Acid-Mediated Tumor Invasion: a Multidisciplinary Study
Abstract
The acid-mediated tumor invasion hypothesis proposes altered glucose metabolism and increased glucose uptake, observed in the vast majority of clinical cancers by fluorodeoxyglucose-positron emission tomography, are critical for development of the invasive phenotype. In this model, increased acid production due to altered glucose metabolism serves as a key intermediate by producing H+ flow along concentration gradients into adjacent normal tissue. This chronic exposure of peritumoral normal tissue to an acidic microenvironment produces toxicity by: (a) normal cell death caused by the collapse of the transmembrane H+ gradient inducing necrosis or apoptosis and (b) extracellular matrix degradation through the release of cathepsin B and other proteolytic enzymes. Tumor cells evolve resistance to acid-induced toxicity during carcinogenesis, allowing them to survive and proliferate in low pH microenvironments. This permits them to invade the damaged adjacent normal tissue despite the acid gradients. Here, we describe theoretical and empirical evidence for acid-mediated invasion. In silico simulations using mathematical models provide testable predictions concerning the morphology and cellular and extracellular dynamics at the tumor-host interface. In vivo experiments confirm the presence of peritumoral acid gradients as well as cellular toxicity and extracellular matrix degradation in the normal tissue exposed to the acidic microenvironment. The acid-mediated tumor invasion model provides a simple mechanism linking altered glucose metabolism with the ability of tumor cells to form invasive cancers. (Cancer Res 2006; 66(10): 5216-23)
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The Warburg effect leads to diversion of glucose to lactate, creating low pH conditions that modulate TME.
“This leads to diversion of glucose to lactate thereby creating low pH conditions which modulates TME (Warburg et al., 1927; Gatenby et al., 2006; Salimian Rizi et al., 2015).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Gatenby et al., 2006
The Warburg effect is the reliance of cancer cells on aerobic glycolysis even under normoxia.
“The Warburg effect, commonly observed characteristic of many cancer types, is identified as the reliance of cancer cells on aerobic glycolysis even under normoxia.”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Gatenby et al., 2006
Cites
Why Do Cancers Have High Aerobic Glycolysis?
Gatenby, R. A., & Gillies, R. J. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1478 · Cited by 4,784 · see citing works
Self-citation(1989) · PubMed · Cited by 3,343 · see citing works
Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours
Graeber, T. G., Osmanian, C., Jacks, T., Housman, D. E., Koch, C. J., Lowe, S. W., & Giaccia, A. J. (1996) · Nature · doi:10.1038/379088a0 · Cited by 2,300 · see citing works
Molecular imaging of cancer with positron emission tomography
Gambhir, S. S. (2002) · Nature reviews. Cancer · doi:10.1038/nrc882 · Cited by 1,658 · see citing works
Helmlinger, G., Yuan, F., Dellian, M., & Jain, R. K. (1997) · Nature Medicine · doi:10.1038/nm0297-177 · Cited by 1,629 · see citing works
The effects of extracellular pH on immune function
Lardner, A. (2001) · Journal of Leukocyte Biology · doi:10.1189/jlb.69.4.522 · Cited by 864 · see citing works
Clinical Applications of PET in Oncology
ROHREN, E. M., Turkington, T. G., & Coleman, R. E. (2004) · Radiology · doi:10.1148/radiol.2312021185 · Cited by 862 · see citing works
Lu, H., Forbes, R. A., & Verma, A. M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202487200 · Cited by 832 · see citing works
WARBURN, O., & Dickens, F. (1931) · The American Journal of the Medical Sciences · doi:10.1097/00000441-193107000-00022 · Cited by 813 · see citing works
A reaction-diffusion model of cancer invasion.
Gatenby, R. A., & Gawlinski, E. T. (1996) · PubMed · Cited by 580 · see citing works
Self-citationFukumura, D., Xu, L., Chen, Y., Gohongi, T., Seed, B., & Jain, R. K. (2001) · PubMed · Cited by 438 · see citing works
Pericellular pH affects distribution and secretion of cathepsin B in malignant cells.
