Abstract

Metastatic tumours resistant to chemotherapy are the major cause of the clinical failure in the treatment of malignant diseases. It is observed often that drugs active against primary tumours do not exhibit the same efficacy towards metastatic tumour cells having modified signaling pathways. Among cellular factors involved in the development of the metastatic potential of multidrug resistant tumour cells are some oncoproteins, antiapoptotic proteins, mutated suppressor proteins, integrins and CD44 receptor. It was also demonstrated that numerous chemotherapeutics have the effect on the emergence of the metastatic potential and multidrug resistance (MDR) phenomenon of tumour cells. The results of numerous studies suggest that genes involved in the development of MDR and metastatic phenotype of tumour cells are regulated by the same signaling pathways. They lead to the activation of transcription factors e.g. HIF-1α, NF-κB, Ets1 and AP-1 controlling the expression of genes involved in the development of the metastatic potential of multidrug resistant tumour cells. The identification of key cellular factors responsible for the emergence of the metastatic potential of MDR tumour cells could lead to the development of new efficient strategies for the treatment of metastatic tumours resistant to the conventional chemotherapy.

References

• 1. Aguirre Ghiso J.A., Alonso D.F., Farías E.F, Gomez D.E., de Kier JoffèE.B: Deregulation of the signaling pathways controlling urokinaseproduction. Its relationship with the invasive phenotype. Eur. J.Biochem., 1999; 263: 295-304
  Google Scholar
• 2. Ahn K.S., Bae E., Jeon S.S., Yoon S.S., Lee Y.Y., Choi H.Y: Microenvironmenteffects on promoting upregulation of matrix metalloproteinasesin bcl-2-overexpressing renal cell carcinoma as a responseto doxorubicin treatment inducing the production of metastasis.Tumour Biol., 2007; 28: 181-188
  Google Scholar
• 3. Albitar L., Carter M.B., Davies S., Leslie K.K.: Consequences of theloss of p53, RB1, and PTEN: relationship to gefitinib resistance inendometrial cancer. Gynecol. Oncol., 2007; 106: 94-104
  Google Scholar
• 4. Almendro V., Ametller E., García-Recio S., Collazo O., Casas I., AugéJ.M., Maurel. J., Gascón P.: The role of MMP7 and its cross-talk withthe FAS/FASL system during the acquisition of chemoresistance tooxaliplatin. PLoS One, 2009; 4: e4728
  Google Scholar
• 5. Backos D.S., Franklin C.C., Reigan P.: The role of glutathione in braintumor drug resistance. Biochem. Pharmacol., 2012; 83: 1005-1012
  Google Scholar
• 6. Bacso Z., Nagy H., Goda K., Bene L., Fenyvesi F., Matkó J., SzabóG.: Raft and cytoskeleton associations of an ABC transporter: P-glycoprotein.Cytometry A, 2004; 61: 105-116
  Google Scholar
• 7. Baker A.M., Bird D., Welti J.C., Gourlaouen M., Lang G., MurrayG.I., Reynolds A.R., Cox T.R., Erler J.T.: Lysyl oxidase plays a criticalrole in endothelial cell stimulation to drive tumor angiogenesis.Cancer Res., 2013; 73: 583-594
  Google Scholar
• 8. Belotti D., Rieppi M., Nicoletti M.I., Casazza A.M., Fojo T., TarabolettiG., Giavazzi R.: Paclitaxel (TaxolR) inhibits motility of paclitaxel-resistanthuman ovarian carcinoma cells. Clin. Cancer Res.,1996; 2: 1725-1730
  Google Scholar
• 9. Bénard J.: Genetic alterations associated with metastatic disseminationand chemoresistance in neuroblastoma. Eur. J. Cancer,1995; 31A: 560-564
  Google Scholar
• 10. Benbow U., Maitra R., Hamilton J.W., Brinckerhoff C.E.: Selectivemodulation of collagenase 1 gene expression by the chemotherapeuticagent doxorubicin. Clin. Cancer Res., 1999; 5: 203-208
  Google Scholar
