title: Acid-mediated tumour cell invasion: a discrete modelling approach using the extended Potts model.
abstract: Acidic extracellular pH has been shown to play a crucial part in the invasive and metastatic cascade of some tumours. In this study, we examine the effect of extracellular acidity on tumour invasion focusing, in particular, on cellular adhesion, proteolytic enzyme activity and cellular proliferation. Our numerical simulations using a cellular Potts model show that, under acidic extracellular pH, changes in cell-matrix adhesion strength has a comparable effect on tumour invasiveness as the increase in proteolytic enzyme activity. We also show that tumour cells cultured under physiological pH tend to be large and the tumours develop a "diffuse" morphology compared to those cultured at acidic pH, which display protruding "fingers" at the advancing front. A key model prediction is the observation that the main effect on invasion from culturing cells at low extracellular pH stems from changes in the intercellular and cell-matrix adhesion strengths and proteolytic enzyme secretion rate. However, we show that the effects of proteolysis needs to be significant as low to moderate changes only has nominal effects on cell invasiveness. We find that the low pH e effects on cell size and proliferation rate have much lower influence on cell invasiveness.
authors.affiliation: Department of Mathematics and Statistics, University of Strathclyde, Glasgow, UK.
authors.forename: Maymona
authors.initials: M
authors.lastname: Al-Husari
authors.forename: Steven D
authors.initials: SD
authors.lastname: Webb
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003198:Computer Simulation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D008962:Models, Theoretical; D009361:Neoplasm Invasiveness
chemical_list: D020778:Matrix Metalloproteinase 2
references.citation: Surg Today. 2008;38(2):115-22
references.pmid: 18239867
references.citation: FEBS J. 2007 Jun;274(12):3171-83
references.pmid: 17540003
references.citation: Surgery. 2009 Aug;146(2):250-7
references.pmid: 19628081
references.citation: J Theor Biol. 2002 May 7;216(1):85-100
references.pmid: 12076130
references.citation: J Theor Biol. 2005 Aug 21;235(4):476-84
references.pmid: 15935166
references.citation: Breast Cancer Res Treat. 1993;24(3):175-84
references.pmid: 8435473
references.citation: Clin Exp Metastasis. 1999 Jul;17(5):397-407
references.pmid: 10651306
references.citation: Am J Physiol Cell Physiol. 2004 Dec;287(6):C1733-46
references.pmid: 15355852
references.citation: Cancer Res. 1989 Dec 1;49(23):6449-65
references.pmid: 2684393
references.citation: Clin Exp Metastasis. 1992 May;10(3):145-55
references.pmid: 1582084
references.citation: Cancer Metastasis Rev. 2007 Jun;26(2):333-9
references.pmid: 17458506
references.citation: J Theor Biol. 2007 Feb 21;244(4):703-13
references.pmid: 17055536
references.citation: J Cell Sci. 2002 Oct 1;115(Pt 19):3719-27
references.pmid: 12235282
references.citation: J Cell Biol. 2002 Dec 23;159(6):1087-96
references.pmid: 12486114
references.citation: J Med Syst. 1984 Oct;8(5):461-75
references.pmid: 6512442
references.citation: Biophys J. 2008 Dec 15;95(12):5661-80
references.pmid: 18835895
references.citation: PLoS One. 2009 Oct 16;4(10):e7190
references.pmid: 19834621
references.citation: Nat Rev Cancer. 2005 Oct;5(10):786-95
references.pmid: 16175178
references.citation: Cancer Res. 2008 Nov 15;68(22):9147-56
references.pmid: 19010886
references.citation: J Theor Biol. 2008 Feb 21;250(4):684-704
references.pmid: 18068728
references.citation: Cancer Res. 1996 Dec 15;56(24):5745-53
references.pmid: 8971186
references.citation: J Physiol. 2007 Dec 1;585(Pt 2):351-60
references.pmid: 17916606
references.citation: Growth. 1966 Jun;30(2):157-76
references.pmid: 5963695
references.citation: PLoS One. 2011 Jan 19;6(1):e15746
references.pmid: 21283814
references.citation: Nat Rev Cancer. 2004 Nov;4(11):891-9
references.pmid: 15516961
