Mechanisms and Pathways to Biomarkers and Chemotherapeutic Targets |
109 |
bears special significance in light of the fact that Src phosphorylates Cas to promote tumor cell growth and migration.88–94 Cas is an important component
of the focal adhesion complex signaling network,95 which also includes FAK, Grb2, Shc and paxillin.96,97 After phosphorylation by Src, Cas can bind to other proteins including Crk, PI-3-kinase, Nck and PLCg.98–100
In addition to genes transcribed into mRNA, alterations in miRNA expression have also been associated with contact normalization. These miRNAs have the ability to downregulate the expression of target genes by binding to the 30 untranslated region of mRNA.101 Some miRNA species, called
‘‘oncomirs’’, can a ect tumor formation by targeting gene products that a ect cell growth and migration.102,103 Analysis of miRNA expression in transformed,
non-transformed and contact normalized cells suggests that approximately 1% of these oncomirs can be a ected by contact normalization.31
miR-126 provides an example of an oncomir a ected during contact normalization. Interestingly, miR-126 can suppress the expression of Crk, which is a focal adhesion adaptor protein that cooperates with Cas to promote non-anchored tumor cell growth and migration. Some transformed cells express lower levels of miR-126 and higher levels of Crk than non-transformed or contact normalized cells. Moreover, miR-126 expression suppresses Crk expression and inhibits transformed cell growth and migration. Evidently, contact normalization induces miR-126 to target Crk production and inhibit the migration of neighboring transformed cells.31
6.6 Contact Normalization and Tumor Promoters
In contrast to tumor suppressors, non-transformed cells can inhibit the expression of specific tumor promoters, including Pdpn, Vegfr2 and Tmem163, in neighboring cancer cells. For example, we have recently reported that Src utilizes Pdpn to promote tumor cell migration, and that Pdpn expression is inhibited in contact normalized cells.
Tmem163 is predicted to form (Figure 6.1) an integral membrane protein with six transmembrane helices. Interestingly, elevated Tmem163 mRNA expression has also been found in papillary thyroid carcinoma (GEO DataSet Browser: GDS1732/1552626_a_at/Tmem163/homo sapiens) and nodular lym- phocyte-predominant Hodgkin’s lymphoma.104 Moreover, recent experiments indicate that Tmem163 can significantly increase cell growth and migration.30
Vegfr2, also called kinase insert domain receptor (Kdr), clearly promotes
tumor cell migration and angiogenesis, and is already a prime target for chemotherapy.105,106 For example, inhibitors have been generated to target in
order to prevent VEGF signaling and suppress angiogenesis required for malignant tumor growth.107
Pdpn belongs to the type-I transmembrane sialo-mucin-like glycoprotein, which consists of an ectodomain having abundant O-glycosylation sites, a
highly hydrophobic membrane spanning domain and a short intracellular domain of nine amino acids.108,109 Increased Pdpn expression has been
110 |
|
Chapter 6 |
|
|
|
Pdpn |
|
connexins |
|
Vegfr2 |
|
cadherins |
Tmem163 |
||
Fhl1 |
Fhl1 |
|
|
Sdpr |
Sdpr |
|
|
miR126 |
miR126 |
|
|
Crk |
Crk |
Crk |
|
Cas Src |
|||
Cas Src |
Cas Src |
||
Nontransformed |
Contact Normalized |
Malignant |
Figure 6.1 Schematic of some e ectors of contact normalization. Non-transformed cells utilize junctional communication to induce the expression of tumor suppressors (e.g. miR-126, Fhl1 and Sdpr) and normalize the growth and morphology of neighboring transformed cells. Tumor cells must escape this form of growth control to express tumor promoters (e.g. Tmem163, Pdpn and Vegfr2) and realize their malignant growth potential.