• 11. Bjørnland K., Lehne G., Johansen H.T., Fodstad O., Rugstad H.E.,Aasen A.O., Ree A.H.: Human hepatoma cells rich in P-glycoproteindisplay enhanced in vitro invasive properties compared to P-glycoprotein-poorhepatoma cells. Oncol. Res., 1998; 10: 255-262
  Google Scholar
• 12. Bratland A., Ragnhildstveit E., Bjørnland K., Andersen K.,Maelandsmo G.M., Fodstad O., Saatcioglu F., Ree A.H.: The metalloproteinaseinhibitor TIMP-2 is down-regulated by androgensin LNCaP prostate carcinoma cells. Clin. Exp. Metastasis,2003; 20: 541-547
  Google Scholar
• 13. Bressin C., Bourgarel-Rey V., Carré M., Pourroy B., Arango D.,Braguer D., Barra Y.: Decrease in c-Myc activity enhances cancercell sensitivity to vinblastine. Anticancer Drugs., 2006; 17: 181-187
  Google Scholar
• 14. Brock I., Hipfner D.R., Nielsen B.S., Jensen P.B., Deeley R.G.,Cole S.P., Sehested M.: Sequential coexpression of the multidrugresistance genes MRP and mdr1 and their products in VP-16 (etoposide)-selectedH69 small cell lung cancer cells. Cancer Res.,1995; 55: 459-462
  Google Scholar
• 15. Broxterman H.J., Lankelma J., Hoekman K.: Resistance to cytotoxicand anti-angiogenic anticancer agents: similarities and differences.Drug Resist. Updat., 2003; 6: 111-127
  Google Scholar
• 16. Cance W.G., Harris J.E., Iacocca M.V., Roche E., Yang X., Chang J.,Simkins S., Xu L.: Immunohistochemical analyses of focal adhesionkinase expression in benign and malignant human breast and colontissues: correlation with preinvasive and invasive phenotypes. Clin.Cancer Res., 2000; 6: 2417-2423
  Google Scholar
• 17. Cheng C., Yaffe M.B., Sharp P.A.: A positive feedback loop couplesRas activation and CD44 alternative splicing. Genes Dev., 2006;20: 1715-1720
  Google Scholar
• 18. Choi J., Choi K., Benveniste E.N., Rho S.B., Hong Y.S., Lee J.H.,Kim J., Park K.: Bcl-2 promotes invasion and lung metastasis by inducingmatrix metalloproteinase-2. Cancer Res., 2005; 65: 5554-5560
  Google Scholar
• 19. Cicek M., Fukuyama R., Welch D.R., Sizemore N., Casey G.: Breastcancer metastasis suppressor 1 inhibits gene expression by targetingnuclear factor-κB activity. Cancer Res., 2005; 65: 3586-3595
  Google Scholar
• 20. Colone M., Calcabrini A., Toccacieli L., Bozzuto G., Stringaro A.,Gentile M., Cianfriglia M., Ciervo A., Caraglia M., Budillon A., MeoG., Arancia G., Molinari A.: The multidrug transporter P-glycoprotein:a mediator of melanoma invasion? J. Invest. Dermatol., 2008;128: 957-971
  Google Scholar
• 21. Cox G., Steward W.P., O’Byrne K.J.: The plasmin cascade andmatrix metalloproteinases in non-small cell lung cancer. Thorax,1999; 54: 169-179
  Google Scholar
• 22. D›Alessio S., Margheri F., Pucci M., Del Rosso A., Monia B., BolognaM., Leonetti C., Scarsella M., Zupi G., Fibbi G., Del Rosso M.:Antisense oligodeoxynucleotides for urokinase-plasminogen activatorreceptor have anti-invasive and anti-proliferative effects invitro and inhibit spontaneous metastases of human melanoma inmice. Int. J. Cancer, 2004; 110: 125-133
  Google Scholar
• 23. Damiano J.S., Cress A.E., Hazlehurst L.A., Shtil A.A., Dalton W.S.Cell adhesion mediated drug resistance (CAM-DR): role of integrinsand resistance to apoptosis in human myeloma cell lines. Blood,1999; 93: 1658-1667
  Google Scholar
• 24. de Kant E., Heide I., Thiede C., Herrmann R., Rochlitz C.F.: MDR1expression correlates with mutant p53 expression in colorectal cancermetastases. J. Cancer Res. Clin. Oncol., 1996; 122: 671-675
  Google Scholar
• 25. Ding X.W., Wu J.H., Jiang C.P.: ABCG2: a potential marker ofstem cells and novel target in stem cell and cancer therapy. LifeSci., 2010; 86: 631-637
  Google Scholar
• 26. Dittmer J.: The biology of the Ets1 proto-oncogene. Mol. Cancer,2003; 2: 29
  Google Scholar
