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Metastatic squamous cell carcinoma cells that overexpress c-Met exhibit enhanced angiogenesis factor expression, scattering and metastasis in response to hepatocyte growth factor

Oncogene volume 23, pages 6199–6208 (2004)Cite this article

Abstract

We previously performed gene expression profiling in a multistep squamous cell carcinoma (SCC) progression model, and identified growth-regulated oncogene-1 (Gro-1/KC) as a factor that contributes to enhanced angiogenesis, tumorigenesis and metastasis. In the present study, we explored molecular pathways coactivated with Gro-1/KC, and identified a transcript that encodes c-Met, the receptor for hepatocyte growth factor/scatter factor (HGF). Northern, Western blot, and immunohistochemical analyses confirm that expression of c-Met mRNA and protein is increased with SCC progression. In vitro, HGF preferentially promoted scattering in the metastatic LY-1 and LY-2 lines, and enhanced angiogenesis factors Gro-1/KC and vascular endothelial growth factor (VEGF) production by all tumor cell lines. In vivo, tumor growth and lung metastasis were promoted by transfection and overexpression of HGF cDNA in metastatic LY-1 cells. Our data indicate that metastatic SCC cells that overexpress c-Met exhibit angiogenesis factor expression and enhanced scattering in response to HGF in vitro, and tumorigenesis and metastasis in response to HGF in the tumor microenvironment in vivo.

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References

  • Aebersold DM, Kollar A, Beer KT, Laissue J, Greiner RH and Djonov V . (2001). Int. J. Cancer, 96, 41–54.

  • Bussolino F, Di Renzo MF, Ziche M, Bocchietto E, Olivero M, Naldini L, Gaudino G, Tamagnone L, Coffer A and Comiglio PM . (1992). J. Cell Biol., 119, 629–641.

  • Cao B, Su Y, Oskarsson M, Zhao P, Kort EJ, Fisher RJ, Wang LM and Vande Woude GF . (2001). Proc. Natl. Acad. Sci., USA, 98, 7443–7448.

  • Chan AM, King HW, Deakin EA, Tempest PR, Hilkens J, Kroezen V, Edwards DR, Wills AJ, Brookes P and Cooper CS . (1988). Oncogene, 2, 593–599.

  • Birchmeier C, Birchmeier W, Gherardi E and Vande Woude GF . (2003). Nat. Rev. Mol. Cell Biol., 4, 915–925.

  • Chen Z, Smith CW, Kiel D and Van Waes C . (1997). Clin. Exp. Metast., 15, 527–535.

  • Chen Z, Colon I, Ortiz N, Callister M, Dong G, Pegram MY, Arosarena O, Strome S, Nicholson JC and Van Waes C . (1998). Cancer Res., 58, 3668–3676.

  • Chen Z, Malhotra PS, Thomas GR, Ondrey FG, Duffey DC, Enamorada I, Mousa S and Van Waes C . (1999). Clin. Cancer Res., 5, 1369–1379.

  • Cortesina G, Martone T, Galeazzi E, Olivero M, De Stefani A, Bussi M, Valente G, Comoglio PM and Di Renzo MF . (2000). Int. J. Cancer, 89, 286–292.

  • Crowl-Bancroft C, Chen Z, Dong G, Sunwoo J, Yeh N, Park C and Van Waes C . (2001). Clin. Cancer Res., 7, 435–442.

  • Dong G, Chen Z, Kato T and Van Waes C . (1999). Cancer Res., 59, 3495–3504.

  • Dong G, Loukinova E, Chen Z, Gangi L, Chanturita TI, Liu E and Van Waes C . (2001a). Cancer Res., 61, 4797–4808.

  • Dong G, Chen Z, Li ZY, Yeh NT, Bancroft CC and Van Waes C . (2001b). Cancer Res., 61, 5911–5918.

  • Duffey D, Chen Z, Dong G, Ondrey FG, Wolf J, Brown K, Siebenlist U and Van Waes C . (1999). Cancer Res., 59, 3468–3474.