reported in several human cancers including angiosarcoma, mesothelioma,
squamous cell carcinoma of oral cavity, lung, skin, head and neck, glioma and gastrointestinal stromal tumors.108,110–114
Like Vegfr2, Pdpn also holds promise as a chemotherapeutic target. Antibodies against Pdpn and a potential Pdpn ligand (tetraspanin CD9) can inhibit
lung metastasis of Chinese hamster ovary and human sarcoma cells transfected with human podoplanin.115,116 Another strategy may be to block glycosylation-
dependent interactions of podoplanin with ligands like Galectin-8.117
6.7 Conclusions
A major problem with most current cancer treatments is that they are not very specific for cancer cells. Anthracyclines, taxanes and nucleotide analogs (such as doxorubicin, taxol and fluorouracil) target dividing cells. This general
toxicity doxorubicin, taxol and fluorouracil causes significant damage to many organs including those of the digestive and immune systems.118–120 The success
of more targeted therapies demonstrates the utility of targeting specific proteins
expressed by malignant cells. These reagents include monoclonal antibodies that target Vegf and other oncogenic kinase activities.105,106,121,122 Under-
standing how contact normalization operates activities can provide us with helpful information on how tumors first form. Identifying key players in this process could provide more specific biomarkers and chemotherapeutic targets for malignant and metastatic cancers.
References
1. Cancer Facts and Figures 2009, American Cancer Society, Atlanta, 2009. 2. C. R. Holst, G. J. Nuovo, M. Esteller, K. Chew, S. B. Baylin,
J. G. Herman and T. D. Tlsty, Cancer Res., 2003, 63, 1596.
Mechanisms and Pathways to Biomarkers and Chemotherapeutic Targets |
111 |
3.R. B. Roberts, L. Min, M. K. Washington, S. J. Olsen, S. H. Settle,
R.J. Co ey and D. W. Threadgill, Proc. Natl. Acad. Sci. U.S.A., 2002, 99, 1521.
4.G. P. Dotto, R. A. Weinberg and A. Ariza, Proc. Natl. Acad. Sci. U.S.A., 1988, 85, 6389.
5.M. A. Nelson, B. W. Futscher, T. Kinsella, J. Wymer and G. T. Bowden,
Proc. Natl. Acad. Sci. U.S.A., 1992, 89, 6398.
6.A. B. Glick and S. H. Yuspa, Semin. Cancer Biol., 2005, 15, 75–83.
7.H. Rubin, Adv. Cancer Res., 2008, 100, 159.
8.H. Rubin, Proc. Natl. Acad. Sci. U.S.A., 2008, 105, 6215.
9.M. G. Stoker, M. Shearer and C. O’Neill, J. Cell Sci., 1966, 1, 297.
10.T. Enomoto and H. Yamasaki, Cancer Res., 1984, 44, 5200.
11.C. B. Esinduy, C. C. Chang, J. E. Trosko and R. J. Ruch, Carcinogenesis, 1995, 16, 915.
12.M. Bignami, S. Rosa, S. A. La Rocca, G. Falcone and F. Tato, Oncogene, 1988, 2, 509.
13.M. Bignami, S. Rosa, G. Falcone, F. Tato, F. Katoh and H. Yamasaki,
Mol. Carcinog., 1988, 1, 67.
14.W. Martin, G. Zempel, D. Hulser and K. Willecke, Cancer Res., 1991, 51, 5348.
15.G. S. Goldberg, K. D. Martyn and A. F. Lau, Mol. Carcinog., 1994, 11, 106.
16.B. Mintz and K. Illmensee, Proc. Natl. Acad. Sci. U.S.A., 1975, 72, 3585.
17.A. Javaherian, M. Vaccariello, N. E. Fusenig and J. A. Garlick, Cancer Res., 1998, 58, 2200.
18.H. R. Herschman and D. W. Brankow, Science, 1986, 234, 1385.
19.M. Aszterbaum, J. Epstein, A. Oro, V. Douglas, P. E. LeBoit, M. P. Scott and E. Epstein, Nat. Med., 1999, 5, 1285.
20.M. Widschwendter, J. Berger, G. Daxenbichler, E. Muller-Holzner,
A.Widschwendter, A. Mayr, C. Marth and A. G. Zeimet, Cancer Res., 1997, 57, 4158.
21.G. N. Naumov, I. C. MacDonald, P. M. Weinmeister, N. Kerkvliet,
K.V. Nadkarni, S. M. Wilson, V. L. Morris, A. C. Groom and
A.F. Chambers, Cancer Res., 2002, 62, 2162.