• 27. Dong Z., Radinsky R., Fan D., Tsan R., Bucana C.D., WilmannsC., Fidler I.J.: Organ-specific modulation of steady-state mdr geneexpression and drug resistance in murine colon cancer cells. J. Natl.Cancer Inst., 1994; 86: 913-920
  Google Scholar
• 28. Dozmorov M.G., Kyker K.D., Saban R., Knowlton N., DozmorovI., Centola M.B., Hurst R.E.: Analysis of the interaction of extracellularmatrix and phenotype of bladder cancer cells. BMC Cancer,2006; 6: 12
  Google Scholar
• 29. Duensing S., Brevis Nunez F., Meyer N., Anastassiou G,, NasarekA,, Grosse J,, Buer J,, Probst M,, Ganser A,, Alzpodien J.: Exposure tovinblastine modulates beta 1 integrin expression and in vitro bindingto extracellular matrix molecules in a human renal carcinomacell line. Invasion Metastasis, 1996; 16: 65-72
  Google Scholar
• 30. Eccles S.A.: Cell biology of lymphatic metastasis. The potentialrole of c-erbB oncogene signalling. Recent Results Cancer Res.,2000; 157: 41-54
  Google Scholar
• 31. Fidler I.J.: Critical determinants of cancer metastasis: rationalefor therapy. Cancer Chemother. Pharmacol., 1999; 43, Suppl.: S3-S10
  Google Scholar
• 32. Fidler I.J.: Orthotopic implantation of human colon carcinomasinto nude mice provides a valuable model for the biology and therapyof metastasis. Cancer Metastasis Rev., 1991; 10: 229-243
  Google Scholar
• 33. Fidler I.J.: The pathogenesis of cancer metastasis: the ‘seed andsoil’ hypothesis revisited. Nature Rev., 2003; 3: 453-458
  Google Scholar
• 34. Fischer K.R., Durrans A., Lee S., Sheng J., Li F., Wong S.T., Choi H., El Rayes T., Ryu S., Troeger J., Schwabe R.F., Vahdat L.T., AltorkiN.K., Mittal V., Gao D.: Epithelial-to-mesenchymal transition is notrequired for lung metastasis but contributes to chemoresistance.Nature, 2015; 527: 472-476
  Google Scholar
• 35. Funato T., Kozawa K., Fujimaki S., Miura T., Kaku M..: Increasedsensitivity to cisplatin in gastric cancer by antisense inhibition ofthe her-2/neu (c-erbB-2) gene. Chemotherapy, 2001; 47: 297-303
  Google Scholar
• 36. Futaki S., Hayashi Y., Yamashita M., Yagi K., Bono H., HayashizakiY., Okazaki Y, Sekiguchi K.: Molecular basis of constitutive productionof basement membrane components. Gene expression profilesof Engelbreth-Holm-Swarm tumor and F9 embryonal carcinomacells. J. Biol. Chem., 2003; 278: 50691-50701
  Google Scholar
• 37. Guo H., Zucker S., Gordon M.K., Toole B.P., Biswas C.: Stimulationof matrix metalloproteinase production by recombinant extracellularmatrix metalloproteinase inducer from transfected Chinesehamster ovary cells. J. Biol. Chem., 1997; 272: 24-27
  Google Scholar
• 38. Guo Y.S., Jin G.F., Houston C.W., Thompson J.C., Townsend C.M.Jr.:Insulin-like growth factor-I promotes multidrug resistance in MCLMcolon cancer cells. J. Cell. Physiol., 1998; 175: 141-148
  Google Scholar
• 39. Harbeck N., Alt U., Berger U., Krüger A., Thomssen C., JänickeF., Höfler H., Kates R.E., Schmitt M.: Prognostic impact of proteolyticfactors (urokinase-type plasminogen activator, plasminogenactivator inhibitor 1, and cathepsins B, D, and L) in primary breastcancer reflects effects of adjuvant systemic therapy. Clin. CancerRes., 2001; 7: 2757-2764
  Google Scholar
• 40. Harisi R., Dudás J., Pogány G., Timár F., Oláh J.N., Szendroi M.,Jeney A..: Repopulation of osteosarcoma cells after treatment withdoxorubicin in the presence of extracellular matrix biopolymers.Cancer Chemother. Pharmacol., 2006; 58: 334-342
  Google Scholar
• 41. Harisi R., Dudás J., Tímár F., Pogány G., Paku S., Tímár J., KovalszkyI., Szendroi M., Jeney A.: Antiproliferative and antimigratoryeffects of doxorubicin in human osteosarcoma cells exposed toextracellular matrix. Anticancer Res., 2005; 25: 805-813
  Google Scholar
