Expression of integrin β6 enhances invasive behavior in oral squamous cell carcinoma

Daniel M. Ramos, Maria But, Joseph Regezi, Brian L. Schmidt, Amha Atakilit, Dongmin Dang, Duncan Ellis, Richard Jordan, Xiaowu Li

Research output: Contribution to journalArticlepeer-review

Abstract

Oral squamous cell carcinoma (SCC) is characterized by invasive growth and the propensity for distant metastasis. The expression of specific adhesion receptors promotes defined interactions with the specific components found within the extracellular matrix (ECM). We previously showed that the αvβ6 fibronectin receptor is highly expressed in oral SCC. Here we forced expression of the β6 subunit into poorly invasive SCC9 cells to establish the SCC9β6 cell line and compared these two cell lines in several independent assays. Whereas adhesion to fibronectin was unaffected by the expression of β6, migration on fibronectin and invasion through a reconstituted basement membrane (RBM) were both increased. Function-blocking antibodies to αvβ6 (10D5) reduced both migration on fibronectin and invasion through an RBM, whereas anti-α5 antibodies were effective only in suppressing migration on fibronectin, not invasion. Expression of β6 also promoted tumor growth and invasion in vivo and modulated fibronectin matrix deposition. When grown as a co-culture with SCC9 cells, peritumor fibroblasts (PTF) organized a dense fibronectin matrix. However, fibronectin matrix assembly was decreased in co-cultures of SCC9β6 cells and PTF and this decrease was reversed by the addition of function-blocking anti-αvβ6 antibodies. The expression of β6 also resulted in increased levels of matrix metalloproteinase 3. Addition of the general MMP inhibitor GM6001 to SCC9β6/PTF co-cultures dramatically increased fibronectin matrix assembly in a similar fashion as incubation with anti-αvβ6 antibodies. These results demonstrate that expression of β6 (1) increases oral SCC cell motility and growth in vitro and in vivo; (2) negatively affects fibronectin matrix assembly; and (3) stimulates the expression and activation of MMP3. We suggest that the integrin αvβ6 is a key component of oral SCC invasion and metastasis through modulation of MMP-3 activity.

Original languageEnglish (US)
Pages (from-to)297-307
Number of pages11
JournalMatrix Biology
Volume21
Issue number3
DOIs
StatePublished - 2002

Keywords

  • Fibronectin
  • Invasion
  • Squamous cell carcinoma
  • β6 integrin

ASJC Scopus subject areas

  • Molecular Biology

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