22.G. N. Naumov, J. L. Townson, I. C. MacDonald, S. M. Wilson,
V.H. Bramwell, A. C. Groom and A. F. Chambers, Breast Cancer Res. Treat., 2003, 82, 199.
23.G. N. Naumov, E. Bender, D. Zurakowski, S. Y. Kang, D. Sampson,
E.Flynn, R. S. Watnick, O. Straume, L. A. Akslen, J. Folkman and
N.Almog, J. Natl. Cancer Inst., 2006, 98, 316.
24.A. S. Jonason, S. Kunala, G. J. Price, R. J. Restifo, H. M. Spinelli,
J.A. Persing, D. J. Le ell, R. E. Tarone and D. E. Brash, Proc. Natl. Acad. Sci. U.S.A., 1996, 93, 14025.
25.J. S. Bertram, Cancer Res., 1977, 37, 514.
26.P. P. Mehta, J. S. Bertram and W. R. Loewenstein, Cell, 1986, 44, 187.
27.H. Hennings, V. A. Robinson, D. M. Michael, G. R. Pettit, R. Jung and
S.H. Yuspa, Cancer Res., 1990, 50, 4794.
112 |
Chapter 6 |
28.M. Vaccariello, A. Javaherian, Y. Wang, N. E. Fusenig and J. A. Garlick,
J.Invest. Dermatol., 1999, 113, 384.
29.D. B. Alexander, H. Ichikawa, J. F. Bechberger, V. Valiunas, M. Ohki,
C.C. Naus, T. Kunimoto, H. Tsuda, W. T. Miller and G. S. Goldberg, Cancer Res., 2004, 64, 1347.
30.Y. Shen, C. S. Chen, H. Ichikawa and G. S. Goldberg, J. Biol. Chem., 2010, 285, 9649.
31.X. Li, Y. Shen, H. Ichikawa, T. Antes and G. S. Goldberg, Oncogene, 2009, 28, 4272.
32.X. Li, Z. Jia, Y. Shen, H. Ichikawa, J. Jarvik, R. G. Nagele and
G.S. Goldberg, Cancer Sci., 2008, 99, 1326.
33.Y. Shen, Z. Jia, R. G. Nagele, H. Ichikawa and G. S. Goldberg, Cancer Res., 2006, 66, 1543.
34.J. Lilien and J. Balsamo, Curr. Opin. Cell Biol., 2005, 17, 459.
35.R. B. Irby and T. J. Yeatman, Cancer Res., 2002, 62, 2669.
36.M. J. Wheelock and K. R. Johnson, Ann. Rev. Cell Dev. Biol., 2003, 19, 207.
37.J. Rios-Doria, K. C. Day, R. Kuefer, M. G. Rashid, A. M. Chinnaiyan,
M.A. Rubin and M. L. Day, J. Biol. Chem., 2003, 278, 1372.
38.R. A. Pagliarini and T. Xu, Science, 2003, 302, 1227.
39.F. Wang, R. K. Hansen, D. Radisky, T. Yoneda, M. H. Barcellos-Ho ,
O.W. Petersen, E. A. Turley and M. J. Bissell, J. Natl. Cancer Inst., 2002, 94, 1494.
40.A. Margulis, F. Andriani, N. Fusenig, K. Hashimoto, Y. Hanakawa and
J.A. Garlick, J. Invest. Dermatol., 2003, 121, 1182.
41.M. Guarino, Int. J. Biochem. Cell Biol., 2007, 39, 2153.
42.L. D. Derycke and M. E. Bracke, Int. J. Dev. Biol., 2004, 48, 463.
43.T. Genda, M. Sakamoto, T. Ichida, H. Asakura and S. Hirohashi, Lab. Invest., 2000, 80, 387.
44.M. Hamaguchi, N. Matsuyoshi, Y. Ohnishi, B. Gotoh, M. Takeichi and
Y.Nagai, EMBO J., 1993, 12, 307.
45.H. Takeda, A. Nagafuchi, S. Yonemura, S. Tsukita, J. Behrens,
W.Birchmeier and S. Tsukita, J. Cell Biol., 1995, 131, 1839.