• 42. Harisi R., Dudás J., Timár F., Pogány G., Timár J., Kovalszky I.,Szendroi M., Jeney A.: Invasive growth and topoisomerase-switchinduced by tumorous extracellular matrix in osteosarcoma cell culture.Cell Biol. Int., 2005; 29: 959-967
  Google Scholar
• 43. Harrington K.J., Syrigos K.N.: The role of E-cadherin-catenincomplex: more than an intercellular glue? Ann. Surg. Oncol., 2000;7: 783-788
  Google Scholar
• 44. Hiscox S., Jordan N.J., Morgan L., Green T.P., Nicholson R.I.: Srckinase promotes adhesion-independent activation of FAK and enhancescellular migration in tamoxifen-resistant breast cancer cells.Clin. Exp. Metastasis, 2007; 24: 157-167
  Google Scholar
• 45. Hiscox S., Morgan L., Barrow D., Dutkowskil C., Wakeling A., NicholsonR.I.: Tamoxifen resistance in breast cancer cells is accompaniedby an enhanced motile and invasive phenotype: inhibitionby gefitinib (‚Iressa‘, ZD1839). Clin. Exp. Metastasis, 2004; 21: 201-212
  Google Scholar
• 46. Huang C., Park C.C., Hilsenbeck S.G., Ward R., Rimawi M.F., WangY.C., Shou J., Bissell M.J., Osborne C.K., Schiff R.: β1 integrin mediatesan alternative survival pathway in breast cancer cells resistant tolapatinib. Breast Cancer Res., 2011; 13: R84
  Google Scholar
• 47. Iizuka N., Hirose K., Noma T., Hazama S., Tangoku A., HayashiH., Abe T., Yamamoto K., Oka M.: The nm23-H1 gene as a predictorof sensitivity to chemotherapeutic agents in oesophageal squamouscell carcinoma. Br. J. Cancer, 1999; 81: 469-475
  Google Scholar
• 48. Kanda R., Kawahara A., Watari K., Murakami Y., Sonoda K., MaedaM., Fujita H., Kage M., Uramoto H., Costa C., Kuwano M., Ono M.:Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling. Cancer Res., 2013; 73: 6243-6253
  Google Scholar
• 49. Karroum A., Mirshahi P., Benabbou N., Faussat A.M., Soria J.,Therwath A., Mirshahi M., Hatmi M.: Matrix metalloproteinase-9 isrequired for tubular network formation and migration of resistant breast cancer cells MCF-7 through PKC and ERK1/2 signalling pathways.Cancer Lett., 2010; 295: 242-251
  Google Scholar
• 50. Kars M.D., Işeri O.D., Gündüz U.: Drug resistant breast cancercells overexpress ETS1 gene. Biomed. Pharmacother., 2010; 64: 458-462
  Google Scholar
• 51. Kerbel R.S.: Tumor angiogenesis: past, present and the nearfuture. Carcinogenesis, 2000; 21: 505-515
  Google Scholar
• 52. Kimbro K.S., Simons J.W.: Hypoxia-inducible factor-1 in humanbreast and prostate cancer. Endocr. Relat. Cancer, 2006; 13: 739-749
  Google Scholar
• 53. Knez L., Sodja E., Kern I., Košnik M., Cufer T.: Predictive value ofmultidrug resistance proteins, topoisomerases II and ERCC1 in smallcell lung cancer: a systematic review. Lung Cancer, 2011; 72: 271-279
  Google Scholar
• 54. Kouniavsky G., Khaikin M., Zvibel I., Zippel D., Brill S., HalpernZ., Papa M.: Stromal extracellular matrix reduces chemotherapy–induced apoptosis in colon cancer cell lines. Clin. Exp. Metastasis,2002; 19: 55-60
  Google Scholar
• 55. Krishnamachary B., Berg-Dixon S., Kelly B., Agani F., FeldserD., Ferreira G., Iyer N., LaRusch J., Pak B., Taghavi P., Semenza G.L.:Regulation of colon carcinoma cell invasion by hypoxia-induciblefactor 1. Cancer Res., 2003; 63: 1138-1143
  Google Scholar
• 56. Lee J.T. Jr, Steelman L.S., McCubrey J.A.: Phosphatidylinositol3‘-kinase activation leads to multidrug resistance protein-1 expressionand subsequent chemoresistance in advanced prostate cancercells. Cancer Res., 2004; 64: 8397-8404
  Google Scholar
• 57. Li C., Teng R.H., Tsai Y.C., Ke H.S, Huang J.Y., Chen C.C., Kao Y.L.,Kuo C.C., Bell W.R., Shieh B.: H-Ras oncogene counteracts the growth–inhibitory effect of genistein in T24 bladder carcinoma cells. Br. J.Cancer, 2005; 92: 80-88
