Polymer free-radical lipid alkene chain-growth biological models particularly for hypoxic cellular mitochondrial metabolic waste can be used to better understand abnormal cancer cell morphology and invasive metastasis. Without oxygen as the final electron acceptor for mitochondrial energy synthesis, protons cannot combine to form water and instead mitochondria produce free radicals and acid during hypoxia. Nonuniform bond-length shrinkage of membranes related to erratic free-radical covalent crosslinking can explain cancer-cell pleomorphism with epithelial-mesenchymal transition for irregular membrane borders that “ruffle” and warp over stiff underlying actin fibers. Further, mitochondrial hypoxic conditions produce acid that can cause molecular degradation. Subsequent low pH-activated enzymes then provide paths for invasive cell movement through tissue and eventually blood-born metastasis. Although free-radical crosslinking creates irregularly shaped membranes with structural actin-polymerized fiber extensions as filopodia and lamellipodia, due to rapid cell division the overall cell modulus (approximately stiffness) is lower than normal cells. When combined with low pH-activated enzymes and lower modulus cells, smaller cancer stem cells subsequently have a large advantage to follow molecular destructive pathways and leave the central tumor. In addition, forward structural spike-like lamellipodia protrusions can leverage to force lower-modulus cancer cells through narrow openings. By squeezing and deforming even smaller to allow for easier movement through difficult passageways, cancer cells can travel into adjacent tissues or possibly metastasize through the blood to new tissue. 1. Introduction Cancer Fundamentals. Cancer is a pathological condition related to malignant uncontrolled rapid cell growth proliferation, invasive cell movement into adjacent tissues, and occasional metastatic spread through blood and lymph to more distant locations [1–4]. Conversely, benign tumors represent uncontrolled cell growth that does not invade other tissues [1–4]. Cancers are the result of progressive accumulations in genetic mutations through cell interactions with carcinogens such as tobacco, sunlight, radiation, infectious microbes, or certain chemicals/material [1–4]. Some genetic changes can be added by being passed along from one generation to another to increase cancer risk [1–4]. Although normal cells have limits to replication or the number of cell divisions to control growth by apoptosis cell death when necessary with a cascade of caspase enzymes, cancer
References
[1]
National Cancer Institute/National Institutes of Health/Department of Health and Human Services, What You Need To Know About Cancer, NIH, 2006.
[2]
T. S. Deisboeck and G. S. Stamatakos, Multiscale Cancer Modeling, Chapman & Hall/ CRC Press, Boca Raton, Fla, USA, 2011.
[3]
B. Kwabi-Addo and T. L. Lindstrom, Cancer Causes and Controversies, Praeger, Barbara, Calif, USA, 2011.
[4]
R. A. Weinberg, The Biology of Cancer, Garland Science, New York, NY, USA, 2007.
[5]
R. Doll and A. B. Hill, “Lung cancer and other causes of death in relation to smoking: a second report on the mortality of British doctors,” British Medical Journal, vol. 233, pp. 1071–1076, 1956.
[6]
G. M. Findlay, “Ultra-violet light and skin cancer,” The Lancet, vol. 212, no. 5491, pp. 1070–1073, 1928.
[7]
H. J. Muller, “The production of mutations by X-rays,” Proceedings of the National Academy of Sciences of the United States of America, vol. 14, no. 9, pp. 714–726, 1928.
[8]
I. Berenblum, “The mechanism of carcinogenesis. A study of the significance of cocarcinogenic action and related phenomena,” Cancer Research, vol. 1, article 807, 1941.
[9]
J. G. Kidd and P. Rous, “The carcinogenic effect of a papilloma virus on the tarred skin of radibts: II Major factors determining the phenomenon: the manifold effects of tarring,” The Journal of Experimental Medicine, vol. 68, pp. 529–562, 1938.
[10]
C. Huggins and C. V. Hodges, “Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate,” Cancer Research, vol. 1, article 293, 1941.
[11]
A. Tanenbaum and H. Silverstone, “The influence of the degree of caloric restriction on the formation of skin tumors and hepatomas in mice,” Cancer Research, vol. 9, no. 12, pp. 724–727, 1949.
[12]
O. Warburg, K. Posener, and E. Negelein, “The metabolism of the cancer cell,” Biochemische Zeitschrift, vol. 152, pp. 319–344, 1924.
[13]
S. Weinhouse, O. Warburg, D. Burk, and A. L. Schade, “On respiratory impairment in cancer cells,” Science, vol. 124, no. 3215, pp. 269–270, 1956.
