetic resonance spectroscopic and growth characteristics within Grades II and III gliomas, J. Neurosurg., 106, 660, 10.3171/jns.2007.106.4.660 Mouw, 2014, Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression, Nat. Med, 20, 360, 10.1038/nm.3497 Nelson, 2005, Modeling dynamic reciprocity: engineering three-dimensional culture models of breast architecture, function, and neoplastic transformation, Semin. Cancer Biol., 15, 342, 10.1016/j.semcancer.2005.05.001 Nelson, 2013, Metabolic imaging of patients with prostate cancer using hyperpolarized [1-13C]pyruvate, Sci. Transl. Med., 5, 10.1126/scitranslmed.3006070 O’Brien, 2001, Rac1 orientates epithelial apical polarity through effects on basolateral laminin assembly, Nat. Cell Biol., 3, 831, 10.1038/ncb0901-831 Ocana, 2014, Activation of the PI3K/mTOR/AKT pathway and survival in solid tumors: systematic review and meta-analysis, PLoS One, 9, e95219, 10.1371/journal.pone.0095219 Osthus, 2000, Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc, J. Biol. Chem., 275, 21797, 10.1074/jbc.C000023200 Ozdemir, 2014, Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival, Cancer Cell, 25, 719, 10.1016/j.ccr.2014.04.005 Pagan, 1996, Vimentin filaments follow the preexisting cytokeratin network during epithelial–mesenchymal transition of cultured neonatal rat hepatocytes, Exp. Cell Res., 222, 333, 10.1006/excr.1996.0043 Papandreou, 2006, HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption, Cell Metab., 3, 187, 10.1016/j.cmet.2006.01.012 Paszek, 2009, Integrin clustering is driven by mechanical resistance from the glycocalyx and the substrate, PLoS Comput. Biol., 5, e1000604, 10.1371/journal.pcbi.1000604 Paszek, 2005, Tensional homeostasis and the malignant phenotype, Cancer Cell, 8, 241, 10.1016/j.ccr.2005.08.010 Patel, 2010, Clinical outcomes after radical prostatectomy in diabetic patients treated with metformin, Urology, 76, 1240, 10.1016/j.urology.2010.03.059 Perepelyuk, 2013, Hepatic stellate cells and portal fibroblasts are the major cellular sources of collagens and lysyl oxidases in normal liver and early after injury, Am. J. Physiol. Gastrointest. Liver Physiol., 304, G605, 10.1152/ajpgi.00222.2012 Phipps, 2011, Body size, physical activity, and risk of triple-negative and estrogen receptor-positive breast cancer, Cancer Epidemiol. Biomarkers Prev, 20, 454, 10.1158/1055-9965.EPI-10-0974 Pickup, 2013, Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-beta-deficient mouse mammary carcinomas, Cancer Res., 73, 5336, 10.1158/0008-5472.CAN-13-0012 Pilie, 2011, Protein microarray analysis of mammary epithelial cells from obese and nonobese women at high risk for breast cancer: feasibility data, Cancer Epidemiol. Biomarkers Prev, 20, 476, 10.1158/1055-9965.EPI-10-0847 Plodinec, 2012, The nanomechanical signature of breast cancer, Nat. Nanotechnol, 7, 757, 10.1038/nnano.2012.167 Provenzano, 2006, Collagen reorganization at the tumor–stromal interface facilitates local invasion, BMC Med., 4, 38, 10.1186/1741-7015-4-38 Provenzano, 2008, Mammary epithelial-specific disruption of focal adhesion kinase retards tumor formation and metastasis in a transgenic mouse model of human breast cancer, Am. J. Pathol., 173, 1551, 10.2353/ajpath.2008.080308 Provenzano, 2009, Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK–ERK linkage, Oncogene, 28, 4326, 10.1038/onc.2009.299 Provenzano, 2008, Collagen density promotes mammary tumor initiation and progression, BMC Med., 6, 11, 10.1186/1741-7015-6-11 Provenzano, 2009, The role of focal adhesion kinase in tumor initiation and progression, Cell Adhes. Migr, 3, 347, 10.4161/cam.3.4.9458 Quail, 2013, Microenvironmental regulation of tumor progression and metastasis, Nat. Med, 19, 1423, 10.1038/nm.3394 Rathmell, 2003, Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival, Mol. Cell. Biol., 23, 7315, 10.1128/MCB.23.20.7315-7328.2003 Rose, 2007, Adiposity, the metabolic syndrome, and breast cancer in African-American and white American women, Endocr. Rev., 28, 763, 10.1210/er.2006-0019 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 Santala, 1999, Type I and III collagen metabolites as predictors of clinical outcome in epithelial ovarian cancer, Clin. Cancer Res., 5, 4091 Sautes-Fridman, 2011, Tumor microenvironment is multifaceted, Cancer Metastasis Rev., 30, 13, 10.1007/s10555-011-9279-y Schafer, 2009, Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment, Nature, 461, 109, 10.1038/nature08268 Schedin, 2009, Breaking down barriers: the importance of the stromal microenvironment in acquiring invasiveness in young women׳s breast