  Google Scholar
• 58. Li G., Bush J.A., Ho V.C.: p53-dependent apoptosis in melanomacells after treatment with camptothecin. J. Invest. Dermatol. 2000;114: 514-519
  Google Scholar
• 59. Li Q.Q., Wang W.J., Xu J.D., Cao X.X., Chen Q., Yang J.M., Xu Z.D.:Up-regulation of CD147 and matrix metalloproteinase-2, -9 inducedby P-glycoprotein substrates in multidrug resistant breast cancercells. Cancer Sci., 2007; 98: 1767-1774
  Google Scholar
• 60. Liang Y., Meleady P., Cleary I., McDonnell S., Connolly L., ClynesM.: Selection with mephalan or paclitaxel (Taxol) yields variantswith different patterns of multidrug resistance, integrin expressionand in vitro invasiveness. Eur. J. Cancer, 2001; 37: 1041-1052
  Google Scholar
• 61. Liang Y., O’Driscoll L., McDonnell S., Doolan P., Oglesby I., DuffyK., O’Connor R., Clynes M.: Enhanced in vitro invasivness and drugresistance with altered gene expression patterns in a human lungcanciroma cell line after pulse selection with anticancer drugs. Int.J. Cancer, 2004; 111: 484-493
  Google Scholar
• 62. Lin Y., Bai L., Chen W., Xu S.: The NF-κB activation pathways,emerging molecular targets for cancer prevention and therapy.Expert Opin. Ther. Targets, 2010; 14: 45-55
  Google Scholar
• 63. Liu B., Staren E., Iwamura T., Appert H., Howard J.: Effects ofTaxotere on invasive potential and multidrug resistance phenotypein pancreatic carcinoma cell line SUIT-2. World J. Gastroenterol.,2001; 7: 143-148
  Google Scholar
• 64. Lizuka N., Miyamoto K., Tangoku A., Hayashi H., Hazama S.,Yoshino S., Yoshimura K., Hirose K., Yoshida H., Oka M.: Downregulationof intracellular nm23-H1 prevents cisplatin-induced DNAdamage in oesophageal cancer cells: possible association with Na+,K+-ATPase. Br. J. Cancer, 2000; 83: 1209-1215
  Google Scholar
• 65. Loe D.W., Deeley R.G., Cole S.P.: Characterization of vincristinetransport by the Mr 190,000 multidrug resistance protein (MRP):evidence for cotransport with reduced glutathione. Cancer Res.,1998; 58: 5130-5136
  Google Scholar
• 66. Lu L.S., Chen L., Ding W.X,. Li K., Wu J.J.: Elevated expressionof both MDR1 and MMP-2 genes in metastasized lymph node of invasive ductal breast cancer. Eur. Rev. Med. Pharmacol. Sci., 2012;16: 2037-2043
  Google Scholar
• 67. Marieb E.A., Zoltan-Jones A., Li R., Misra S., Ghatak S., Cao J.,Zucker S., Toole B.P.: Emmprin promotes anchorage-independentgrowth in human mammary carcinoma cells by stimulating hyaluronanproduction. Cancer Res., 2004; 64: 1229-1232
  Google Scholar
• 68. Meng Q., Mason J.M., Porti D., Goldberg I.D., Rosen E.M., Fan S.:Hepatocyte growth factor decreases sensitivity to chemotherapeuticagents and stimulates cell adhesion, invasion, and migration.Biochem. Biophys. Res. Commun., 2000; 274: 772-779
  Google Scholar
• 69. Miletti-González K.E., Chen S., Muthukumaran N., SaglimbeniG.N., Wu X., Yang J., Apolito K., Shih W.J., Hait W.N., Rodríguez–Rodríguez L.: The CD44 receptor interacts with P-glycoprotein topromote cell migration and invasion in cancer. Cancer Res., 2005;65: 6660-6667
  Google Scholar
• 70. Misra S., Ghatak S., Toole B.P.: Regulation of MDR1 expressionand drug resistance by a positive feedback loop involving hyaluronan,phosphoinositide 3-kinase, and ErbB2. J. Biol. Chem., 2005;280: 20310-20315
  Google Scholar
• 71. Misra S., Ghatak S., Zoltan-Jones A., Toole B.P.: Regulation ofmultidrug resistance in cancer cells by hyaluronan. J. Biol. Chem.,2003; 278: 25285-25288
  Google Scholar
• 72. Misra S., Obeid L.M., Hannun Y.A., Minamisawa S., Berger F.G.,Markwald R.R., Toole B.P., Ghatak S.: Hyaluronan constitutively regulatesactivation of COX-2-mediated cell survival activity in intestinalepithelial and colon carcinoma cells. J. Biol. Chem., 2008;283: 14335-14344
