Tumour-associated Tenascin-C Isoforms Promote Breast Cancer Cell Invasion and Growth by Matrix Metalloproteinase-dependent and Independent Mechanisms

Overview

Journal Breast Cancer Res

Specialty Oncology

Date 2009 May 2

PMID 19405959

Citations 70

Authors

Rachael A Hancox

Michael D Allen

Deborah L Holliday

Dylan R Edwards

Caroline J Pennington

David S Guttery

Jacqueline A Shaw

Rosemary A Walker

J Howard Pringle

J Louise Jones

Affiliations

Soon will be listed here.

Abstract

Introduction: The stromal microenvironment has a profound influence on tumour cell behaviour. In tumours, the extracellular matrix (ECM) composition differs from normal tissue and allows novel interactions to influence tumour cell function. The ECM protein tenascin-C (TNC) is frequently up-regulated in breast cancer and we have previously identified two novel isoforms - one containing exon 16 (TNC-16) and one containing exons 14 plus 16 (TNC-14/16).

Methods: The present study has analysed the functional significance of this altered TNC isoform profile in breast cancer. TNC-16 and TNC-14/16 splice variants were generated using PCR-ligation and over-expressed in breast cancer cells (MCF-7, T47D, MDA-MD-231, MDA-MB-468, GI101) and human fibroblasts. The effects of these variants on tumour cell invasion and proliferation were measured and compared with the effects of the large (TNC-L) and fully spliced small (TNC-S) isoforms.

Results: TNC-16 and TNC-14/16 significantly enhanced tumour cell proliferation (P < 0.05) and invasion, both directly (P < 0.01) and as a response to transfected fibroblast expression (P < 0.05) with this effect being dependent on tumour cell interaction with TNC, because TNC-blocking antibodies abrogated these responses. An analysis of 19 matrix metalloproteinases (MMPs) and tissue inhibitor of matrix metalloproteinases 1 to 4 (TIMP 1 to 4) revealed that TNC up-regulated expression of MMP-13 and TIMP-3 two to four fold relative to vector, and invasion was reduced in the presence of MMP inhibitor GM6001. However, this effect was not isoform-specific but was elicited equally by all TNC isoforms.

Conclusions: These results demonstrate a dual requirement for TNC and MMP in enhancing breast cancer cell invasion, and identify a significant role for the tumour-associated TNC-16 and TNC-14/16 in promoting tumour invasion, although these isoform-specific effects appear to be mediated through MMP-independent mechanisms.

Citing Articles

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References

Siri A, Knauper V, Veirana N, Caocci F, Murphy G, Zardi L . Different susceptibility of small and large human tenascin-C isoforms to degradation by matrix metalloproteinases. J Biol Chem. 1995; 270(15):8650-4. DOI: 10.1074/jbc.270.15.8650. View

Chung C, Erickson H . Cell surface annexin II is a high affinity receptor for the alternatively spliced segment of tenascin-C. J Cell Biol. 1994; 126(2):539-48. PMC: 2200039. DOI: 10.1083/jcb.126.2.539. View

Nielsen B, Rank F, Lopez J, Balbin M, Vizoso F, Lund L . Collagenase-3 expression in breast myofibroblasts as a molecular marker of transition of ductal carcinoma in situ lesions to invasive ductal carcinomas. Cancer Res. 2001; 61(19):7091-100. View

Brack S, Silacci M, Birchler M, Neri D . Tumor-targeting properties of novel antibodies specific to the large isoform of tenascin-C. Clin Cancer Res. 2006; 12(10):3200-8. DOI: 10.1158/1078-0432.CCR-05-2804. View

Katenkamp K, Berndt A, Hindermann W, Wunderlich H, Haas K, Borsi L . mRNA expression and protein distribution of the unspliced tenascin-C isoform in prostatic adenocarcinoma. J Pathol. 2004; 203(3):771-9. DOI: 10.1002/path.1589. View

Nuttall R, Pennington C, Taplin J, Wheal A, Yong V, Forsyth P . Elevated membrane-type matrix metalloproteinases in gliomas revealed by profiling proteases and inhibitors in human cancer cells. Mol Cancer Res. 2003; 1(5):333-45. View

