Tumor-dependent Effects of Proteoglycans and Various Glycosaminoglycan Synthesizing Enzymes and Sulfotransferases on Patients’ Outcome

Cancer Genome Atlas Research Network. Weinstein, J.N.; Collisson, E.A.; Mills, G.B.; Shaw, K.R.M.; Ozenberger, B.A.; Ellrott, K.; Shmulevich, I.; Sander, C.; Stuart, J.M.; Chu, A.; Chuah, E.; Chun, H.-J.E.; Dhalla, N.; Guin, R.; Hirst, M.; Hirst, C.; Holt, R.A.; Jones, S.J.M.; Lee, D.; Li, H.I.; Marra, M.A.; Mayo, M.; Moore, R.A.; Mungall, A.J.; Robertson, A.G.; Schein, J.E.; Sipahimalani, P.; Tam, A.; Thiessen, N.; Varhol, R.J.; Beroukhim, R.; Bhatt, A.S.; Brooks, A.N.; Cherniack, A.D.; Freeman, S.S.; Gabriel, S.B.; Helman, E.; Jung, J.; Meyerson, M.; Ojesina, A.I.; Pedamallu, C.S.; Saksena, G.; Schumacher, S.E.; Tabak, B.; Zack, T.; Lander, E.S.; Bristow, C.A.; Hadjipanayis, A.; Haseley, P.; Kucherlapati, R.; Lee, S.; Lee, E.; Luquette, L.J.; Mahadeshwar, H.S.; Pantazi, A.; Parfenov, M.; Park, P.J.; Protopopov, A.; Ren, X.; Santoso, N.; Seidman, J.; Seth, S.; Song, X.; Tang, J.; Xi, R.; Xu, A.W.; Yang, L.; Zeng, D.; Auman, J.T.; Balu, S.; Buda, E.; Fan, C.; Hoadley, K.A.; Jones, C.D.; Meng, S.; Mieczkowski, P.A.; Parker, J.S.; Perou, C.M.; Roach, J.; Shi, Y.; Silva, G.O.; Tan, D.; Veluvolu, U.; Waring, S.; Wilkerson, M.D.; Wu, J.; Zhao, W.; Bodenheimer, T.; Hayes, D.N.; Hoyle, A.P.; Jeffreys, S.R.; Mose, L.E.; Simons, J. V; Soloway, M.G.; Baylin, S.B.; Berman, B.P.; Bootwalla, M.S.; Danilova, L.; Herman, J.G.; Hinoue, T.; Laird, P.W.; Rhie, S.K.; Shen, H.; Triche, T.; Weisenberger, D.J.; Carter, S.L.; Cibulskis, K.; Chin, L.; Zhang, J.; Getz, G.; Sougnez, C.; Wang, M.; Saksena, G.; Carter, S.L.; Cibulskis, K.; Chin, L.; Zhang, J.; Getz, G.; Dinh, H.; Doddapaneni, H.V.; Gibbs, R.; Gunaratne, P.; Han, Y.; Kalra, D.; Kovar, C.; Lewis, L.; Morgan, M.; Morton, D.; Muzny, D.; Reid, J.; Xi, L.; Cho, J.; DiCara, D.; Frazer, S.; Gehlenborg, N.; Heiman, D.I.; Kim, J.; Lawrence, M.S.; Lin, P.; Liu, Y.; Noble, M.S.; Stojanov, P.; Voet, D.; Zhang, H.; Zou, L.; Stewart, C.; Bernard, B.; Bressler, R.; Eakin, A.; Iype, L.; Knijnenburg, T.; Kramer, R.; Kreisberg, R.; Leinonen, K.; Lin, J.; Liu, Y.; Miller, M.; Reynolds, S.M.; Rovira, H.; Shmulevich, I.; Thorsson, V.; Yang, D.; Zhang, W.; Amin, S.; Wu, C.-J.; Wu, C.