  Google Scholar
• 73. Mogi M., Yang J., Lambert J.F., Colvin G.A., Shiojima I., Skurk C.,Summer R., Fine A., Quesenberry P.J., Walsh K.: Akt signaling regulatesside population cell phenotype via Bcrp1 translocation. J. Biol.Chem., 2003; 278: 39068-39075
  Google Scholar
• 74. Molinari A., Stringaro A., Gentile M., Colone M., Toccacieli L.,Arancia G.: Invasive properties of multidrug resistant human melanomacells. Ital. J. Anat. Embryol., 2005; 110: 135-141
  Google Scholar
• 75. Nakamura Y., Sato H., Motokura T.: Development of multidrugresistance due to multiple factors including P-glycoprotein overexpressionunder K-selection after MYC and HRAS oncogene activation.Int. J. Cancer, 2006; 118: 2448-2454
  Google Scholar
• 76. Narita T., Kimura N., Sato M., Matsuura N., Kannagi R.: Alteredexpression of integrins in adriamycin-resistant human breast cancercells. Anticancer Res., 1998; 18: 257-262
  Google Scholar
• 77. Noguchi K., Katayama K., Sugimoto Y.: Human ABC transporterABCG2/BCRP expression in chemoresistance: basic and clinicalperspectives for molecular cancer therapeutics. PharmgenomicsPers. Med., 2014; 7: 53-64
  Google Scholar
• 78. Nokihara H., Yano S., Nishioka Y., Hanibuchi M., Higasida T.,Tsuruo T., Sone S.: A new quinoline derivative MS-209 reverses multidrugresistance and inhibits multiorgan metastases by P-glycoprotein-expressinghuman small cell lung cancer cells. Jpn. J. CancerRes., 2001; 92: 785-792
  Google Scholar
• 79. Nollet F., Berx G., van Roy F.: The role of the E-cadherin/cateninadhesion complex in the development and progression of cancer.Mol. Cell. Biol. Res. Commun., 1999; 2: 77-85
  Google Scholar
• 80. Ohashi R., Takahashi F., Cui R., Yoshioka M., Gu T., Sasaki S., TominagaS., Nishio K., Tanabe K.K., Takahashi K.: Interaction betweenCD44 and hyaluronate induces chemoresistance in non-small celllung cancer cell. Cancer Lett., 2007; 252: 225-234
  Google Scholar
• 81. Osmak M., Niksíc D., Brozović A. Ristov A.A., Vrhovec I., Skrk J.:Drug resistant tumor cells have increased levels of tumor markersfor invasion and metastasis. Anticancer Res., 1999; 19: 3193-3197
  Google Scholar
• 82. Osmak M., Svetić B., Gabrijelcić-Geiger D., Skrk J.: Drug-resistanthuman laryngeal carcinoma cells have increased levels of cathepsinB. Anticancer Res., 2001; 21: 481-483
  Google Scholar
• 83. Osmak M., Vrhovec I., Skrk J.: Cisplatin resistant glioblastomacells may have increased concentration of urokinase plasminogenactivator and plasminogen activator inhibitor type 1. J. Neurooncol.,1999; 42: 95-102
  Google Scholar
• 84. Owens L.V., Xu L., Marston W.A., Yang X., Farber M.A., IacoccaM.V., Cance W.G., Keagy B.A.: Overexpression of the focal adhesionkinase (p125FAK) in the vascular smooth muscle cells of intimal hyperplasia.J. Vasc. Surg., 2001; 34: 344-349
  Google Scholar
• 85. Pogány G., Timár F., Oláh J., Harisi R., Polony G., Paku S., BocsiJ., Jeney A., Laurie G.W.: Role of the basement membrane in tumorcell dormancy and cytotoxic resistance. Oncology, 2001; 60: 274-281
  Google Scholar
• 86. Pozzatti R., Muschel R., Williams J., Padmanabhan R., Howard B.,Liotta L., Khoury G.: Primary rat embryo cells transformed by oneor two oncogenes show different metastatic potentials. Science,1986; 232: 223-227
  Google Scholar
• 87. Pulukuri S.M., Gondi C.S., Lakka S.S., Jutla A., Estes N., GujratiM., Rao J.S.: RNA interference-directed knockdown of urokinase plasminogenactivator and urokinase plasminogen activator receptorinhibits prostate cancer cell invasion, survival, and tumorigenicityin vivo. J. Biol. Chem., 2005; 280: 36529-36540
  Google Scholar