Rozhin, J., Sameni, M., Ziegler, G., & Sloane, B. F. (1994) · PubMed · Cited by 373 · see citing works
Kimura, H., Braun, R. D., Ong, E. T., Hsu, R., Secomb, T. W., Papahadjopoulos, D., Hong, K., & Dewhirst, M. W. (1996) · PubMed · Cited by 368 · see citing works
31P-MRS measurements of extracellular pH of tumors using 3-aminopropylphosphonate
Gillies, R. J., Liu, Z., & Bhujwalla, Z. M. (1994) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1994.267.1.c195 · Cited by 351 · see citing works
Self-citationIzuishi, K., Kato, K., Ogura, T., Kinoshitá, T., & Esumi, H. (2000) · PubMed · Cited by 347 · see citing works
Transport of sugars in tumor cell membranes
Hatanaka, M. (1974) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/0304-419x(74)90008-0 · Cited by 335 · see citing works
The glycolytic phenotype in carcinogenesis and tumor invasion: insights through mathematical models.
Gatenby, R. A., & Gawlinski, E. T. (2003) · PubMed · Cited by 314 · see citing works
Self-citationMartin, G., & Jain, R. K. (1994) · PubMed · Cited by 310 · see citing works
Extracellular Acidification Alters Lysosomal Trafficking in Human Breast Cancer Cells
Glunde, K., Guggino, S. E., Solaiyappan, M., Pathak, A. P., Ichikawa, Y., & Bhujwalla, Z. M. (2003) · Neoplasia · doi:10.1016/s1476-5586(03)80037-4 · Cited by 284 · see citing works
A transparent access chamber for the rat dorsal skin fold
Papenfuss, H. D., Gross, J. F., Intaglietta, M., & Treese, F. A. (1979) · Microvascular Research · doi:10.1016/0026-2862(79)90039-6 · Cited by 282 · see citing works
Contributions of Cell Metabolism and H+ Diffusion to the Acidic pH of Tumors
Schornack, P. A., & Gillies, R. J. (2003) · Neoplasia · doi:10.1016/s1476-5586(03)80005-2 · Cited by 263 · see citing works
Self-citationRegulation of vascular endothelial growth factor expression by acidosis in human cancer cells
Shi, Q., Le, X., Wang, B., Abbruzzese, J. L., Xiong, Q., He, Y., & Xie, K. (2001) · Oncogene · doi:10.1038/sj.onc.1204500 · Cited by 262 · see citing works
Vansteenkiste, J., Fischer, B. M., Dooms, C., & Mortensen, J. (2004) · The Lancet Oncology · doi:10.1016/s1470-2045(04)01564-5 · Cited by 231 · see citing works
Williams, A. C., Collard, T. J., & Paraskeva, C. (1999) · Oncogene · doi:10.1038/sj.onc.1202660 · Cited by 198 · see citing works
Acidic environment causes apoptosis by increasing caspase activity
Park, H. J., Lyons, J., Ohtsubo, T., & Song, C. W. (1999) · British Journal of Cancer · doi:10.1038/sj.bjc.6690617 · Cited by 189 · see citing works
FDG-PET Prediction of Head and Neck Squamous Cell Cancer Outcomes
Schwartz, D. L., Rajendran, J. G., Yueh, B., Coltrera, M. D., LeBlanc, M. L., Eary, J. F., & Krohn, K. (2004) · Archives of Otolaryngology - Head and Neck Surgery · doi:10.1001/archotol.130.12.1361 · Cited by 189 · see citing works
18F-FDG PET detection of colonic adenomas.
Yasuda, S., Fujii, H., Nakahara, T., Nishiumi, N., Takahashi, W., Ide, M., & Shohtsu, A. (2001) · PubMed · Cited by 183 · see citing works
Microvascular studies on the origins of perfusion-limited hypoxia.
Dewhirst, M. W., Kimura, H., Rehmus, W., Braun, R. D., Papahadjopoulos, D., Hong, K., & Secomb, T. W. (1996) · Europe PMC (PubMed Central) · Cited by 157 · see citing works
Combined vascular and extracellular pH imaging of solid tumors
Bhujwalla, Z. M., Artemov, D., Ballesteros, P., Cerdán, S., Gillies, R. J., & Solaiyappan, M. (2002) · NMR in Biomedicine · doi:10.1002/nbm.743 · Cited by 131 · see citing works
Self-citationSchwarzbach, M., Hinz, U., Dimitrakopoulou‐Strauss, A., Willeke, F., Cardona, S., Mechtersheimer, G., Lehnert, T., Strauss, L. G., Herfarth, C. H., & Büchler, M. W. (2005) · Annals of Surgery · doi:10.1097/01.sla.0000152663.61348.6f · Cited by 112 · see citing works
The potential role of transformation-induced metabolic changes in tumor-host interaction.