46.K. Reiss, T. Maretzky, A. Ludwig, T. Tousseyn, B. De Strooper,
D.Hartmann and P. Saftig, EMBO J., 2005, 24, 742.
47.T. Kashima, K. Nakamura, J. Kawaguchi, M. Takanashi, T. Ishida,
H.Aburatani, A. Kudo, M. Fukayama and A. E. Grigoriadis, Int.
J.Cancer, 2003, 104, 147.
48.S. A. Peralta, K. A. Knudsen, A. Tecson-Miguel, F. X. McBrearty,
A.C. Han and H. Salazar, Hum. Pathol., 1997, 28, 734.
49.K. Asano, O. Kubo, Y. Tajika, K. Takakura and S. Suzuki, Neurosurg. Rev., 2000, 23, 39.
50.N. Shinoura, N. E. Paradies, R. E. Warnick, H. Chen, J. J. Larson,
J.J. Tew, M. Simon, R. A. Lynch, Y. Kanai and S. Hirohashi, Br. J. Cancer, 1995, 72, 627.
51.S. Utsuki, Y. Sato, H. Oka, B. Tsuchiya, S. Suzuki and K. Fujii,
J.Neurooncol., 2002, 57, 187.
Mechanisms and Pathways to Biomarkers and Chemotherapeutic Targets |
113 |
52.A. Harris, Quarterly Rev. Biophys., 2001, 34, 325.
53.G. Sohl and K. Willecke, Cardiovasc. Res., 2004, 62, 228.
54.N. M. Kumar and N. B. Gilula, Cell, 1996, 84, 381.
55.G. S. Goldberg, P. D. Lampe and B. J. Nicholson, Nat. Cell Biol., 1999, 1, 457.
56.G. S. Goldberg, A. P. Moreno and P. D. Lampe, J. Biol. Chem., 2002, 277, 36725.
57.D. B. Alexander and G. S. Goldberg, Curr. Med. Chem., 2003, 10, 2045.
58.C. C. Naus and D. W. Laird, Nat. Rev. Cancer, 2010, 10, 435.
59.D. Zhu, S. Caveney, G. M. Kidder and C. C. Naus, Proc. Natl. Acad. Sci.
U.S.A., 1991, 88, 1883.
60. D. W. Laird, P. Fistouris, G. Batist, L. Alpert, H. T. Huynh,
G.D. Carystinos and M. A. Alaoui-Jamali, Cancer Res., 1999, 59, 4104.
61.K. K. Hirschi, C. E. Xu, T. Tsukamoto and R. Sager, Cell Growth Di er., 1996, 7, 861.
62.C. C. Naus, G. S. Goldberg and W. C. Sin, in Gap Junctions in Development and Disease, ed. E. Winterhager, Springer-Verlag, New York, 2005.
63.C. C. Naus, Can. J. Physiol. Pharmacol., 2002, 80, 136.
64.R. P. Huang, Y. Fan, M. Z. Hossain, A. Peng, Z. L. Zeng and
A.L. Boynton, Cancer Res., 1998, 58, 5089.
65.H. Qin, Q. Shao, H. Curtis, J. Galipeau, D. J. Belliveau, T. Wang,
M.A. Alaoui-Jamali and D. W. Laird, J. Biol. Chem., 2002, 277, 29132.
66.J. E. Strickland, M. Ueda, H. Hennings and S. H. Yuspa, Cancer Res., 1992, 52, 1439.
67.D. Zhu, G. M. Kidder, S. Caveney and C. C. Naus, Proc. Natl. Acad. Sci. U.S.A., 1992, 89, 10218.
68.W. Zhang, W. T. Couldwell, M. F. Simard, H. Song, J. H. Lin and
M.Nedergaard, Cancer Res., 1999, 59, 1994.
69.V. Valiunas, J. F. Bechberger, C. C. Naus, P. R. Brink and G. S. Goldberg,
Biochem. Biophys. Res. Commun., 2005, 333, 174.
70.P. D. Lampe and A. F. Lau, Int. J. Biochem. Cell Biol., 2004, 36, 1171.
71.R. Lin, B. J. Warn-Cramer, W. E. Kurata and A. F. Lau, J. Cell Biol., 2001, 154, 815.