- C.; Akbani, R.; Aldape, K.; Baggerly, K.A.; Broom, B.; Casasent, T.D.; Cleland, J.; Creighton, C.; Dodda, D.; Edgerton, M.; Han, L.; Herbrich, S.M.; Ju, Z.; Kim, H.; Lerner, S.; Li, J.; Liang, H.; Liu, W.; Lorenzi, P.L.; Lu, Y.; Melott, J.; Mills, G.B.; Nguyen, L.; Su, X.; Verhaak, R.; Wang, W.; Weinstein, J.N.; Wong, A.; Yang, Y.; Yao, J.; Yao, R.; Yoshihara, K.; Yuan, Y.; Yung, A.K.; Zhang, N.; Zheng, S.; Ryan, M.; Kane, D.W.; Aksoy, B.A.; Ciriello, G.; Dresdner, G.; Gao, J.; Gross, B.; Jacobsen, A.; Kahles, A.; Ladanyi, M.; Lee, W.; Lehmann, K.-V.; Miller, M.L.; Ramirez, R.; Rätsch, G.; Reva, B.; Sander, C.; Schultz, N.; Senbabaoglu, Y.; Shen, R.; Sinha, R.; Sumer, S.O.; Sun, Y.; Taylor, B.S.; Weinhold, N.; Fei, S.; Spellman, P.; Benz, C.; Carlin, D.; Cline, M.; Craft, B.; Ellrott, K.; Goldman, M.; Haussler, D.; Ma, S.; Ng, S.; Paull, E.; Radenbaugh, A.; Salama, S.; Sokolov, A.; Stuart, J.M.; Swatloski, T.; Uzunangelov, V.; Waltman, P.; Yau, C.; Zhu, J.; Hamilton, S.R.; Getz, G.; Sougnez, C.; Abbott, S.; Abbott, R.; Dees, N.D.; Delehaunty, K.; Ding, L.; Dooling, D.J.; Eldred, J.M.; Fronick, C.C.; Fulton, R.; Fulton, L.L.; Kalicki-Veizer, J.; Kanchi, K.-L.; Kandoth, C.; Koboldt, D.C.; Larson, D.E.; Ley, T.J.; Lin, L.; Lu, C.; Magrini, V.J.; Mardis, E.R.; McLellan, M.D.; McMichael, J.F.; Miller, C.A.; O’Laughlin, M.; Pohl, C.; Schmidt, H.; Smith, S.M.; Walker, J.; Wallis, J.W.; Wendl, M.C.; Wilson, R.K.; Wylie, T.; Zhang, Q.; Burton, R.; Jensen, M.A.; Kahn, A.; Pihl, T.; Pot, D.; Wan, Y.; Levine, D.A.; Black, A.D.; Bowen, J.; Frick, J.; Gastier- Foster, J.M.; Harper, H.A.; Helsel, C.; Leraas, K.M.; Lichtenberg, T.M.; McAllister, C.; Ramirez, N.C.; Sharpe, S.; Wise, L.; Zmuda, E.; Chanock, S.J.; Davidsen, T.; Demchok, J.A.; Eley, G.; Felau, I.; Ozenberger, B.A.; Sheth, M.; Sofia, H.; Staudt, L.; Tarnuzzer, R.; Wang, Z.; Yang, L.; Zhang, J.; Omberg, L.; Margolin, A.; Raphael, B.J.; Vandin, F.; Wu, H.-T.; Leiserson, M.D.M.; Benz, S.C.; Vaske, C.J.; Noushmehr, H.; Knijnenburg, T.; Wolf, D.; Veer, L.V.; Collisson, E.A.; Anastassiou, D.; Yang, T.-H.O.; Lopez- Bigas, N.; Gonzalez-Perez, A.; Tamborero, D.; Xia, Z.; Li, W.; Cho, D.-Y.; Przytycka, T.; Hamilton, M.; McGuire, S.; Nelander, S.; Johansson, P.; Jörnsten, R.; Kling, T.; Sanchez, J.; Weinstein, J.N.; Collisson, E.A.; Mills, G.B.; Shaw, K.R.M.; Ozenberger, B.A.; Ellrott, K.; Shmulevich, I.; Sander, C.; Stuart, J.M. The cancer genome atlas pan-cancer analysis project. Nat. Genet., 2013, 45, 1113-1120.

Afratis N, Gialeli C, Nikitovic D, et al. Glycosaminoglycans: key players in cancer cell biology and treatment. FEBS J 2012; 279: 1177-97.