[14]
R. J. Gillies, The Tumour Microenvironment: Causes and Consequences of Hypoxia and Acidity, Novartis Foundation Symposium 240, John Wiley & Sons, New York, NY, USA, 2001.
[15]
J. C. Stavridis, Oxidation: the Cornerstone of Carcinogenesis, Springer, New York, NY, USA, 2008.
[16]
V. C. Fogg, N. J. Lanning, and J. P. MacKeigan, “Mitochondria in cancer: at the crossroads of life and death,” Chinese Journal of Cancer, vol. 30, no. 8, pp. 526–539, 2011.
[17]
L. Sherwood, Human Physiology, Thompson Brooks/Cole, Belmont, Calif, USA, 5th edition, 2004.
[18]
R. Harvey and D. Ferrier, Biochemistry, Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, Pa, USA, 5th edition, 2011.
[19]
A. J. Schetter, N. H. H. Heegaard, and C. C. Harris, “Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways,” Carcinogenesis, vol. 31, no. 1, pp. 37–49, 2009.
[20]
J. Wang and J. Yi, “Cancer cell killing via ROS: to increase or decrease, that is a question,” Cancer Biology and Therapy, vol. 7, no. 12, pp. 1875–1884, 2008.
[21]
M. P. Murphy, “How mitochondria produce reactive oxygen species,” Biochemical Journal, vol. 417, no. 1, pp. 1–13, 2009.
[22]
R. C. Petersen, “Reactive secondary sequence oxidative pathology polymer model and antioxidant tests,” International Journal of Pure and Applied Chemistry, vol. 2, no. 4, pp. 247–285, 2012.
[23]
J. McMurry, Organic Chemistry, Thomson/Brooks/Cole, Belmont, Calif, USA, 6th edition, 2004.
[24]
J. M. Lü, P. H. Lin, Q. Yao, and C. Chen, “Chemical and molecular mechanisms of antioxidants: experimental approaches and model systems,” Journal of Cellular and Molecular Medicine, vol. 14, no. 4, pp. 840–860, 2010.
[25]
X. A. J. Peacock and A. Calhoun, Polymer Chemistry Properties and Applications, Hanser, Munich, Germany, 2006.
[26]
I. Mironi-Harpaz, M. Narkis, and A. Siegmann, “Peroxide crosslinking of a styrene-free unsaturated polyester,” Journal of Applied Polymer Science, vol. 105, no. 2, pp. 885–892, 2007.
[27]
Y. Wang, L. Woodworth, and B. Han, “Simultaneous measurement of effective chemical shrinkage and modulus evolutions during polymerization,” Experimental Mechanics, vol. 51, no. 7, pp. 1155–1169, 2011.
[28]
D. Recupero, L. Annaratone, F. Maletta, and G. Bussolati, “Nuclear shape in papillary thyroid carcinoma: a role for lamin b receptor?” Romanian Journal of Morphology and Embryology, vol. 51, no. 4, pp. 615–620, 2010.
[29]
V. A. McCormack and I. Dos Santos Silva, “Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis,” Cancer Epidemiology Biomarkers and Prevention, vol. 15, no. 6, pp. 1159–1169, 2006.
[30]
C. M. Kraning-Rush, J. P. Califano, and C. A. Reinhart-King, “Cellular traction stresses increase with increasing metastatic potential,” PLoS ONE, vol. 7, no. 2, Article ID e32572, 2012.
[31]
G. Y. Li and J. L. Koenig, “FTIR imaging of oxidation of polyisoprene 2. The role of N-phenyl-N′-dimethyl-butyl-p-phenylenediamine antioxidant,” Polymer Degradation and Stability, vol. 81, no. 3, pp. 377–385, 2003.
[32]
G. Helmlinger, F. Yuan, M. Dellian, and R. K. Jain, “Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation,” Nature Medicine, vol. 3, no. 2, pp. 177–182, 1997.
[33]
J. Michael and S. Sircar, Fundamentals of Medical Physiology, Thieme, New York, NY, USA, 2011.
[34]
B. Alberts, A. Johnson, J. Lewis, M. Raff, K. Roberts, and P. Walters, Molecular Biology of the Cell, Garland Science, New York, NY, USA, 4th edition, 2002.