Gatenby, R. A. (1995) · PubMed · Cited by 79 · see citing works
Self-citationMavi, A., Lakhani, P. C., Zhuang, H., Gupta, N. C., & Alavi, A. A. (2005) · Radiologic Clinics of North America · doi:10.1016/j.rcl.2004.09.001 · Cited by 71 · see citing works
Selective cell culture of primary breast carcinoma.
Dairkee, S. H., Deng, G., Stampfer, M. R., Waldman, F. M., & Hs, S. (1995) · PubMed · Cited by 62 · see citing works
Gilead, A., & Neeman, M. (1999) · Neoplasia · doi:10.1038/sj.neo.7900032 · Cited by 59 · see citing works
Gatenby, R. A., Gawlinski, E. T., Tangen, C. M., Flanigan, R. C., & Crawford, E. D. (2002) · PubMed · Cited by 55 · see citing works
Self-citationAbbey, C. K., Borowsky, A. D., McGoldrick, E. T., Gregg, J. P., Maglione, J. E., Cardiff, R. D., & Cherry, S. R. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404396101 · Cited by 55 · see citing works
Flagged first, then by citations
1 of the 37 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis
Menendez, J. A., & Lupu, R. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2222 · Cited by 2,941 · see citing works
Dysregulated pH: a perfect storm for cancer progression
Webb, B. A., Chimenti, M. S., Jacobson, M. P., & Barber, D. L. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3110 · Cited by 2,246 · see citing works
Acidity Generated by the Tumor Microenvironment Drives Local Invasion
Estrella, V. C., Chen, T., Lloyd, M. C., Wojtkowiak, J. W., Cornnell, H. H., Ibrahim‐Hashim, A., Bailey, K. M., Balagurunathan, Y., Rothberg, J. M., Sloane, B. F., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-2796 · Cited by 1,404 · see citing works
Self-citationFunction of alternative splicing
Stamm, S., Ben‐Ari, S., Rafalska, I., Tang, Y., Zhang, Z., Toiber, D., Thanaraj, T. A., & Soreq, H. (2004) · Gene · doi:10.1016/j.gene.2004.10.022 · Cited by 1,373 · see citing works
Collagen density promotes mammary tumor initiation and progression
Provenzano, P. P., Inman, D. R., Eliceiri, K. W., Knittel, J. G., Yan, L., Rueden, C., White, J. G., & Keely, P. J. (2008) · BMC Medicine · doi:10.1186/1741-7015-6-11 · Cited by 1,364 · see citing works
multifunctional enzymes in cancer
Mohamed, M. M., & Sloane, B. F. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1949 · Cited by 1,267 · see citing works
The Acidic Tumor Microenvironment as a Driver of Cancer
Boedtkjer, E., & Pedersen, S. F. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021119-034627 · Cited by 1,248 · see citing works
Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy?
Hay, N. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.77 · Cited by 1,124 · see citing works
Targeting metabolic transformation for cancer therapy
Tennant, D. A., Durán, R. V., & Gottlieb, E. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2817 · Cited by 1,057 · see citing works
Chen, Q., Feng, L., Liu, J., Zhu, W., Dong, Z., Wu, Y., & Liu, Z. (2016) · Advanced Materials · doi:10.1002/adma.201601902 · Cited by 1,037 · see citing works
Tumour acidosis: from the passenger to the driver's seat
Corbet, C., & Féron, O. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2017.77 · Cited by 1,000 · see citing works
Yuan, Z., Li, Y., Zhang, S., Wang, X., Dou, H., Yu, X., Zhang, Z., Yang, S., & Xiao, M. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01744-8 · Cited by 977 · see citing works
Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism
Zhao, H., Yang, L., Baddour, J., Achreja, A., Bernard, V., Moss, T., Marini, J. C., Tudawe, T., Seviour, E. G., San Lucas, F. A., et al. (2016) · eLife · doi:10.7554/elife.10250 · Cited by 927 · see citing works
Function of alternative splicing
Kelemen, O., Convertini, P., Zhang, Z., Wen, Y., Shen, M., Falaleeva, M., & Stamm, S. (2013) · Gene · doi:10.1016/j.gene.2012.07.083 · Cited by 743 · see citing works
A microenvironmental model of carcinogenesis
Gatenby, R. A., & Gillies, R. J. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2255 · Cited by 725 · see citing works