cancer, Breast Cancer Res., 11, 102, 10.1186/bcr2235 Schedin, 2011, Mammary gland ECM remodeling, stiffness, and mechanosignaling in normal development and tumor progression, Cold Spring Harbor Perspect Biol, 3, a003228, 10.1101/cshperspect.a003228 Selbekk, 2005, Strain processing of intraoperative ultrasound images of brain tumours: initial results, Ultrasound Med. Biol., 31, 45, 10.1016/j.ultrasmedbio.2004.09.011 Shackelford, 2009, The LKB1–AMPK pathway: metabolism and growth control in tumour suppression, Nat. Rev. Cancer, 9, 563, 10.1038/nrc2676 Shah, 2014, Optical metabolic imaging of treatment response in human head and neck squamous cell carcinoma, PLoS One, 9, e90746, 10.1371/journal.pone.0090746 Skala, 2007, In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia, Proc. Natl. Acad. Sci. USA, 104, 19494, 10.1073/pnas.0708425104 Solaini, 2011, Oxidative phosphorylation in cancer cells, Biochim. Biophys. Acta, 1807, 534, 10.1016/j.bbabio.2010.09.003 Spano, 2012, Tumor microenvironment: a main actor in the metastasis process, Clin. Exp. Metastasis, 29, 381, 10.1007/s10585-012-9457-5 Stambolic, 2001, Regulation of PTEN transcription by p53, Mol. Cell, 8, 317, 10.1016/S1097-2765(01)00323-9 Sung, 2007, Tumor microenvironment promotes cancer progression, metastasis, and therapeutic resistance, Curr. Probl. Cancer, 31, 36, 10.1016/j.currproblcancer.2006.12.002 Szatrowski, 1991, Production of large amounts of hydrogen peroxide by human tumor cells, Cancer Res., 51, 794 Takahashi, 2006, Mitogenic signalling and the p16INK4a–Rb pathway cooperate to enforce irreversible cellular senescence, Nat. Cell Biol., 8, 1291, 10.1038/ncb1491 Thomas, 2008, Redox control of endothelial function and dysfunction: molecular mechanisms and therapeutic opportunities, Antioxid. Redox Signaling, 10, 1713, 10.1089/ars.2008.2027 Tilghman, 2010, Matrix rigidity regulates cancer cell growth and cellular phenotype, PLoS One, 5, e12905, 10.1371/journal.pone.0012905 Toyokuni, 1995, Persistent oxidative stress in cancer, FEBS Lett., 358, 1, 10.1016/0014-5793(94)01368-B Tzima, 2002, Activation of Rac1 by shear stress in endothelial cells mediates both cytoskeletal reorganization and effects on gene expression, EMBO J., 21, 6791, 10.1093/emboj/cdf688 Unsgaard, 2006, Intra-operative 3D ultrasound in neurosurgery, Acta Neurochir. (Wien), 148, 235, 10.1007/s00701-005-0688-y Vaupel, 2009, Prognostic potential of the pre-therapeutic tumor oxygenation status, Adv. Exp. Med. Biol., 645, 241, 10.1007/978-0-387-85998-9_36 Vaupel, 2004, Tumor hypoxia and malignant progression, Methods Enzymol., 381, 335, 10.1016/S0076-6879(04)81023-1 Villette, 2006, Ultraviolet-induced autofluorescence characterization of normal and tumoral esophageal epithelium cells with quantitation of NAD(P)H, Photochem. Photobiol. Sci., 5, 483, 10.1039/b514801d Wahdan-Alaswad, 2013, Glucose promotes breast cancer aggression and reduces metformin efficacy, Cell Cycle, 12, 3759, 10.4161/cc.26641 Walsh, 2013, Optical metabolic imaging identifies glycolytic levels, subtypes, and early-treatment response in breast cancer, Cancer Res., 73, 6164, 10.1158/0008-5472.CAN-13-0527 Wang, 2000, Substrate flexibility regulates growth and apoptosis of normal but not transformed cells, Am. J. Physiol. Cell Physiol, 279, C1345, 10.1152/ajpcell.2000.279.5.C1345 Warburg, 1956, On the origin of cancer cells, Science, 123, 309, 10.1126/science.123.3191.309 Warburg, 1927, The metabolism of tumors in the body, J. Gen. Physiol., 8, 519, 10.1085/jgp.8.6.519 Willipinski-Stapelfeldt, 2005, Changes in cytoskeletal protein composition indicative of an epithelial–mesenchymal transition in human micrometastatic and primary breast carcinoma cells, Clin. Cancer Res., 11, 8006, 10.1158/1078-0432.CCR-05-0632 Wozniak, 2003, ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix, J. Cell Biol., 163, 583, 10.1083/jcb.200305010 Wyckoff, 2007, Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors, Cancer Res., 67, 2649, 10.1158/0008-5472.CAN-06-1823 Xia, 2004, Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway, J. Biol. Chem., 279, 33024, 10.1074/jbc.M313265200 Xiao, 2010, Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1–Smad3 signalling pathway, Cardiovasc. Res., 87, 504, 10.1093/cvr/cvq066 Zhu, 1995, Immunohistochemical study of type I collagen and type I pN-collagen in benign and malignant ovarian neoplasms, Cancer, 75, 1010, 10.1002/1097-0142(19950215)75:4<1010::AID-CNCR2820750417>3.0.CO;2-O Zipfel, 2003, Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation, Proc. Natl. Acad. Sci. USA, 100, 7075, 10.1073/pnas.0832308100