[35]
L. Stryer, Biochemistry, W. H. Freeman and Company, New York, NY, USA, 4th edition, 1995.
[36]
J. B. Wenger, S. Y. Chun, D. T. Dang, H. Luesch, and L. H. Dang, “Combination therapy targeting cancer metabolism,” Medical Hypotheses, vol. 76, no. 2, pp. 169–172, 2011.
[37]
N. J. Vardaxis, A Textbook of Pathology, Elsevier, New York, NY, USA, 2010.
[38]
S. L. Robbins and M. Angell, Basic Pathology, WB Saunders, Philadelphia, Pa, USA, 1971.
[39]
J. F. Kerr, A. H. Wyllie, and A. R. Currie, “Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics,” British Journal of Cancer, vol. 26, no. 4, pp. 239–257, 1972.
[40]
L. A. Liotta, K. Tryggvason, and S. Garbisa, “Metastatic potential correlates with enzymatic degradation of basement membrane collagen,” Nature, vol. 284, no. 5751, pp. 67–68, 1980.
[41]
P. A. Jones and S. M. Taylor, “Cellular differentiation, cytidine analogs and DNA methylation,” Cell, vol. 20, no. 1, pp. 85–93, 1980.
[42]
A. Loveless, “Possible relevance of O-6 alkylation of deoxyguanosine to the mutagenicity and carcinogenicity of nitrosamines and nitrosamides,” Nature, vol. 223, no. 5202, pp. 206–207, 1969.
[43]
P. F. Swann and P. N. Magee, “Nitrosamine-induced carcinogenesis. The alklylation of nucleic acids of the rat by N-methyl-N-nitrosourea, dimethylnitrosamine, dimethyl sulphate and methyl methanesulphonate,” Biochemical Journal, vol. 110, no. 1, pp. 39–47, 1968.
[44]
M. Bignami, M. O'Driscoll, G. Aquilina, and P. Karran, “Unmasking a killer: DNA O6-methylguanine and the cytotoxicity of methylating agents,” Mutation Research, vol. 462, no. 2-3, pp. 71–82, 2000.
[45]
P. Whyte, K. J. Buchkovich, J. M. Horowitz et al., “Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product,” Nature, vol. 334, no. 6178, pp. 124–129, 1988.
[46]
J. M. Nigro, S. J. Baker, A. C. Preisinger et al., “Mutations in the p53 gene occur in diverse human tumour types,” Nature, vol. 342, no. 6250, pp. 705–708, 1989.
[47]
S. J. Baker, E. R. Fearon, J. M. Nigro et al., “Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas,” Science, vol. 244, no. 4901, pp. 217–221, 1989.
[48]
C. J. Tabin, S. M. Bradley, and C. I. Bargmann, “Mechanism of activation of a human oncogene,” Nature, vol. 300, no. 5888, pp. 143–149, 1982.
[49]
E. P. Reddy, R. K. Reynolds, E. Santos, and M. Barbacid, “A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene,” Nature, vol. 300, no. 5888, pp. 149–152, 1982.
[50]
E. Taparowsky, Y. Suard, and O. Fasano, “Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change,” Nature, vol. 300, no. 5894, pp. 762–765, 1982.
[51]
S. T. Peters, Handbook of Composites, Chapman and Hall, New York, NY, USA, 2nd edition, 1998.
[52]
K. M. B. Jansen, J. Vreugd de, and L. J. Ernst, “Analytical estimate for curing-induced stress and warpage in coating layers,” Journal of Applied Polymer Science, vol. 126, pp. 1623–1630, 2012.
[53]
L. J. Deterding, D. C. Ramirez, J. R. Dubin, R. P. Mason, and K. B. Tomer, “Identification of free radicals on hemoglobin from its self-peroxidation using mass spectrometry and immuno-spin trapping: observation of a histidinyl radical,” The Journal of Biological Chemistry, vol. 279, no. 12, pp. 11600–11607, 2004.
[54]
I. Ayala, K. Range, D. York, and B. A. Barry, “Spectroscopic properties of tyrosyl radicals in dipeptides,” Journal of the American Chemical Society, vol. 124, no. 19, pp. 5496–5505, 2002.
[55]
I. R. Vassiliev, A. R. Offenbacher, and B. A. Barry, “Redox-active tyrosine residues in pentapeptides,” Journal of Physical Chemistry B, vol. 109, no. 48, pp. 23077–23085, 2005.
[56]
T. Vinogradova, P. M. Miller, and I. Kaverina, “Microtubule network asymmetry in motile cells: role of Golgi-derived array,” Cell Cycle, vol. 8, no. 14, pp. 2168–2174, 2009.