Self-citationZeolitic imidazolate framework-8 as efficient pH-sensitive drug delivery vehicle
Sun, C., Qin, C., Wang, X., Yang, G., Shao, K., Lan, Y., Su, Z., Huang, P., Wang, C., & Wang, E. (2012) · Dalton Transactions · doi:10.1039/c2dt30357d · Cited by 708 · see citing works
Evolutionary dynamics of carcinogenesis and why targeted therapy does not work
Gillies, R. J., Verduzco, D., & Gatenby, R. A. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3298 · Cited by 677 · see citing works
Self-citationBicarbonate Increases Tumor pH and Inhibits Spontaneous Metastases
Robey, I., Baggett, B. K., Kirkpatrick, N. D., Roe, D. J., Dosescu, J., Sloane, B. F., Hashim, A. I., Morse, D. L., Raghunand, N., Gatenby, R. A., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-07-5575 · Cited by 663 · see citing works
Self-citationCauses and Consequences of Increased Glucose Metabolism of Cancers
Gillies, R. J., Robey, I., & Gatenby, R. A. (2008) · Journal of Nuclear Medicine · doi:10.2967/jnumed.107.047258 · Cited by 617 · see citing works
Self-citationDisrupting proton dynamics and energy metabolism for cancer therapy
Parks, S. K., Chiche, J., & Pouysségur, J. (2013) · Nature reviews. Cancer · doi:10.1038/nrc3579 · Cited by 613 · see citing works
Nonlinear modelling of cancer: bridging the gap between cells and tumours
Lowengrub, J. S., Frieboes, H. B., Jin, F., Chuang, Y.-L., Li, X., Macklin, P., Wise, S. M., & Vittorio Cristini, C. (2009) · Nonlinearity · doi:10.1088/0951-7715/23/1/r01 · Cited by 549 · see citing works
Mathematical Models of Avascular Tumor Growth
Roose, T., Chapman, S. J., & Maini, P. K. (2007) · SIAM Review · doi:10.1137/s0036144504446291 · Cited by 550 · see citing works
Regulation of tumor pH and the role of carbonic anhydrase 9
Swietach, P., Vaughan-Jones, R. D., & Harris, A. L. (2007) · Cancer and Metastasis Reviews · doi:10.1007/s10555-007-9064-0 · Cited by 539 · see citing works
Albers, M. J., Bok, R., Chen, A. P., Cunningham, C. H., Zierhut, M. L., Zhang, V. Y., Kohler, S. J., Tropp, J. S., Hurd, R. E., Yen, Y., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0749 · Cited by 521 · see citing works
Han, X., Huang, J., Lin, H., Wang, Z., Li, P., & Chen, Y. (2018) · Advanced Healthcare Materials · doi:10.1002/adhm.201701394 · Cited by 511 · see citing works
Cell-penetrating and cell-targeting peptides in drug delivery
Vivès, É., Schmidt, J., & Pèlegrin, A. (2008) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2008.03.001 · Cited by 442 · see citing works
Molecular Biology of Bone Metastasis
Kingsley, L. A., Fournier, P. G. J., Chirgwin, J. M., & Guise, T. A. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-07-0234 · Cited by 437 · see citing works
ON THE FOUNDATIONS OF CANCER MODELLING: SELECTED TOPICS, SPECULATIONS, AND PERSPECTIVES
Bellomo, N., LI, N. K., & Maini, P. K. (2008) · Mathematical Models and Methods in Applied Sciences · doi:10.1142/s0218202508002796 · Cited by 420 · see citing works
Dhup, S., Dadhich, R. K., Porporato, P. E., & Sonveaux, P. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212799504902 · Cited by 419 · see citing works
Systems analysis of intracellular pH vulnerabilities for cancer therapy
Persi, E., Duran‐Frigola, M., Damaghi, M., Roush, W. R., Aloy, P., Cleveland, J. L., Gillies, R. J., & Ruppin, E. (2018) · Nature Communications · doi:10.1038/s41467-018-05261-x · Cited by 410 · see citing works
Self-citationCancer cell metabolism: implications for therapeutic targets
Jang, M., Kim, S. S., & Lee, J. (2013) · Experimental & Molecular Medicine · doi:10.1038/emm.2013.85 · Cited by 398 · see citing works
Molecular control of bacterial death and lysis
Rice, K. C., & Bayles, K. W. (2008) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00030-07 · Cited by 362 · see citing works
The molecular determinants of de novo nucleotide biosynthesis in cancer cells
Tong, X., Zhao, F., & Thompson, C. B. (2009) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2009.01.002 · Cited by 351 · see citing works
