Abstract
The involvement of Mts1(S100A4), a small Ca2+-binding protein in tumor progression and metastasis had been demonstrated. However, the mechanism by which mts1(S100A4) promoted metastasis had not been identified. Here we demonstrated that Mts1(S100A4) had significant stimulatory effect on the angiogenesis. We detected high incidence of hemangiomas – benign tumors of vascular origin in aged transgenic mice ubiquitously expressing the mts1(S100A4) gene. Furthermore, the serum level of the Mts1(S100A4) protein increased with ageing. Tumors developed in Mts1-transgenic mice revealed an enhanced vascular density. We showed that an oligomeric, but not a dimeric form of the Mts1(S100A4) protein was capable of enhancing the endothelial cell motility in vitro and stimulate the corneal neovascularization in vivo. An oligomeric fraction of the protein was detected in the conditioned media as well as in human serum. The data obtained allowed us to conclude that mts1(S100A4) might induce tumor progression via stimulation of angiogenesis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ambartsumian N, Grigorian M, Larsen I, Karlstrom O, Sidenius N, Rugaard J, Georgiev G, Lukanidin E . 1996 Oncogene 13: 1621–1630
Ambartsumian N, Klingelhöfer J, Grigorian M, Karlstrøm O, Sidenius N, Georgiev G, Lukanidin E . 1999 Invasion and Metastasis 18: 96–104
Barraclough R . 1998 Biochim. Biophys. Acta. 1448: 190–199
Booth C, Sundberg JP . 1995 Lab. Anim. Sci. 45: 497–502
Cao Y, Cao Y, Linden P, Farnebo J, Cao R, Eriksson A, Kumar V, Qi J-H, Claesson-Welsh L, Alitalo K . 1998 Proc. Natl. Acad. Sci. USA 95: 14389–14394
Cao Y, Chen C, Weatherbee JA, Tsang M, Folkman J . 1995 J. Exp. Med. 182: 2069–2077
Carreira CM, La Vallee T, Tarantini F, Jackson A, Lathrop JT, Hampton B, Burgess WH, Maciag T . 1998 J. Biol. Chem. 237: 22224–22231
Davies M, Rudland P, Robertson L, Parry E, Jolicoeur P, Barraclough R . 1996 Oncogene 13: 1631–1637
Donato R . 1999 Biochim. Biophys. Acta. 1450: 191–231
Duarte WR, Iimura T, Takenaga K, Ohya K, Ishikawa I, Kasugai S . 1999 Biochem. Biophys. Res. Commun. 255: 416–420
Dunn GA . 1983 Agents Actions Suppl. 12: 14–33
Ebralidze A, Tulchinsky E, Grigorian M, Afanasyeva A, Senin V, Revazova E, Lukanidin E . 1989 Genes Dev. 3: 1086–1093
Ellis LM, Fidler IJ . 1996 Eur. J. of Cancer 32A: 2451–2460
Ferrara N, Chen H, Davis-Smyth T, Gerber HP, Nguyen TN, Peers D, Chisholm V, Hillan KJ, Schwall RH . 1998 Nature Med. 4: 336–340
Folkman J . 1971 N. Engl. J. Med. 285: 1182–1186
Folkman J, Watson K, Ingberg D, Hanahan D . 1989 Nature 339: 58–61
Ford HL, Zain SB . 1995 Oncogene 10: 1597–1605
Frith C, Wiley L . 1982 Lab. Anim. Sci. 32: 157–162
Geszy C . 1996 Biochim.Biophys. Acta 1313: 246–252
Gimbrone M, Leapman S, Cotran R, Folkman J . 1972 J. Exp. Med. 136: 261–276
Goldman CK, Kendall RL, Cabrera G, Soroceanu L, Heike Y, Gillespie GY, Siegal GP, Mao X, Bett AJ, Huckle WR, Thomas KA, Curiel DT . 1998 Proc. Nat. Acad. Sci. USA 95: 8795–8800
Gossen M, Freundlieb S, Bender G, Muller G, Hillen W, Bujard H . 1995 Science 268: 1766
Gossen M, Bujard H . 1992 Proc. Natl. Acad. Sci. USA 89: 5547–5551
Grigorian M, Tulchinsky E, Burrone O, Tarabykina S, Georgiev G, Lukanidin E . 1994 Electrophoresis 15: 463–468
Grigorian M, Andresen S, Tulchinsky E, Kriajevska M, Carlberg C, Kruse C, Cohn M, Ambartsumian N, Christensen A, Georgiev G, Selivanova G, Lukanidin E . 2001 J. Biol. Chem. 255: 22699–22708
Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM . 1999 Cell 97: 889–901
Jinquan T, Vorum H, Larsen CG, Madsen HP, Rasmussen HH, Gesser B, Etzerodt M, Honore B, Celis J, Thestrup-Pedersen K . 1996 J. Invest. Dermatol. 107: 5–10
Kligman D, Hilt DC . 1988 Trends. Biochem. Sci. 13: 437–443