Bianco P, Fisher LW, Young MF, Termine JD, Robey PG. Expression and localization of the two small proteoglycans biglycan and decorin in developing human skeletal and non-skeletal tissues. J Histochem Cytochem 1990; 38: 1549-63.

LeBaron RG, Esko JD, Woods A, Johansson S, Höök M. Adhesion of glycosaminoglycan-deficient chinese hamster ovary cell mutants to fibronectin substrata. J Cell Biol 1988; 106: 945-52.

Liotta LA, Rao CN, Wewer UM. Biochemical interactions of tumor cells with the basement membrane. Annu Rev Biochem 1986; 55: 1037-57.

Esko JD, Rostand KS, Weinke JL. Tumor formation dependent on proteoglycan biosynthesis. Science 1988; 241: 1092-6.

Andrlová H, Mastroianni J, Madl J, et al. Biglycan expression in the melanoma microenvironment promotes invasiveness via increased tissue stiffness inducing integrin-β1 expression. Oncotarget 2017; 8: 42901-16.

Hu L, Zang M, Wang H-X, et al. Biglycan stimulates VEGF expression in endothelial cells by activating the TLR signaling pathway. Mol Oncol 2016; 10: 1473-84.

Brandan E, Cabello-Verrugio C, Vial C. Novel regulatory mechanisms for the proteoglycans decorin and biglycan during muscle formation and muscular dystrophy. Matrix Biol 2008; 27: 700-8.

Subbarayan K, Leisz S, Wickenhauser C, et al. Biglycan-mediated upregulation of MHC class I expression in HER-2/neu-transformed cells. OncoImmunology 2017; e1373233.

Neill T, Schaefer L, Iozzo RV. Decorin: a guardian from the matrix. Am J Pathol 2012; 181: 380-7.

Troup S, Njue C, Kliewer EV, et al. Reduced expression of the small leucine-rich proteoglycans, lumican, and decorin is associated with poor outcome in node-negative invasive breast cancer. Clin Cancer Res 2003; 9: 207-14.

Crnogorac-Jurcevic T, Efthimiou E, Capelli P, et al. Gene expression profiles of pancreatic cancer and stromal desmoplasia. Oncogene 2001; 20: 7437-46.

Chatzinikolaou G, Nikitovic D, Stathopoulos EN, Velegrakis GA, Karamanos NK, Tzanakakis GN. Protein tyrosine kinase and estrogen receptor-dependent pathways regulate the synthesis and distribution of glycosaminoglycans/proteoglycans produced by two human colon cancer cell lines. Anticancer Res 27: 4101-6.

Nikitovic D, Chatzinikolaou G, Tsiaoussis J, Tsatsakis A, Karamanos NK, Tzanakakis GN. Insights into targeting colon cancer cell fate at the level of proteoglycans / glycosaminoglycans. Curr Med Chem 2012; 19: 4247-58.

Curtis C, Shah SP, Chin S-F, et al. C.; Langerød, A.; Green, A.; Provenzano, E.; Wishart, G.; Pinder, S.; Watson, P.; Markowetz, F.; Murphy, L.; Ellis, I.; Purushotham, A.; Børresen-Dale, A.-L.; Brenton, J.D.; Tavaré, S.; Caldas, C.; Aparicio, S.; Chin, S.-F.; Curtis, C.; Ding, Z.; Gräf, S.; Jones, L.; Liu, B.; Lynch, A.G.; Papatheodorou, I.; Sammut, S.J.; Wishart, G.; Aparicio, S.; Chia, S.; Gelmon, K.; Huntsman, D.; McKinney, S.; Speers, C.; Turashvili, G.; Watson, P.; Ellis, I.; Blamey, R.; Green, A.; Macmillan, D.; Rakha, E.; Purushotham, A.; Gillett, C.; Grigoriadis, A.; Pinder, S.; di Rinaldis, E.; Tutt, A.; Murphy, L.; Parisien, M.; Troup, S.; Caldas, C.; Chin, S.-F.; Chan, D.; Fielding, C.; Maia, A.-T.; McGuire, S.; Osborne, M.; Sayalero, S.M.; Spiteri, I.; Hadfield, J.; Aparicio, S.; Turashvili, G.; Bell, L.; Chow, K.; Gale, N.; Huntsman, D.; Kovalik, M.; Ng, Y.; Prentice, L.; Caldas, C.; Tavaré, S.; Curtis, C.; Dunning, M.J.; Gräf, S.; Lynch, A.G.; Rueda, O.M.; Russell, R.; Samarajiwa, S.; Speed, D.; Markowetz, F.; Yuan, Y.; Brenton, J.D.; Aparicio, S.; Shah, S.P.; Bashashati, A.; Ha, G.; Haffari, G.; McKinney, S.; Langerød, A.; Green, A.; Provenzano, E.; Wishart, G.; Pinder, S.; Watson, P.; Markowetz, F.; Murphy, L.; Ellis, I.; Purushotham, A.; Børresen-Dale, A.-L.; Brenton, J.D.; Tavaré, S.; Caldas, C.; Aparicio, S. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 2012; 486: 346-52.