pH control mechanisms of tumor survival and growth
Parks, S. K., Chiche, J., & Pouysségur, J. (2010) · Journal of Cellular Physiology · doi:10.1002/jcp.22400 · Cited by 356 · see citing works
Metabolic phenotype of bladder cancer
Massari, F., Ciccarese, C., Santoni, M., Iacovelli, R., Roberta Mazzucchelli, A., Piva, F., Scarpelli, M., Berardi, R., Tortora, G., Antonio Lopez-beltran, B., et al. (2016) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2016.03.005 · Cited by 337 · see citing works
Biology, vulnerabilities and clinical applications of circulating tumour cells
Ring, A., Nguyen-Sträuli, B. D., WICKI, A. N., & Aceto, N. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-022-00536-4 · Cited by 334 · see citing works
Lactic Acid: No Longer an Inert and End-Product of Glycolysis
Sun, S., Li, H., Chen, J., & Qian, Q. (2017) · Physiology · doi:10.1152/physiol.00016.2017 · Cited by 319 · see citing works
Critical Role of Glucose Metabolism in Rheumatoid Arthritis Fibroblast‐like Synoviocytes
Garcia‐Carbonell, R., Divakaruni, A. S., Lodi, A., Vicente-Suarez, I., Saha, A., Cheroutre, H., Boss, G. R., Tiziani, S., Murphy, A. N., & Gumá, M. (2016) · Arthritis & Rheumatology · doi:10.1002/art.39608 · Cited by 312 · see citing works
Glycolysis in cancer: A potential target for therapy
Gatenby, R. A., & Gillies, R. J. (2007) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2007.03.021 · Cited by 305 · see citing works
Self-citationHypoxia signalling controls metabolic demand
Brahimi-Horn, M. C., Chiche, J., & Pouysségur, J. (2007) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2007.02.003 · Cited by 298 · see citing works
Swietach, P., Patiar, S., Supuran, C. T., Harris, A. L., & Vaughan‐Jones, R. D. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.006478 · Cited by 298 · see citing works
A Self‐Assembled Albumin‐Based Nanoprobe for In Vivo Ratiometric Photoacoustic pH Imaging
Chen, Q., Liu, X., Chen, J., Zeng, J., Cheng, Z., & Liu, Z. (2015) · Advanced Materials · doi:10.1002/adma.201503194 · Cited by 285 · see citing works
Causes, consequences, and therapy of tumors acidosis
Pillai, S., Damaghi, M., Marunaka, Y., Spugnini, E. P., Fais, S., & Gillies, R. J. (2019) · Cancer and Metastasis Reviews · doi:10.1007/s10555-019-09792-7 · Cited by 282 · see citing works
Self-citationImpact of Metabolic Heterogeneity on Tumor Growth, Invasion, and Treatment Outcomes
Robertson‐Tessi, M., Gillies, R. J., Gatenby, R. A., & Anderson, A. R. A. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-1428 · Cited by 274 · see citing works
Self-citationAdaptation to hypoxia and acidosis in carcinogenesis and tumor progression
Fang, J. S., Gillies, R. D., & Gatenby, R. A. (2008) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2008.03.011 · Cited by 279 · see citing works
Self-citationTherapies targeting cancer stem cells: Current trends and future challenges
Dragu, D. (2015) · World Journal of Stem Cells · doi:10.4252/wjsc.v7.i9.1185 · Cited by 271 · see citing works
Microenvironment and tumor cell plasticity: An easy way out
Taddei, M. L., Giannoni, E., Comito, G., & Chiarugi, P. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.01.042 · Cited by 263 · see citing works
Pathania, D., Millard, M., & Neamati, N. (2009) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2009.05.010 · Cited by 265 · see citing works
Targeting adaptive glioblastoma: an overview of proliferation and invasion
Xie, Q. R., Mittal, S., & Berens, M. E. (2014) · Neuro-Oncology · doi:10.1093/neuonc/nou147 · Cited by 258 · see citing works
Carbon‐Based Nanomaterials for Cancer Therapy via Targeting Tumor Microenvironment
Saleem, J., Wang, L., & Chen, C. (2018) · Advanced Healthcare Materials · doi:10.1002/adhm.201800525 · Cited by 263 · see citing works
Tumor Cell Infiltration into the Brain in Glioblastoma: From Mechanisms to Clinical Perspectives