72.G. S. Goldberg and A. F. Lau, Biochem. J., 1993, 295(3), 735.
73.K. I. Swenson, H. Piwnica-Worms, H. McNamee and D. L. Paul, Cell Regul., 1990, 1, 989.
74.R. Lin, K. D. Martyn, C. V. Guyette, A. F. Lau and B. J. Warn-Cramer,
Cell Commun. Adhes., 2006, 13, 199.
75.L. Zhou, E. M. Kasperek and B. J. Nicholson, J. Cell Biol., 1999, 144, 1033.
76.G. M. O’Neill, S. J. Fashena and E. A. Golemis, Trends Cell Biol., 2000, 10, 111.
77.M. Pahujaa, M. Anikin and G. S. Goldberg, Exp. Cell Res., 2007, 313, 4083.
78.Y. Shen, P. R. Khusial, X. Li, H. Ichikawa, A. P. Moreno and
G.S. Goldberg, J. Biol. Chem., 2007, 282, 18914.
114 |
Chapter 6 |
79.L. A. Jansen, M. Mesnil and W. M. Jongen, Carcinogenesis, 1996, 17, 1527.
80.R. W. Keane, P. P. Mehta, B. Rose, L. S. Honig, W. R. Loewenstein and
U.Rutishauser, J. Cell Biol., 1988, 106, 1307.
81.J. Kamei, T. Toyofuku and M. Hori, Biochem. Biophys. Res. Commun., 2003, 312, 380.
82.H. Y. Huang, R. Li, Q. Sun, J. Wang, P. Zhou, H. Han and W. H. Zhang,
Yi Chuan Xue Bao, 2002, 29, 953.
83.S. Brown, M. J. McGrath, L. M. Ooms, R. Gurung, M. M. Maimone and
C.A. Mitchell, J. Biol. Chem., 1999, 274, 27083.
84.Y. Taniguchi, T. Furukawa, T. Tun, H. Han and T. Honjo, Mol. Cell Biol., 1998, 18, 644.
85.H. Qin, D. Du, Y. Zhu, J. Li, L. Feng, Y. Liang and H. Han, FEBS Lett., 2005, 579, 1220.
86.S. Gustincich, P. Vatta, S. Goruppi, M. Wolf, S. Saccone, V. G. Della,
M.Baggiolini and C. Schneider, Genomics, 1999, 57, 120.
87.S. Gustincich and C. Schneider, Cell Growth Di er., 1993, 4, 753.
88.H. Honda, H. Oda, T. Nakamoto, Z. Honda, R. Sakai, T. Suzuki,
T.Saito, K. Nakamura, K. Nakao, T. Ishikawa, M. Katsuki, Y. Yazaki and H. Hirai, Nat. Genet., 1998, 19, 361.
89.J. Huang, H. Hamasaki, T. Nakamoto, H. Honda, H. Hirai, M. Saito,
T.Takato and R. Sakai, J. Biol. Chem., 2002, 277, 27265.
90.S. Y. Cho and R. L. Klemke, J. Cell Biol., 2000, 149, 223–236.
91.R. L. Klemke, J. Leng, R. Molander, P. C. Brooks, K. Vuori and
D.A. Cheresh, J. Cell Biol., 1998, 140, 961.
92.J. Brabek, S. S. Constancio, N. Y. Shin, A. Pozzi, A. M. Weaver and
S.K. Hanks, Oncogene, 2004, 23, 7406.
93.N. Y. Shin, R. S. Dise, J. Schneider-Mergener, M. D. Ritchie,
D.M. Kilkenny and S. K. Hanks, J. Biol. Chem., 2004, 279, 38331.
94.G. S. Goldberg, D. B. Alexander, P. Pellicena, Z. Y. Zhang, H. Tsuda and
W.T. Miller, J. Biol. Chem., 2003, 278, 46533.
95.A. H. Bouton, R. B. Riggins and P. J. Bruce-Staskal, Oncogene, 2001, 20, 6448.
96.D. D. Schlaepfer, C. R. Hauck and D. J. Sieg, Prog. Biophys. Mol. Biol., 1999, 71, 435.