  • Ferrara N . (2002). Semin. Oncol., 29, 10–14.

  • Fukuura T, Miki C, Inoue T, Matsumoto K and Suzuki H . (1998). Br. J. Cancer, 78, 454–459.

  • Gohji K, Nomi M, Niitani Y, Kitazawa S, Fujii A, Katsuoka Y and Nakajima M . (2000). J. Clin. Oncol., 18, 2963–2971.

  • Grant DS, Kleinman HK, Goldberg ID, Bhargava MM, Nickoloff BJ, Kinsella JL, Polverini P and Rosen EM . (1993). Proc. Natl. Acad. Sci. USA, 90, 1937–1941.

  • Hanahan D and Weinberg RA . (2000). Cell, 100, 57–70.

  • Hu YC, Lam KY, Law S, Wong J and Srivastava G . (2001). Clin. Cancer Res., 7, 3519–3525.

  • Iyer A, Kmiecik TE, Park M, Daar I, Blair D, Dunn KJ, Sutrave P, Ihle JN, Bodescot M and Vande Woude GF . (1990). Cell Growth Differ., 1, 87–95.

  • Junbo H, Li Q, Zaide W and Yunde H . (1999). In Vivo , 13, 177–180.

  • Kitadai Y, Takahashi Y, haruma K, Naka K, Sumii K, Yokozaki H, Yasui W, Mukaida N, Ohmoto Y, Kajiyama G, Fidler IJ and Tahara E . (1999). Br. J. Cancer, 81, 647–653.

  • Leethanakul C, Patel V, Gillespie J, Pallente M, Ensley JF, Koontongkaew S, Liotta LA, Emmert-Buck M and Gutkind JS . (2000). Oncogene, 19, 3220–3224.

  • Liotta LA and Kohn EC . (2001). Nature, 411, 375–379.

  • Loukinova E, Dong G, Enamorado-Ayalya I, Thomas GR, Chen Z, Schreiber H and Van Waes C . (2000). Oncogene, 19, 3477–3486.

  • Luan J, Shattuck-Brandt R, Haghnegahdar H, Owen JD, Strieter R, Burdick M, Nirodi C, Beauchamp D, Johnson KN and Richmond A . (1997). J. Leukoc. Biol., 62, 588–597.

  • Marshall DD and Kornberg LJ . (1998). Laryngoscope, 108, 1413–1417.

  • Naughton M, Picus J, Zhu X, Catalona WJ, Vollmer RT and Humphrey PA . (2001). J. Urol., 165, 1325–1328.

  • Porte H, Triboulet JP, Kotelevets L, Carrat F, Prevot S, Nordlinger B, DiGioia Y, Wurtz A, Comoglio P, Gespach C and Chastre E . (1998). Clin. Cancer Res., 4, 1375–1382.

  • Qian CN, Guo X, Cao B, Kort EJ, Lee CC, Chen J, Wang LM, Mai WY, Min HQ, Hong MH, Vande Woude GF, Resau JH and Teh BT . (2002). Cancer Res., 62, 589–596.

  • Rong S, Bodescot M, Blair D, Dunn J, Nakamura T, Mizuno K, Park M, Chan A, Aaronson S and Vande Woude GF . (1992). Mol. Cell Biol., 12, 5152–5158.

  • Rong S, Oskarsson M, Faletto D, Tsarfaty I, Resau JH, Nakamura T, Rosen E, Hopkins 3rd RF and Vande Woude GF . (1993). Cell Growth Diff., 4, 563–569.

  • Schmidt L, Duh F-M, Chen F, Kishida T, Glenn G, Choyke P, Scherer S W, Zhuang Z, Lubensky I, Dean M, Allikmets R and Chidambaram A . (1997). Nature Genet., 16, 68–73.

  • Smith CW, Chen Z, Dong G, Loukinova E, Pegram MY, Nicholas-Figueroa L and Van Waes C . (1998). Clin. Exp. Metast., 16, 655–664.

  • Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lønning PE and Børresen-Dale AL . (2001). Proc. Natl. Acad. Sci. USA, 98, 10869–10874.

  • Takayama H, LaRochelle WJ, Sharp R, Otsuka T, Kriebel P, Anver M, Aaronson SA and Merlino G . (1997). Proc. Natl. Acad. Sci. USA, 94, 701–706.

  • Takeo S, Arai H, Kusano N, Harada T, Furuya T, Kawauchi S, Oga A, Hirano T, Yoshida T, Okita K and Sasaki K . (2001). Cancer Genet. Cytogenet., 130, 127–132.

  • Takigawa N, Segawa Y, Maeda Y, Takata I and Fujimoto N . (1997). Lung Cancer, 17, 211–218.

  • Taniguchi T, Kitamura M, Arai K, Iwasaki Y, Yamamoto Y, Igari A and Toi M . (1997). Br. J. Cancer, 75, 673–677.

  • Toi M, Taniguchi T, Ueno T, Asano M, Funata N, Sekiguchi K, Iwanari H and Tominaga T . (1998). Clin. Cancer Res., 4, 659–664.

  • Thomas GR, Chen Z, Oechsli MN, Hindler F and Van Waes C . (1999). Int. J. Cancer, 82, 377–384.

  • Uchida D, Kawamata H, Omotehara F, Nakashiro K, Kimura-Yanagawa T, Hino S, Begum NM, Hoque MO, Yoshida H, Sato M and Fujimori T . (2001). Int. J. Cancer, 93, 489–496.

  • Vande Woude GF, Jeffers M, Cortner J, Alvord G, Tsarfaty I and Resau J . (1997). Ciba Found Symp., 212, 119–130.

  • Wojta J, Kaun C, Breuss JM, Koshelnick Y, Beckmann R, Hattey E, Mildner M, Weninger W, Nakamura T, Tschachler E and Binder BR . (1999). Lab. Invest., 79, 427–438.

  • Yu Y and Merlino G . (2002). Cancer Res., 62, 2951–2956.

  • Yuspa SH, Dlugosz AA, Cheng CK, Denning MF, Tennenbaum T, Glick AB and Weinberg WC . (1994). J. Invest. Dermatol., 103 (5 Suppl), 90S–95S.

  • Yuspa SH, Hawley-Nelson P, Koehler B and Stanley JR . (1980). Cancer Res., 40, 4694–4703.

  • Zhang YW, Su Y, Volpert OV and Vande Woude GF . (2003). Proc. Natl. Acad. Sci. USA, 100, 12718–12723.

  • Zhuang Z, Park W-S, Pack S, Schmidt L, Vortmeyer AO, Pak E, Pham T, Weil RJ, Candidus S, Lubensky IA, Linehan WM, Zbar B and Weirich G . (1998). Nat. Genet., 20, 66–69.

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Acknowledgements

The authors would like to express their gratitude to Dr George Vande Woude of NCI (Frederick, MD, USA) for kindly providing human HGF, Madin-darby canine kidney epithelial cells (MDCKII), and expression vectors for human HGF and murine c-Met. The authors also would like to express their appreciation to Drs Donald P Bottaro (Entremed) and Yanlin Yu (NCI) for their critical readings and helpful suggestions of the manuscript. Supported by NIDCD intramural research project Z01-DC-00016.

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  1. Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 10/5D55, MSC-1419, Bethesda, 20892-1419, MD, USA

    Gang Dong, Tin Lap Lee, Ning T Yeh, Joel Geoghegan, Carter Van Waes & Zhong Chen

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Correspondence to Zhong Chen.

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Dong, G., Lee, T., Yeh, N. et al. Metastatic squamous cell carcinoma cells that overexpress c-Met exhibit enhanced angiogenesis factor expression, scattering and metastasis in response to hepatocyte growth factor. Oncogene 23, 6199–6208 (2004). https://doi.org/10.1038/sj.onc.1207851

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