[57]
U. Lindberg, R. Karlsson, I. Lassing, C. E. Schutt, and A. S. H？glund, “The microfilament system and malignancy,” Seminars in Cancer Biology, vol. 18, no. 1, pp. 2–11, 2008.
[58]
A. San Martín and K. K. Griendling, “Redox control of vascular smooth muscle migration,” Antioxidants and Redox Signaling, vol. 12, no. 5, pp. 625–640, 2010.
[59]
L.-E. Copstead and J. Banasik, Pathophysiology, Elsevier Saunders, St. Louis, Mo, USA, 6th edition, 2005.
[60]
Z. Li, M. Hannigan, Z. Mo et al., “Directional Sensing Requires Gβγ-Mediated PAK1 and PIXα-Dependent Activation of Cdc42,” Cell, vol. 114, no. 2, pp. 215–227, 2003.
[61]
H. Hattori, K. K. Subramanian, J. Sakai, Y. Jia, Y. Li, T. F. Porter, et al., “Small-molecule screen identifies reacive oxygen species as key regulators of neutorphil chemotaxis,” PNAS, vol. 107, no. 8, pp. 3546–3551, 2010.
[62]
F. Parisi and M. Vidal, “Epithelial delamination and migration: lessons from Drosophila,” Cell Adhesion & Migration, vol. 5, no. 4, pp. 366–372, 2011.
[63]
A. I. M. Barth, H. Y. Caro-Gonzalez, and W. J. Nelson, “Role of adenomatous polyposis coli (APC) and microtubules in directional cell migration and neuronal polarization,” Seminars in Cell and Developmental Biology, vol. 19, no. 3, pp. 245–251, 2008.
[64]
E. W. Dent, S. L. Gupton, and F. B. Gertler, “The growth cone cytoskeleton in axon outgrowth and guidance,” Cold Spring Harbor Perspectives in Biologyl, vol. 3, no. 3, article 42, 2010.
[65]
B. D. Ratner, A. S. Hoffman, F. J. Schoen, and J. E. Lemons, Biomaterials Science, Elsevier, San Diego, Calif, USA, 2004.
[66]
J. Pokorny, A. Jandová, M. Nedbalová, et al., “Mitochondrial metabolism-neglected link of cancer transformation and treatment,” Prague Medical Report, vol. 113, no. 2, pp. 81–94, 2012.
[67]
X. Zhu, M. M. Gallogly, J. J. Mieyal, V. E. Anderson, and L. M. Sayre, “Covalent cross-linking of glutathione and carnosine to proteins by 4-oxo-2-nonenal,” Chemical Research in Toxicology, vol. 22, no. 6, pp. 1050–1059, 2009.
[68]
S. Saraswathy, G. Wu, and N. A. Rao, “Retinal microglial activation and chemotaxis by docosahexaenoic acid hydroperoxide,” Investigative Ophthalmology and Visual Science, vol. 47, no. 8, pp. 3656–3663, 2006.
[69]
H. Zhang, B. C. Gau, L. M. Jones, I. Vidavsky, and M. L. Gross, “Fast photochemical oxidation of proteins for comparing structures of protein-ligand complexes: the calmodulin-peptide model system,” Analytical Chemistry, vol. 83, no. 1, pp. 311–318, 2011.
[70]
R. Torosantucci, O. Mozziconacci, V. Sharov, C. Sch？neich, and W. Jiskoot, “Chemical modifications in aggregates of recombinant human insulin induced by metal-catalyzed oxidation: covalent cross-linking via michael addition to tyrosine oxidation products,” Pharmaceutical Research, vol. 29, no. 8, pp. 2276–2293, 2012.
[71]
R. A. Dunlop, R. T. Dean, and K. J. Rodgers, “The impact of specific oxidized amino acids on protein turnover in J774 cells,” Biochemical Journal, vol. 410, no. 1, pp. 131–140, 2008.
[72]
E. M. Darling, S. Zauscher, J. A. Block, and F. Guilak, “A thin-layer model for viscoelastic, stress-relaxation testing of cells using atomic force microscopy: do cell properties reflect metastatic potential?” Biophysical Journal, vol. 92, no. 5, pp. 1784–1791, 2007.
[73]
F. Fleischer, R. Ananthakrishnan, S. Eckel et al., “Actin network architecture and elasticity in lamellipodia of melanoma cells,” New Journal of Physics, vol. 9, article 420, 2007.