97.D. J. Sieg, C. R. Hauck and D. D. Schlaepfer, J. Cell Sci., 1999, 112(16), 2677.
98.R. Sakai, A. Iwamatsu, N. Hirano, S. Ogawa, T. Tanaka, H. Mano,
Y.Yazaki and H. Hirai, EMBO J., 1994, 13, 3748.
99.M. R. Burnham, M. T. Harte, A. Richardson, J. T. Parsons and
A.H. Bouton, Oncogene, 1996, 12, 2467.
100.K. Vuori, H. Hirai, S. Aizawa and E. Ruoslahti, Mol. Cell Biol., 1996, 16, 2606.
101.D. P. Bartel, Cell, 2009, 136, 215–233.
102.C. Caldas and J. D. Brenton, Nat. Med., 2005, 11, 712.
103.G. A. Calin and C. M. Croce, Cancer Res., 2006, 66, 7390.
Mechanisms and Pathways to Biomarkers and Chemotherapeutic Targets |
115 |
104.V. Brune, E. Tiacci, I. Pfeil, C. Doring, S. Eckerle, C. J. van Noesel,
W.Klapper, B. Falini, A. von Heydebreck, D. Metzler, A. Brauninger,
M.L. Hansmann and R. Kuppers, J. Exp. Med., 2008, 205, 2251.
105.J. Bange, E. Zwick and A. Ullrich, Nat. Med., 2001, 7, 548.
106.M. Los, J. M. Roodhart and E. E. Voest, Oncologist, 2007, 12, 443.
107.S. Schenone, F. Bondavalli and M. Botta, Curr. Med. Chem., 2007, 14, 2495.
108.E. Martin-Villar, F. G. Scholl, C. Gamallo, M. M. Yurrita, M. MunozGuerra, J. Cruces and M. Quintanilla, Int. J. Cancer, 2005, 113, 899.
109.M. K. Kaneko, Y. Kato, T. Kitano and M. Osawa, Gene, 2006, 378, 52.
110.S. Breiteneder-Gele , A. Soleiman, H. Kowalski, R. Horvat, G. Amann,
E.Kriehuber, K. Diem, W. Weninger, E. Tschachler, K. Alitalo and
D.Kerjaschki, Am. J. Pathol., 1999, 154, 385.
111.N. Kimura and I. Kimura, Pathol. Int., 2005, 55, 83.
112.A. Wicki and G. Christofori, Br. J. Cancer, 2007, 96, 1.
113.A. Wicki, F. Lehembre, N. Wick, B. Hantusch, D. Kerjaschki and
G.Christofori, Cancer Cell, 2006, 9, 261.
114.Y. Kato, M. Kaneko, M. Sata, N. Fujita, T. Tsuruo and M. Osawa,
Tumour Biol., 2005, 26, 195.
115.Y. Kato, M. K. Kaneko, A. Kunita, H. Ito, A. Kameyama, S. Ogasawara,
N.Matsuura, Y. Hasegawa, K. Suzuki-Inoue, O. Inoue, Y. Ozaki and
H.Narimatsu, Cancer Sci., 2008, 99, 54.
116.Y. Nakazawa, S. Sato, M. Naito, Y. Kato, K. Mishima, H. Arai,
T.Tsuruo and N. Fujita, Blood, 2008, 112, 1730.
117.L. N. Cueni and M. Detmar, Exp. Cell Res., 2009, 315, 1715.
118.J. Schwartz, Am. J. Health Syst. Pharm., 2009, 66, S3.
119.G. N. Hortobagyi, J. Natl. Cancer Inst. Monogr., 2001, 30, 72.
120.D. Robson and S. Verma, Oncologist, 2009, 14, 950.
121.E. R. Wood, A. T. Truesdale, O. B. McDonald, D. Yuan, A. Hassell,
S.H. Dickerson, B. Ellis, C. Pennisi, E. Horne, K. Lackey, K. J. Alligood,
D.W. Rusnak, T. M. Gilmer and L. Shewchuk, Cancer Res., 2004, 64, 6652.
122.M. H. Nelson and C. R. Dolder, Ann. Pharmacother., 2006, 40, 261.