• 88. Qin H., Sun Y., Benveniste E.N.: The transcription factors Sp1,Sp3, and AP-2 are required for constitutive matrix metalloproteinase-2gene expression in astroglioma cells. J. Biol. Chem., 1999;274: 29130-29137
  Google Scholar
• 89. Raguz S., Tamburo De Bella M., Tripuraneni G., Slade M.J., HigginsC.F., Coombes R.C., Yagüe E.: Activation of the MDR1 upstreampromoter in breast carcinoma as a surrogate for metastatic invasion.Clin. Cancer Res., 2004; 10: 2776-2783
  Google Scholar
• 90. Ricca A., Biroccio A., Del Bufalo D., Mackay A.R., Santoni A., CippitelliM.: bcl-2 over-expression enhances NF-κB activity and inducesmmp-9 transcription in human MCF7ADR breast-cancer cells. Int. J.Cancer, 2000; 86: 188-196
  Google Scholar
• 91. Rintoul R.C., Sethi T.: Extracellular matrix regulation of drugresistance in small-cell lung cancer. Clin. Sci., 2002; 102: 417-424
  Google Scholar
• 92. Rintoul R.C., Sethi T.: The role of extracellular matrix in small–cell lung cancer. Lancet Oncol., 2001; 2: 437-442
  Google Scholar
• 93. Roger L., Gadea G., Roux P.: Control of cell migration: a tumoursuppressor function for p53? Biol. Cell., 2006; 98: 141-152
  Google Scholar
• 94. Rovin J.D., Frierson H.F.Jr., Ledinh W., Parsons J.T., Adams R.B.:Expression of focal adhesion kinase in normal and pathologic humanprostate tissues. Prostate, 2002; 53: 124-132
  Google Scholar
• 95. Sampath J., Sun D., Kidd V.J., Grenet J., Gandhi A., Shapiro L.H.,Wang Q., Zambetti G.P., Schuetz J.D.: Mutant p53 cooperates withETS and selectively up-regulates human MDR1 not MRP1. J. Biol.Chem., 2001; 276: 39359-39367
  Google Scholar
• 96. Sau A., Pellizzari Tregno F., Valentino F., Federici G., Caccuri A.M.:Glutathione transferases and development of new principles to overcomedrug resistance. Arch. Biochem. Biophys., 2010; 500: 116-122
  Google Scholar
• 97. Savagner P.: The epithelial-mesenchymal transition (EMT) phenomenon.Ann. Oncol., 2010; 21: vii89-vii92
  Google Scholar
• 98. Schneider J., Gonzalez-Roces S., Pollán M,. Lucas R., TejerinaA., Martin M., Alba A.: Expression of LRP and MDR1 in locally advancedbreast cancer predicts axillary node invasion at the time ofrescue mastectomy after induction chemotherapy. Breast CancerRes., 2001; 3: 183-191
  Google Scholar
• 99. Scotto K.W.: Transcriptional regulation of ABC drug transporters.Oncogene, 2003; 22: 7496-7511
  Google Scholar
• 100. Seguin L., Desgrosellier J.S., Weis S.M., Cheresh D.A.: Integrinsand cancer: regulators of cancer stemness, metastasis, and drugresistance. Trends Cell Biol., 2015; 25: 234-240
  Google Scholar
• 101. Sethi G., Aggarwal B.B.: Role of NF-κB and NF-κB-regulatedgene products in chemoresistance and radioresistance. Curr. Cancer Ther. Rev., 2006; 2: 115-125
  Google Scholar
• 102. Song S., Wientjes M.G., Gan Y., Au J.L.: Fibroblast growth factors:an epigenetic mechanism of broad spectrum resistance to anticancerdrugs. Proc. Natl. Acad. Sci. USA, 2000; 97: 8658-8663
  Google Scholar
• 103. Staroselsky A.N., Fan D., O’Brian C.A., Bucana C.D., Gupta K.P.,Fidler I.J.: Site-dependent differences in response of the UV-2237murine fibrosarcoma to systemic therapy with adriamycin. CancerRes., 1990; 50: 7775-7780
  Google Scholar
• 104. Staroselsky A.N., Mahlin T., Savion N., Klein O., Nordenberg J.,Donin N., Michowitz M., Leibovici J.: Metastatic potential and multidrugresistance correlation in the B16 melanoma system. J. Exp.Ther. Oncol., 1996; 1: 251-259
  Google Scholar
• 105. Stavrovskaya A.A.: Cellular mechanisms of multidrug resistanceof tumor cells. Biochemistry, 2000; 65: 95-106
  Google Scholar
• 106. Steeg P.S.: Perspectives on classic article: metastasis suppressorgenes. J. Natl. Cancer Inst., 2004; 96: E4