references.citation: J Pathol. 1999 Nov;189(3):300-8
references.pmid: 10547590
references.citation: Bull Math Biol. 2009 Jul;71(5):1189-227
references.pmid: 19234746
references.citation: Biophys J. 2005 Dec;89(6):3884-94
references.pmid: 16199495
references.citation: Nature. 2007 Jun 21;447(7147):924-31
references.pmid: 17581575
references.citation: J Math Biol. 2004 Aug;49(2):111-87
references.pmid: 15293017
references.citation: Neoplasia. 2008 May;10(5):481-8
references.pmid: 18472965
references.citation: Cancer Res. 1996 Dec 15;56(24):5754-7
references.pmid: 8971187
references.citation: Cancer Res. 1991 Sep 15;51(18 Suppl):5054s-5059s
references.pmid: 1884381
references.citation: J Am Stat Assoc. 1949 Sep;44(247):335-41
references.pmid: 18139350
references.citation: J Exp Med. 1973 Oct 1;138(4):745-53
references.pmid: 4744009
references.citation: Cancer. 1996 Sep 15;78(6):1179-86
references.pmid: 8826938
references.citation: Cancer Res. 1994 Dec 15;54(24):6517-25
references.pmid: 7987851
references.citation: Math Med Biol. 2005 Jun;22(2):163-86
references.pmid: 15781426
references.citation: Annu Rev Biomed Eng. 2006;8:233-57
references.pmid: 16834556
references.citation: J Theor Biol. 2001 Dec 7;213(3):315-31
references.pmid: 11735284
references.citation: Mol Cancer Ther. 2006 May;5(5):1275-9
references.pmid: 16731760
references.citation: PLoS One. 2012;7(3):e33726
references.pmid: 22461894
references.citation: Phys Rev Lett. 1992 Sep 28;69(13):2013-2016
references.pmid: 10046374
references.citation: Phys Rev E Stat Nonlin Soft Matter Phys. 2002 Feb;65(2 Pt 1):021907
references.pmid: 11863563
references.citation: J Cell Sci. 2001 Jul;114(Pt 14):2665-72
references.pmid: 11683393
references.citation: Genes Dev. 2009 Mar 15;23(6):660-74
references.pmid: 19299557
references.citation: Mod Pathol. 2003 Apr;16(4):376-88
references.pmid: 12692203
references.citation: Biophys J. 2000 Oct;79(4):2138-49
references.pmid: 11023917
references.citation: Cancer Res. 2006 Jul 1;66(13):6699-707
references.pmid: 16818644
references.citation: J Theor Biol. 2012 Sep 7;308:1-19
references.pmid: 22659352
references.citation: Ann Surg. 1970 Nov;172(5):902-8
references.pmid: 5477666
references.citation: J Math Biol. 2011 Jul;63(1):141-71
references.pmid: 20872264
references.citation: Curr Opin Cell Biol. 1999 Oct;11(5):614-21
references.pmid: 10508651
references.citation: Clin Exp Metastasis. 1996 Mar;14(2):176-86
references.pmid: 8605731
references.citation: J Theor Biol. 2013 Apr 7;322:58-71
references.pmid: 23340437
references.citation: Histopathology. 1986 May;10(5):437-59
references.pmid: 3721406
references.citation: J Physiol. 2005 Aug 15;567(Pt 1):225-38
references.pmid: 15946960
references.citation: Bull Math Biol. 2008 Oct;70(7):2055-76
references.pmid: 18716846
references.citation: Neoplasia. 2003 Nov-Dec;5(6):533-45
references.pmid: 14965446
references.citation: J Cell Sci. 1997 Mar;110 ( Pt 5):663-71
references.pmid: 9092948
references.citation: J Theor Biol. 2004 Jul 7;229(1):101-11
references.pmid: 15178188
references.citation: Am J Physiol Cell Physiol. 2011 Mar;300(3):C490-5
references.pmid: 21148407
references.citation: J Theor Biol. 1999 Jan 21;196(2):237-50
references.pmid: 9990741
references.citation: Cancer Lett. 2008 Aug 18;267(1):37-48
references.pmid: 18423982
references.citation: J Cell Biochem. 2009 Nov 1;108(4):851-9
references.pmid: 19711372
references.citation: FEBS Lett. 2011 Feb 18;585(4):705-10
references.pmid: 21251911
references.citation: Br J Cancer. 1955 Dec;9(4):539-49
references.pmid: 13304213
references.citation: Front Biosci. 2008 May 01;13:6537-53
references.pmid: 18508679
references.citation: Adv Physiol Educ. 2004 Dec;28(1-4):135-8
references.pmid: 15545341
references.citation: J Cell Physiol. 1992 May;151(2):386-94
references.pmid: 1572910
references.citation: Cell. 2006 Nov 17;127(4):679-95
references.pmid: 17110329
references.citation: Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):3942-6
references.pmid: 8632994