Seker-Polat, F., Degirmenci, N. P., Solaroğlu, İ., & Onder, T. B. (2022) · Cancers · doi:10.3390/cancers14020443 · Cited by 261 · see citing works
Taylor, S., Spugnini, E. P., Assaraf, Y. G., Azzarito, T., Rauch, C., & Fais, S. (2015) · Drug Resistance Updates · doi:10.1016/j.drup.2015.08.004 · Cited by 259 · see citing works
Lactate promotes glioma migration by TGF-β2–dependent regulation of matrix metalloproteinase-2
Baumann, F., Leukel, P., Doerfelt, A., Beier, C. P., Dettmer, K., Oefner, P. J., Kastenberger, M., Kreutz, M. P., Nickl‐Jockschat, T., Bogdahn, U., et al. (2008) · Neuro-Oncology · doi:10.1215/15228517-2008-106 · Cited by 256 · see citing works
The Prodrug Platin‐A: Simultaneous Release of Cisplatin and Aspirin
Pathak, R., Marrache, S., Choi, J. H., Berding, T. B., & Dhar, S. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201308899 · Cited by 255 · see citing works
Tian, X.-P., Wang, C.-Y., Jin, X.-H., Li, M., Wang, F., Huang, W.-J., Yun, J., Xu, R., Cai, Q.-Q., & Xie, D. (2019) · Theranostics · doi:10.7150/thno.30958 · Cited by 246 · see citing works
Distinct mechanisms of tumor invasion and metastasis
Yilmaz, M., Christofori, G., & Lehembre, F. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.10.004 · Cited by 245 · see citing works
Intracellular pH is a tightly controlled signal in yeast
Orij, R., Brul, S., & Smits, G. J. (2011) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2011.03.011 · Cited by 243 · see citing works
TGFβ-induced metabolic reprogramming during epithelial-to-mesenchymal transition in cancer
Hua, W., ten Dijke, P., Kostidis, S., Giera, M. A., & Hornsveld, M. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03398-6 · Cited by 237 · see citing works
McIntyre, A., Patiar, S., Wigfield, S., Li, J.-L., Ledaki, I., Turley, H., Leek, R., Snell, C., Gatter, K., Sly, W. S., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1877 · Cited by 239 · see citing works
Computer simulation of glioma growth and morphology
Frieboes, H. B., Lowengrub, J. S., Wise, S. M., Zheng, X., Macklin, P., Bearer, E. L., & Vittorio Cristini, C. (2007) · NeuroImage · doi:10.1016/j.neuroimage.2007.03.008 · Cited by 235 · see citing works
Three-dimensional multispecies nonlinear tumor growth—II: Tumor invasion and angiogenesis
Frieboes, H. B., Jin, F., Chuang, Y.-L., Wise, S. M., Lowengrub, J. S., & Vittorio Cristini, C. (2010) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2010.02.036 · Cited by 231 · see citing works
Protons make tumor cells move like clockwork
Stock, C. M., & Schwab, A. (2009) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-009-0677-8 · Cited by 228 · see citing works
Lim, E., Huh, Y., Yang, J., Lee, K., Suh, J., & Haam, S. (2011) · Advanced Materials · doi:10.1002/adma.201100351 · Cited by 221 · see citing works
Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis?
Gillies, R. J., & Gatenby, R. A. (2007) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-007-9085-y · Cited by 219 · see citing works
Self-citationProbe for the measurement of cell surface pH in vivo and ex vivo
Anderson, M., Moshnikova, A., Engelman, D. M., Reshetnyak, Y. K., & Andreev, O. A. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1608247113 · Cited by 217 · see citing works
Swietach, P., Wigfield, S., Cobden, P. M., Supuran, C. T., Harris, A. L., & Vaughan‐Jones, R. D. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801330200 · Cited by 216 · see citing works
Is there a role for carbohydrate restriction in the treatment and prevention of cancer?
Klement, R. J., & Kämmerer, U. (2011) · Nutrition & Metabolism · doi:10.1186/1743-7075-8-75 · Cited by 208 · see citing works
Silva, A. S., Yunes, J. A., Gillies, R. J., & Gatenby, R. A. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-2394 · Cited by 205 · see citing works
Self-citationProvenzano, P. P., Eliceiri, K. W., & Keely, P. J. (2008) · Clinical & Experimental Metastasis · doi:10.1007/s10585-008-9204-0 · Cited by 202 · see citing works
How does cancer cell metabolism affect tumor migration and invasion?