Komada TR, Araki K, Nakatani I, Yada M, Tanaka T . 1996 Biochem. Biophys. Res. Comm. 220: 871–874
Kriajevska MV, Cardenas MN, Grigorian MS, Ambartsumian NS, Georgiev GP, Lukanidin E . 1994 J. Biol. Chem. 269: 19679–19682
Kumar R, Yoneda J, Bucana CD, Fidler I . 1998 Int. J. Oncology 12: 749–757
Kustikova O, Kramerov D, Grigorian M, Berezin V, Bock E, Lukanidin E, Tulchinsky E . 1998 Mol. Cell. Biol. 18: 7095–7105
Lin P, Buxton JA, Acheson A, Radziejewski C, Maisonpierre PC, Yancopoulos GD, Channon KM, Hale LP, Dewhirst MW, George SE, Peters KG . 1998 Proc. Nat. Acad. Sci. USA 95: 8829–8834
Liotta L, Kleinerman J, Saidel F . 1974 Cancer. Res. 34: 997–1004
Lukanidin E, Georgiev G . 1996 In Current Topics in Microbiology and Immunology (Eds. Gunter, U. and Birchmeier, W Springer-Verlag, Heidelberg 213/II: pp. 171–195
Markovitz D, Goff S, Bank A . 1988 J. Virol. 62: 1120–1124
Novitskaya V, Grigorian M, Kriajevska M, Tarabykina S, Bronstein I, Berezin V, Bock E, Lukanidin E . 2000 J. Biol. Chem. 275: 41278–41286
Peters RL, Rabstein LS, Spahn GJ, Madison RM, Huebner RJ . 1972 Int. J. Cancer 10: 273–282
Polverini PJ . 1996 Eur. J. Cancer 32A: 2430–2437
Rudland PS, Platt-Higgins A, Renshaw C, West CR, Winstanley JH, Robertson L, Barraclough R . 2000 Cancer Res. 60: 1595–1603
Schafer BW, Heizmann CW . 1996 TIBS 21: 134–140
Senin VM, Ivanov AV, Afanasjeva AV, Kiseleva NS . 1983 Exp. Oncology, USSR 5: 35–39
Senin VM, Ivanov AM, Afanasjeva AV, Buntsevich AM . 1984 Vestnik USSR Acad. Med. Sci. 5: 85–91
Skobe M, Rockwell P, Goldstein N, Vosseler S, Fusenig N . 1997 Nature Medicine 3: 1222–1227
Takenaga K, Nakamura Y, Endo H, Sakiyama S . 1994 Jpn. J. Cancer Res. 85: 831–839
Takenaga K, Nakanishi H, Wada K, Suzuki M, Matsuzaki O, Matsuura A, Endo H . 1997 Clin. Cancer Res. 12: 2309–2316
Taraboletti G, Roberts D, Liotta L . 1987 J. Cell Biol. 105: 2409–2415
Walmod PS, Foley A, Berezin A, Ellerbeck U, Nau H, Bock E, Berezin V . 1998 Cell Motil. Cytoskeleton 40: 220–237
Watanabe Y, Usuda N, Minami H, Morita T, Tsugane S, Ishikawa R, Kohama K, Tomoda Y, Hidaka H . 1993 FEBS Lett. 324: 51–55
Watanabe Y, Usuda N, Tsugane S, Kobayashi R, Hidaki H . 1992 J. Biol. Chem. 267: 17136–17140
Weidner N . 1995 Am. J. Pathol. 147: 9–15
Winningham-Major F, Staecker JL, Barger SW, Coats S, Van Eldik LJ . 1989 J. Cell. Biol. 109: 3063–3071
Zetter BR . 1998 Annu. Rev. Med. 49: 407–424
Zimmer DB, Cornwall H, Landar A, Song W . 1995 Brain Res. Bull. 37: 417–429
Acknowledgements
We thank IF Larsen, B Kaas, I Skibshøj and D Lützhøft for careful technical assistance. This work was supported by grants from Danish Cancer Society, Danish Medical Research Council, Dansk Kræftforskningsfond, INTAS Programme and the Lundbeck Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ambartsumian, N., Klingelhöfer, J., Grigorian, M. et al. The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor. Oncogene 20, 4685–4695 (2001). https://doi.org/10.1038/sj.onc.1204636
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204636
Keywords
This article is cited by
-
Inhibition of TLR4/NF-κB pathway and endoplasmic reticulum stress by overexpressed S100A4 ameliorates retinal ischemia-reperfusion injury of mice
Molecular Neurobiology (2023)
-
A functional role of S100A4/non-muscle myosin IIA axis for pro-tumorigenic vascular functions in glioblastoma
Cell Communication and Signaling (2022)
-
The role of S100A4 for bone metastasis in prostate cancer cells
BMC Cancer (2021)
-
iTRAQ-based quantitative proteomic analysis of thoracic aortas from adult rats born to preeclamptic dams
Clinical Proteomics (2021)
-
Central nervous system involvement in rheumatoid arthritis: possible role of chronic inflammation and tnf blocker therapy
Acta Neurologica Belgica (2020)