[74]
V. C. Abraham, V. Krishnamurthi, D. Lansing Taylor, and F. Lanni, “The actin-based nanomachine at the leading edge of migrating cells,” Biophysical Journal, vol. 77, no. 3, pp. 1721–1732, 1999.
[75]
E. Atilgan, D. Wirtz, and S. X. Sun, “Morphology of the lamellipodium and organization of actin filaments at the leading edge of crawling cells,” Biophysical Journal, vol. 89, no. 5, pp. 3589–3602, 2005.
[76]
Y. Qian, J. Luo, S. S. Leonard et al., “Hydrogen peroxide formation and actin filament reorganization by Cdc42 are essential for ethanol-induced in vitro angiogenesis,” The Journal of Biological Chemistry, vol. 278, no. 18, pp. 16189–16197, 2003.
[77]
B. Gawdzik, J. Ksi？zopolski, and T. Matynia, “Synthesis of new free-radical initiators for polymerization,” Journal of Applied Polymer Science, vol. 87, no. 14, pp. 2238–2243, 2003.
[78]
Y. I. Miller, D. S. Worrall, C. D. Funk, J. R. Feramisco, and J. L. Witztum, “Actin polymerization in macrophages in response to oxidized LDL and apoptotic cells: role of 12/15-lipoxygenase and phosphoinositide 3-kinase,” Molecular Biology of the Cell, vol. 14, no. 10, pp. 4196–4206, 2003.
[79]
M. Ushio-Fukai and Y. Nakamura, “Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy,” Cancer Letters, vol. 266, no. 1, pp. 37–52, 2008.
[80]
M. J. Hitchler and F. E. Domann, “Metabolic defects provide a spark for the epigenetic switch in cancer,” Free Radical Biology and Medicine, vol. 47, no. 2, pp. 115–127, 2009.
[81]
C. L. Grek and K. D. Twe, “Redox metabolism and malignancy,” Current Opinion in Pharmacology, vol. 10, no. 4, pp. 362–368, 2010.
[82]
M. H？ckel and P. Vaupel, “Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects,” Journal of the National Cancer Institute, vol. 93, no. 4, pp. 266–276, 2001.
[83]
P. Vaupel, “The role of hypoxia-induced factors in tumor progression,” Oncologist, vol. 9, no. 5, pp. 10–17, 2004.
[84]
D. M. Brizel, S. P. Scully, J. M. Harrelson et al., “Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma,” Cancer Research, vol. 56, no. 5, pp. 941–943, 1996.
[85]
S. P. Hussain and C. C. Harris, “Inflammation and cancer: an ancient link with novel potentials,” International Journal of Cancer, vol. 121, no. 11, pp. 2373–2380, 2007.
[86]
G. W. Burton, K. H. Cheeseman, T. Doba, K. U. Ingold, and T. F. Slater, “Vitamin E as an antioxidant in vitro and in vivo,” Ciba Foundation symposium, vol. 101, pp. 4–18, 1983.
[87]
G. W. Burton, K. H. Cheeseman, T. Doba, K. U. Ingold, and T. F. Slater, “Vitamin E as an antioxidant in vitro and in vivo,” in Ciba Foundation Symposium 101, Biology of Vitamin E, Pitman, London, UK, 1983.
[88]
N. A. Porter, S. E. Caldwell, and K. A. Mills, “Mechanisms of free radical oxidation of unsaturated lipids,” Lipids, vol. 30, no. 4, pp. 277–290, 1995.
[89]
C. Schneider, “An update on products and mechanisms of lipid peroxidation,” Molecular Nutrition and Food Research, vol. 53, no. 3, pp. 315–321, 2009.
[90]
X. Lu and Y. Kang, “Hypoxia and hypoxia-inducible factors: master regulators of metastasis,” Clinical Cancer Research, vol. 16, no. 24, pp. 5928–5935, 2010.
[91]
V. Swaminathan, K. Mythreye, E. Tim O'Brien, A. Berchuck, G. C. Blobe, and R. Superfine, “Mechanical Stiffness grades metastatic potential in patient tumor cells and in cancer cell lines,” Cancer Research, vol. 71, no. 15, pp. 5075–5080, 2011.
[92]
G. L. Johanning, “Modulation of breast cancer cell adhesion by unsaturated fatty acids,” Nutrition, vol. 12, no. 11-12, pp. 810–816, 1996.