Pereira B, Chin S-F, Rueda OM, et al. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun 2016; 7: 11479.

Ceccarelli M, Barthel FP, Malta TM, et al. TCGA Research Network, H.; Noushmehr, H.; Iavarone, A.; Verhaak, R.G.W.; Arachchi, H.; Auman, J.T.; Balasundaram, M.; Balu, S.; Barnett, G.; Baylin, S.; Bell, S.; Benz, C.; Bir, N.; Black, K.L.; Bodenheimer, T.; Boice, L.; Bootwalla, M.S.; Bowen, J.; Bristow, C.A.; Butterfield, Y.S.N.; Chen, Q.-R.; Chin, L.; Cho, J.; Chuah, E.; Chudamani, S.; Coetzee, S.G.; Cohen, M.L.; Colman, H.; Couce, M.; D’Angelo, F.; Davidsen, T.; Davis, A.; Demchok, J.A.; Devine, K.; Ding, L.; Duell, R.; Elder, J.B.; Eschbacher, J.M.; Fehrenbach, A.; Ferguson, M.; Frazer, S.; Fuller, G.; Fulop, J.; Gabriel, S.B.; Garofano, L.; Gastier-Foster, J.M.; Gehlenborg, N.; Gerken, M.; Getz, G.; Giannini, C.; Gibson, W.J.; Hadjipanayis, A.; Hayes, D.N.; Heiman, D.I.; Hermes, B.; Hilty, J.; Hoadley, K.A.; Hoyle, A.P.; Huang, M.; Jefferys, S.R.; Jones, C.D.; Jones, S.J.M.; Ju, Z.; Kastl, A.; Kendler, A.; Kim, J.; Kucherlapati, R.; Lai, P.H.; Lawrence, M.S.; Lee, S.; Leraas, K.M.; Lichtenberg, T.M.; Lin, P.; Liu, Y.; Liu, J.; Ljubimova, J.Y.; Lu, Y.; Ma, Y.; Maglinte, D.T.; Mahadeshwar, H.S.; Marra, M.A.; McGraw, M.; McPherson, C.; Meng, S.; Mieczkowski, P.A.; Miller, C.R.; Mills, G.B.; Moore, R.A.; Mose, L.E.; Mungall, A.J.; Naresh, R.; Naska, T.; Neder, L.; Noble, M.S.; Noss, A.; O’Neill, B.P.; Ostrom, Q.T.; Palmer, C.; Pantazi, A.; Parfenov, M.; Park, P.J.; Parker, J.S.; Perou, C.M.; Pierson, C.R.; Pihl, T.; Protopopov, A.; Radenbaugh, A.; Ramirez, N.C.; Rathmell, W.K.; Ren, X.; Roach, J.; Robertson, A.G.; Saksena, G.; Schein, J.E.; Schumacher, S.E.; Seidman, J.; Senecal, K.; Seth, S.; Shen, H.; Shi, Y.; Shih, J.; Shimmel, K.; Sicotte, H.; Sifri, S.; Silva, T.; Simons, J.V.; Singh, R.; Skelly, T.; Sloan, A.E.; Sofia, H.J.; Soloway, M.G.; Song, X.; Sougnez, C.; Souza, C.; Staugaitis, S.M.; Sun, H.; Sun, C.; Tan, D.; Tang, J.; Tang, Y.; Thorne, L.; Trevisan, F.A.; Triche, T.; Van Den Berg, D.J.; Veluvolu, U.; Voet, D.; Wan, Y.; Wang, Z.; Warnick, R.; Weinstein, J.N.; Weisenberger, D.J.; Wilkerson, M.D.; Williams, F.; Wise, L.; Wolinsky, Y.; Wu, J.; Xu, A.W.; Yang, L.; Yang, L.; Zack, T.I.; Zenklusen, J.C.; Zhang, J.; Zhang, W.; Zhang, J.; Zmuda, E. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 2016; 164: 550-63.

Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012; 2: 401-4.

Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013; 6: pl1.

Li X-B, Yang G, Zhu L, et al. Gastric Lgr5(+) stem cells are the cellular origin of invasive intestinal-type gastric cancer in mice. Cell Res 2016; 26: 838-49.

Keshava Prasad TS, Goel R, Kandasamy K, et al. Human protein reference database--2009 Update. Nucleic Acids Res 2009; 37: D767-72.

Matthews L, Gopinath G, Gillespie M, et al. Reactome knowledgebase of human biological pathways and processes. Nucleic Acids Res 2009; 37: D619-22.

Schaefer CF, Anthony K, Krupa S, et al. PID: The pathway interaction database. Nucleic Acids Res 2009; 37: D674-9.

Cerami EG, Gross BE, Demir E, et al. Pathway commons, a web resource for biological pathway data. Nucleic Acids Res 2011; 39: D685-90.

Clarke C, Madden SF, Doolan P, et al. Correlating transcriptional networks to breast cancer survival: a large-scale coexpression analysis. Carcinogenesis 2013; 34: 2300-8.

Gravendeel LAM, Kouwenhoven MCM, Gevaert O, et al. Intrinsic gene expression profiles of gliomas are a better predictor of survival than histology. Cancer Res 2009; 69: 9065-72.

Reddy EP, Reynolds RK, Santos E, Barbacid M. A Point mutation is responsible for the acquisition of transforming properties by the t24 human bladder carcinoma oncogene. Nature 1982; 300: 149-52.

Ladenson RP, Schwartz SO, Ivy AC. Incidence of the blood groups and the secretor factor in patients with pernicious anemia and stomach carcinoma. Am J Med Sci 1949; 217: 194-7.

Hakomori SI, Murakami WT. Glycolipids of hamster fibroblasts and derived malignant-transformed cell lines. Proc Natl Acad Sci USA 1968; 59: 254-61.

Du G, Zhao B, Zhang Y, et al. Hypothermia activates adipose tissue to promote malignant lung cancer progression. PLoS One 2013; 8: e72044.

Baghy K, Tátrai P, Regős E, Kovalszky I. Proteoglycans in Liver Cancer. World J Gastroenterol 2016; 22: 379-93.

Rangel MP, de Sá VK, Prieto T, et al. Biomolecular analysis of matrix proteoglycans as biomarkers in non small cell lung cancer. Glycoconj J 2018; 35: 233-42.

Qian Z, Zhang G, Song G, et al. Integrated analysis of genes associated with poor prognosis of patients with colorectal cancer liver metastasis. Oncotarget 2017; 8: 25500-12.

Zhu Y-H, Yang F, Zhang S-S, Zeng T-T, Xie X, Guan X-Y. High expression of biglycan is associated with poor prognosis in patients with esophageal squamous cell carcinoma. Int J Clin Exp Pathol 2013; 6: 2497-505.

Lagadec C, Vlashi E, Frohnen P, Alhiyari Y, Chan M, Pajonk F. The RNA-binding protein Musashi-1 regulates proteasome subunit expression in breast cancer- and glioma-initiating cells. Stem Cells 2014; 32: 135-44.

Yue P, Lopez-Tapia F, Paladino D, et al. Hydroxamic acid and benzoic acid-based STAT3 inhibitors suppress human glioma and breast cancer phenotypes In Vitro and In Vivo. Cancer Res 2016; 76: 652-63.

Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013; 499: 214-8.

Lu L, Zeng J. Evaluation of K-Ras and p53 expression in pancreatic adenocarcinoma using the cancer genome atlas. PLoS One 2017; 12: e0181532.

Schaefer L, Gröne HJ, Raslik I, et al. Small proteoglycans of normal adult human kidney: distinct expression patterns of decorin, biglycan, fibromodulin, and lumican. Kidney Int 2000; 58: 1557-68.

Pinho SS, Reis CA. Glycosylation in cancer: mechanisms and clinical implications. Nat Rev Cancer 2015; 15: 540-55.

Iozzo RV, Chakrani F, Perrotti D, et al. Cooperative action of germ-line mutations in decorin and p53 accelerates lymphoma tumorigenesis. Proc Natl Acad Sci USA 1999; 96: 3092-7.

Matullo G, Guarrera S, Carturan S, et al. DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case-control study. Int J Cancer 2001; 92: 562-7.

Winsey SL, Haldar NA, Marsh HP, et al. A Variant within the DNA repair gene XRCC3 is associated with the development of melanoma skin cancer. Cancer Res 2000; 60: 5612-6.

Weber CK, Sommer G, Michl P, et al. Biglycan Is Overexpressed in pancreatic cancer and induces G1-Arrest in pancreatic cancer cell lines. Gastroenterology 2001; 121: 657-67.

Köninger J, Giese NA, di Mola FF, et al. Overexpressed decorin in pancreatic cancer: potential tumor growth inhibition and attenuation of chemotherapeutic action. Clin Cancer Res 2004; 10: 4776-83.

Niedworok C, Röck K, Kretschmer I, et al. Inhibitory role of the small leucine-rich proteoglycan biglycan in bladder cancer. PLoS One 2013; 8: e80084.

Bischof AG, Yüksel D, Mammoto T, Mammoto A, Krause S, Ingber DE. Breast cancer normalization induced by embryonic mesenchyme is mediated by extracellular matrix biglycan. Integr Biol 2013; 5: 1045-56.

Goldoni S, Seidler DG, Heath J, et al. An antimetastatic role for decorin in breast cancer. Am J Pathol 2008; 173: 844-55.

Svensson KJ, Christianson HC, Kucharzewska P, et al. Chondroitin sulfate expression predicts poor outcome in breast cancer. Int J Oncol 2011; 39: 1421-8.

Vallen MJE, Massuger LFAG, ten Dam GB, Bulten J, van Kuppevelt TH. Highly sulfated chondroitin sulfates, a novel class of prognostic biomarkers in ovarian cancer tissue. Gynecol Oncol 2012; 127: 202-9.

Momose T, Yoshimura Y, Harumiya S, et al. Chondroitin sulfate synthase 1 expression is associated with malignant potential of Soft tissue sarcomas with myxoid substance. Hum Pathol 2016; 50: 15-23.

Kalathas D, Theocharis DA, Bounias D, et al. Chondroitin synthases i, ii, iii and chondroitin sulfate glucuronyltransferase expression in colorectal cancer. Mol Med Rep 2011; 4: 363-8.

Dennis JW, Pawling J, Cheung P, Partridge E, Demetriou M. UDP-N-acetylglucosamine:alpha-6-D-mannoside beta1,6 N-acetylglucosaminyltransferase V (Mgat5) deficient mice. Biochim Biophys Acta 2002; 1573: 414-22.

Hofree M, Shen JP, Carter H, Gross A, Ideker T. Network-based stratification of tumor mutations. Nat Methods 2013; 10: 1108-15.

Dalziel M, Crispin M, Scanlan CN, Zitzmann N, Dwek RA. Emerging principles for the therapeutic exploitation of glycosylation. Science 2014; 343: 1235681.

Julien S, Picco G, Sewell R, et al. Sialyl-Tn vaccine induces antibody-mediated tumour protection in a relevant murine model. Br J Cancer 2009; 100: 1746-54.

English NM, Lesley JF, Hyman R. Site-Specific de-N-glycosylation of CD44 can activate hyaluronan binding, and cd44 activation states show distinct threshold densities for hyaluronan binding. Cancer Res 1998; 58: 3736-42.