Han, T., Kang, D., Ji, D., Wang, X., Zhan, W., Fu, M., Xin, H.-B., & Wang, J.-B. (2013) · Cell Adhesion & Migration · doi:10.4161/cam.26345 · Cited by 198 · see citing works
Molecular mechanisms and clinical management of cancer bone metastasis
Wang, M., Xia, F., Wei, Y., & Wei, X. (2020) · Bone Research · doi:10.1038/s41413-020-00105-1 · Cited by 200 · see citing works
Shi, M., Cui, J., Du, J., Wei, D., Jia, Z., Zhang, J., Zhu, Z., Gao, Y., & Xie, K. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-0186 · Cited by 195 · see citing works
Evaluations of extracellular pH within in vivo tumors using acidoCEST MRI
Chen, L. Q., Howison, C. M., Jeffery, J. J., Robey, I., Kuo, P. H., & Pagel, M. D. (2013) · Magnetic Resonance in Medicine · doi:10.1002/mrm.25053 · Cited by 194 · see citing works
Paradoxical effects of cytokines in tumor immune surveillance and tumor immune escape
Salazar‐Onfray, F., López, M. N., & Mendoza‐Naranjo, A. (2007) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2007.01.015 · Cited by 216 · see citing works
Chen, X., Zhang, H., Zhang, M., Zhao, P., Song, R., Gong, T., Liu, Y., He, X., Zhao, K., & Bu, W. (2019) · Advanced Functional Materials · doi:10.1002/adfm.201908365 · Cited by 193 · see citing works
Tumor pH and metastasis: a malignant process beyond hypoxia
Thews, O., & Riemann, A. (2019) · Cancer and Metastasis Reviews · doi:10.1007/s10555-018-09777-y · Cited by 190 · see citing works
Disulfide-containing parenteral delivery systems and their redox-biological fate
Brülisauer, L., Gauthier, M. A., & Leroux, J. (2014) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.06.012 · Cited by 190 · see citing works
Colen, C. B., Shen, Y., Ghoddoussi, F., Yu, P., Francis, T. B., Koch, B. J., Monterey, M. D., Galloway, M. P., Sloan, A. E., & Mathupala, S. P. (2011) · Neoplasia · doi:10.1593/neo.11134 · Cited by 187 · see citing works
Mathupala, S. P., Ko, Y. H., & Pedersen, P. L. (2010) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2010.03.025 · Cited by 186 · see citing works
Damaghi, M., Tafreshi, N. K., Lloyd, M. C., Sprung, R. W., Estrella, V. C., Wojtkowiak, J. W., Morse, D. L., Koomen, J. M., Bui, M. M., Gatenby, R. A., et al. (2015) · Nature Communications · doi:10.1038/ncomms9752 · Cited by 186 · see citing works
Self-citationBiophysical models of tumour growth
Tracqui, P. (2009) · Reports on Progress in Physics · doi:10.1088/0034-4885/72/5/056701 · Cited by 182 · see citing works
Hyaluronan, CD44 and Emmprin: Partners in cancer cell chemoresistance
Toole, B. P., & Slomiany, M. G. (2008) · Drug Resistance Updates · doi:10.1016/j.drup.2008.04.002 · Cited by 182 · see citing works
The impact of tumour pH on cancer progression: strategies for clinical intervention
Ward, C., Meehan, J., Gray, M., Murray, A. F., Argyle, D. J., Kunkler, I. H., & Langdon, S. P. (2020) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2020.00005 · Cited by 180 · see citing works
Lessons from patient-derived xenografts for better in vitro modeling of human cancer
Choi, S. Y. C., Lin, D., Gout, P. W., Collins, C. C., Xu, Y., & Wang, Y. Z. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.09.009 · Cited by 174 · see citing works
Wilson, D. M., Keshari, K. R., Larson, P. E. Z., Chen, A. P., Hu, S., Criekinge, M. V., Bok, R., Nelson, S. J., Macdonald, J. M., Vigneron, D. B., et al. (2010) · Journal of Magnetic Resonance · doi:10.1016/j.jmr.2010.04.012 · Cited by 175 · see citing works
Palmer, C. S., Ostrowski, M., Gouillou, M., Tsai, L. M., Yu, D., Zhou, J., Henstridge, D. C., Maisa, A., Hearps, A. C., Lewin, S. R., et al. (2013) · AIDS · doi:10.1097/qad.0000000000000128 · Cited by 171 · see citing works
Cathepsin B Mediates the pH-Dependent Proinvasive Activity of Tumor-Shed Microvesicles
Giusti, I., D’Ascenzo, S., Millimaggi, D., Taraboletti, G., Carta, G., Franceschini, N., Pavan, A., & Dolo, V. (2008) · Neoplasia · doi:10.1593/neo.08178 · Cited by 170 · see citing works
The Metabolomic Signature of Malignant Glioma Reflects Accelerated Anabolic Metabolism