[93]
Y. Yang, H. Hong, Y. Zhang, and W. Cai, “Molecular imaging of proteases in cancer,” Cancer Growth Metast, vol. 17, no. 2, pp. 13–27, 2009.
[94]
J. Kim, W. Yu, K. Kovalski, and L. Ossowski, “Requirement for specific proteases in cancer cell intravasation as revealed by a novel semiquantitative PCR-based assay,” Cell, vol. 94, no. 3, pp. 353–362, 1998.
[95]
E. Lee, J. Jeong, S. E. Kim, E. J. Song, S. W. Kang, and K. J. Lee, “Multiple functions of Nm23-H1 are regulated by oxido-reduction system,” PLoS ONE, vol. 4, no. 11, Article ID e7949, 2009.
[96]
W. Xu, R. Mezencev, B. Kim, L. Wang, J. McDonald, and T. Sulchek, “Cell stiffness is a biomarker of the metastatic potential of ovarian cancer cells,” PLoS ONE, vol. 7, no. 10, Article ID e46609, 2012.
[97]
S. Ghosh, T. Kang, H. Wang, Y. Hu, and R. Li, “Mechanical phenotype is important for stromal aromatase expression,” Steroids, vol. 76, no. 8, pp. 797–801, 2011.
[98]
K. Hoyt, B. Castaneda, M. Zhang et al., “Tissue elasticity properties as biomarkers for prostate cancer,” Cancer Biomarkers, vol. 4, no. 4-5, pp. 213–225, 2008.
[99]
L. Trichet, J. Le Digabel, R. J. Hawkins et al., “Evidence of a large-scale mechanosensing mechanism for cellular adaptation to substrate stiffness,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 18, pp. 6933–6938, 2012.
[100]
E. M. Darling, S. Zauscher, J. A. Block, and F. Guilak, “A thin-layer model for viscoelastic, stress-relaxation testing of cells using atomic force microscopy: do cell properties reflect metastatic potential?” Biophysical Journal, vol. 92, no. 5, pp. 1784–1791, 2007.
[101]
R. A. Marcus and N. Sutin, “Electron transfers in chemistry and biology,” Biochimica et Biophysica Acta, vol. 811, no. 3, pp. 265–322, 1985.
[102]
Y. H. Soung, J. L. Clifford, and J. Chung, “Crosstalk between integrin and receptor tyrosine kinase signaling in breast carcinoma progression,” BMB Reports, vol. 43, no. 5, pp. 311–318, 2010.
[103]
R. R. Valiathan, M. Marco, B. Leitinger, C. G. Kleer, and R. Fridman, “Discoidin domain receptor tyrosine kinases: new players in cancer progression,” Cancer and Metastasis Reviews, vol. 31, no. 1-2, pp. 295–321, 2012.
[104]
K. Wolf, I. Mazo, H. Leung et al., “Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis,” Journal of Cell Biology, vol. 160, no. 2, pp. 267–277, 2003.
[105]
American Cancer Society, “Nutrition and physical activity guidelines for cancer survivors,” CA—Cancer Journal for Clinicians, vol. 62, no. 4, pp. 275–276, 2012.
[106]
M. Goodman, R. M. Bostick, O. Kucuk, and D. P. Jones, “Clinical trials of antioxidants as cancer prevention agents: past, present, and future,” Free Radical Biology and Medicine, vol. 51, no. 5, pp. 1068–1084, 2011.
[107]
F. Rodriquez, Principles of Polymer SystemsEdition, Taylor & Francis, Washington, DC, USA, 4th edition, 1996.
[108]
M. Jaffar, N. Abou-Zeid, L. Bai et al., “Quinone bioreductive prodrugs as delivery agents,” Current Drug Delivery, vol. 1, no. 4, pp. 345–350, 2004.
[109]
S. J. Ralph, S. Rodríguez-Enríquez, J. Neuzil, E. Saavedra, and R. Moreno-Sánchez, “The causes of cancer revisited: “Mitochondrial malignancy” and ROS-induced oncogenic transformation—why mitochondria are targets for cancer therapy,” Molecular Aspects of Medicine, vol. 31, no. 2, pp. 145–170, 2010.
[110]
N. Raghunand and R. J. Gillies In:, “pH and chemotherapy,” in The Tumour Microenvironment: Causes and Consequence of Hypoxia and Acidity, Novartis Foundation Symposium 240, pp. 199–211, Wiley, Chichester, UK, 2001.