Balduyck M, Zerimech F, Gouyer V, Lemaire R, Hemon B, Grard G . Specific expression of matrix metalloproteinases 1, 3, 9 and 13 associated with invasiveness of breast cancer cells in vitro. Clin Exp Metastasis. 2001; 18(2):171-8. DOI: 10.1023/a:1006762425323. View

Roskelley C, Bissell M . The dominance of the microenvironment in breast and ovarian cancer. Semin Cancer Biol. 2002; 12(2):97-104. PMC: 3771861. DOI: 10.1006/scbi.2001.0417. View

Joester A, Faissner A . Evidence for combinatorial variability of tenascin-C isoforms and developmental regulation in the mouse central nervous system. J Biol Chem. 1999; 274(24):17144-51. DOI: 10.1074/jbc.274.24.17144. View

10.

Westernoff T, Jordan R, Regezi J, Ramos D, Schmidt B . Beta-6 Integrin, tenascin-C, and MMP-1 expression in salivary gland neoplasms. Oral Oncol. 2005; 41(2):170-4. DOI: 10.1016/j.oraloncology.2004.08.002. View

11.

Tremble P, Chiquet-Ehrismann R, Werb Z . The extracellular matrix ligands fibronectin and tenascin collaborate in regulating collagenase gene expression in fibroblasts. Mol Biol Cell. 1994; 5(4):439-53. PMC: 301053. DOI: 10.1091/mbc.5.4.439. View

12.

Cai M, Onoda K, Takao M, Shimpo H, Yoshida T, Yada I . Degradation of tenascin-C and activity of matrix metalloproteinase-2 are associated with tumor recurrence in early stage non-small cell lung cancer. Clin Cancer Res. 2002; 8(4):1152-6. View

13.

Mercado M, Nur-E-Kamal A, Liu H, Gross S, Movahed R, Meiners S . Neurite outgrowth by the alternatively spliced region of human tenascin-C is mediated by neuronal alpha7beta1 integrin. J Neurosci. 2004; 24(1):238-47. PMC: 6729556. DOI: 10.1523/JNEUROSCI.4519-03.2004. View

14.

Orimo A, Gupta P, Sgroi D, Arenzana-Seisdedos F, Delaunay T, Naeem R . Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005; 121(3):335-48. DOI: 10.1016/j.cell.2005.02.034. View

15.

Jones J, Glynn P, Walker R . Expression of MMP-2 and MMP-9, their inhibitors, and the activator MT1-MMP in primary breast carcinomas. J Pathol. 1999; 189(2):161-8. DOI: 10.1002/(SICI)1096-9896(199910)189:2<161::AID-PATH406>3.0.CO;2-2. View

16.

Meiners S, Geller H . Long and short splice variants of human tenascin differentially regulate neurite outgrowth. Mol Cell Neurosci. 1997; 10(1-2):100-16. DOI: 10.1006/mcne.1997.0643. View

17.

Kalembeyi I, Inada H, Nishiura R, Imanaka-Yoshida K, Sakakura T, Yoshida T . Tenascin-C upregulates matrix metalloproteinase-9 in breast cancer cells: direct and synergistic effects with transforming growth factor beta1. Int J Cancer. 2003; 105(1):53-60. DOI: 10.1002/ijc.11037. View

18.

Garcia A, Vega M, Boettiger D . Modulation of cell proliferation and differentiation through substrate-dependent changes in fibronectin conformation. Mol Biol Cell. 1999; 10(3):785-98. PMC: 25202. DOI: 10.1091/mbc.10.3.785. View

19.

Brown L, Guidi A, Schnitt S, Van de Water L, Iruela-Arispe M, Yeo T . Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast. Clin Cancer Res. 1999; 5(5):1041-56. View

20.

Aukhil I, Joshi P, Yan Y, Erickson H . Cell- and heparin-binding domains of the hexabrachion arm identified by tenascin expression proteins. J Biol Chem. 1993; 268(4):2542-53. View