Chinnaiyan, P., Kensicki, E., Bloom, G. C., Prabhu, A. H., Sarcar, B., Kahali, S., Eschrich, S. A., Qu, X., Forsyth, P. A., & Gillies, R. J. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-1572-t · Cited by 168 · see citing works
Self-citationImaging tumor acidosis: a survey of the available techniques for mapping in vivo tumor pH
Anemone, A., Consolino, L., Arena, F., Capozza, M., & Longo, D. L. (2019) · Cancer and Metastasis Reviews · doi:10.1007/s10555-019-09782-9 · Cited by 163 · see citing works
The Warburg effect version 2.0: Metabolic reprogramming of cancer stem cells
Menéndez, J. A., Joven, J., Cufí, S., Corominas-Faja, B., Oliveras‐Ferraros, C., Cuyàs, E., Martı́n-Castillo, B., López‐Bonet, E., Alarcón, T., & Vázquez‐Martín, A. (2013) · Cell Cycle · doi:10.4161/cc.24479 · Cited by 158 · see citing works
T-cells produce acidic niches in lymph nodes to suppress their own effector functions
Wu, H., Estrella, V. C., Beatty, M. S., Abrahams, D. F., El-Kenawi, A., Russell, S., Ibrahim‐Hashim, A., Longo, D. L., Reshetnyak, Y. K., Moshnikova, A., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17756-7 · Cited by 159 · see citing works
Self-citationHarguindey, S., Arranz, J. A., Orozco, J. D. P., Rauch, C., Fais, S., Cardone, R. A., & Reshkin, S. J. (2013) · Journal of Translational Medicine · doi:10.1186/1479-5876-11-282 · Cited by 158 · see citing works
Lee, S., & Griffiths, J. R. (2020) · Cancers · doi:10.3390/cancers12061616 · Cited by 159 · see citing works
Bellomo, N., Outada, N., Soler, J., Tao, Y., & Winkler, M. (2022) · Mathematical Models and Methods in Applied Sciences · doi:10.1142/s0218202522500166 · Cited by 157 · see citing works
The Role of Cysteine Cathepsins in Cancer Progression and Drug Resistance
Rudzińska, M., Parodi, A., Soond, S. M., Винаров, А. З., Korolev, D. O., Morozov, A., Dağlıoğlu, C., Tutar, Y., & Zamyatnin, A. A. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20143602 · Cited by 155 · see citing works
Acidosis and cancer: from mechanism to neutralization
Ibrahim‐Hashim, A., & Estrella, V. C. (2019) · Cancer and Metastasis Reviews · doi:10.1007/s10555-019-09787-4 · Cited by 150 · see citing works
Hyperthermia can alter tumor physiology and improve chemo- and radio-therapy efficacy
Dunne, M., Regenold, M., & Allen, C. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.07.007 · Cited by 150 · see citing works
Lee, Z., Teo, X., Tay, E. Y., Tan, C., Hagen, T., Moore, P. K., & Deng, L. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12773 · Cited by 149 · see citing works
Carbonic Anhydrase IX: Regulation and Role in Cancer
Benej, M., Pastoreková, S., & Pastorek, J. (2013) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-007-7359-2_11 · Cited by 148 · see citing works
Digitoxin as an anticancer agent with selectivity for cancer cells: possible mechanisms involved
López-Lázaro, M. (2007) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.11.8.1043 · Cited by 145 · see citing works
- Authors
- Gatenby, R. A., Gawlinski, E. T., Gmitro, A. F., Kaylor, B., & Gillies, R. J.
- Affiliations
- University of Arizona (US)
- Temple University (US)
- Venue
- Cancer Research
- Published
- 2006-05-15
- Volume
- 66
- Issue
- 10
- Pages
- 5216-5223
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2118604693
- Cited by
- 771
- References
- 37
- Citations by year
- 2026: 19 · 2025: 18 · 2024: 25 · 2023: 31 · 2022: 42 · 2021: 47 · 2020: 54 · 2019: 46 · 2018: 36 · 2017: 48 · 2016: 48 · 2015: 48 · 2014: 41 · 2013: 44 · 2012: 36
- FWCI
- 12.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (U56CA113004, R01CA093650)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- tumor acidosis, extracellular matrix degradation, cathepsin B, normal tissue toxicity, tumor-host interface, carcinogenesis, acid resistance
- MeSH terms
- Acidosis, Animals, Breast Neoplasms, Cell Movement, Glucose, Glycolysis, Humans, Hydrogen-Ion Concentration, Male, Models, Biological, Neoplasm Invasiveness, Neoplasm Metastasis, Prostatic Neoplasms, Mice, SCID, Cell Line, Tumor, Cell Growth Processes, Mice
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