  Google Scholar
• 107. Vaupel P.: The role of hypoxia-induced factors in tumor progression.Oncologist, 2004; 9: 10-17
  Google Scholar
• 108. Volm M., Mattern J., Koomägi R.: Association between nm23–H1 expression, proliferation and apoptosis in non-small cell lungcarcinomas. Clin. Exp. Metastasis, 1998; 16: 595-602
  Google Scholar
• 109. Wang L.S., Chow K.C., Lien Y.C., Kuo K.T., Li W.Y.: Prognosticsignificance of nm23-H1 expression in esophageal squamous cellcarcinoma. Eur. J. Cardiothorac. Surg., 2004; 26: 419-424
  Google Scholar
• 110. Wang X., Wu X., Wang C., Zhang W., Ouyang Y., Yu Y., He Z.:Transcriptional suppression of breast cancer resistance protein(BCRP) by wild-type p53 through the NF-κB pathway in MCF-7 cells.FEBS Lett., 2010; 584: 3392-3397
  Google Scholar
• 111. Webb C.P., Vande Woude G.F.: Genes that regulate metastasisand angiogenesis. J. Neurooncol., 2000; 50: 71-87
  Google Scholar
• 112. Weinstein R.S., Jakate S.M., Dominguez J.M., Lebovitz M.D.,Koukoulis G.K., Kuszak J.R., Klusens L.F., Grogan T.M., Saclarides T.J.,Roninson I.B.: Relationship of the expression of the multidrug resistancegene product (P-glycoprotein) in human colon carcinomato local tumor aggressiveness and lymph node metastasis. CancerRes., 1991; 51: 2720-2726
  Google Scholar
• 113. Westermarck J., Kähäri V.M.: Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J., 1999; 13: 781-792
  Google Scholar
• 114. Xue C., Liang F., Mahmood R., Vuolo M., Wyckoff J., Qian H.,Tsai K.L., Kim M., Locker J., Zhang Z.Y., Segall J.E.: ErbB3-dependentmotility and intravasation in breast cancer metastasis. Cancer Res.,2006; 66: 1418-1426
  Google Scholar
• 115. Yang J., Mani S.A., Donaher J.L., Ramaswamy S., Itzykson R.A.,Come C., Savagner P., Gitelman I., Richardson A., Weinberg R.A.:Twist, a master regulator of morphogenesis, plays an essential rolein tumor metastasis. Cell, 2004; 117: 927-939
  Google Scholar
• 116. Yang J.M., O›Neill P., Jin W., Foty R., Medina D.J., Xu Z., LomasM., Arndt G.M., Tang Y., Nakada M., Yan L., Hait W.N.: Extracellularmatrix metalloproteinase inducer (CD147) confers resistance of breastcancer cells to Anoikis through inhibition of Bim. J. Biol. Chem.,2006; 281: 9719-9727
  Google Scholar
• 117. Yang J.M., Xu Z., Wu H., Zhu H., Wu X., Hait W.N.: Overexpressionof extracellular matrix metalloproteinase inducer in multidrugresistant cancer cells. Mol. Cancer Res., 2003; 1: 420-427
  Google Scholar
• 118. Yoshida B.A., Sokoloff M.M., Welch D.R., Rinker-Schaeffer C.W.:Metastasis-suppressor genes: a review and perspective on an emergingfield. J. Natl. Cancer Inst., 2000; 92: 1717-1730
  Google Scholar
• 119. Zheng X., Carstens J.L., Kim J., Scheible M., Kaye J., SugimotoH., Wu C.C., Le Bleu V.S., Kalluri R.: Epithelial-to-mesenchymal transitionis dispensable for metastasis but induces chemoresistance inpancreatic cancer. Nature, 2015; 527: 525-530
  Google Scholar
• 120. Zöchbauer-Müller S., Filipits M., Rudas M., Brunner R., KrajnikG., Suchomel R., Schmid K., Pirker R.: P-glycoprotein and MRP1expression in axillary lymph node metastases of breast cancer patients.Anticancer Res., 2001; 21: 119-124
  Google Scholar
• 121. Zou W., Yang H., Hou X., Zhang W., Chen B., Xin X.: Inhibitionof CD147 gene expression via RNA interference reduces tumor cellinvasion, tumorigenicity and increases chemosensitivity to paclitaxelin HO-8910pm cells. Cancer Lett., 2007; 248: 211-218
  Google Scholar
• 122. Zvibel I., Brill S., Halpern Z., Moskovitz S., Yayon A., Papa M.:Soluble and matrix-associated heparan sulfate proteoglycans increaseexpression of erb-B2 and erb-B3 in colon cancer cell lines. Int. J.Cancer, 2001; 91: 316-321
  Google Scholar

Full text