Role of the αvβ6 Integrin in Human Oral Squamous Cell Carcinoma Growth in Vivo and in Vitro

Xue, Hui; Atakilit, Amha; Zhu, Weimin; Li, Xiaowu; Ramos, Daniel M.; Pytela, Robert

doi:10.1006/bbrc.2001.5813

Cited by 62 publications

(84 citation statements)

References 44 publications

(34 reference statements)

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“…We have previously shown that the expression of the integrin ␣ v ␤ 6 promotes cell migration onto fibronectin rather than adhesion to fibronectin (30,40). In this study, we found that interaction of the integrin ␣ v ␤ 6 with FN-mediated Fyn activation occurred simultaneously with cell migration.…”

Section: Discussionsupporting

confidence: 49%

αvβ6-Fyn Signaling Promotes Oral Cancer Progression

Yang

et al. 2003

Journal of Biological Chemistry

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We have previously shown that the integrin ␤ 6 is neoexpressed in invasive oral squamous cell carcinoma (SCC) and is correlated with oral tumor progression. However, the mechanism by which the integrin ␤ 6 promotes oral tumor progression is not well understood. The purpose of the present study was to determine whether integrin ␤ 6 signaling activates Fyn and thus promotes oral squamous cell carcinoma progression. We analyzed the integrin ␤ 6 signaling complex and investigated the function of these signaling molecules in oral SCC cells. We found that, upon ligation of the integrin ␤ 6 with fibronectin, ␤ 6 complexed with Fyn and activated it. The activation of Fyn recruited and activated focal adhesion kinase to this complex. This complex was necessary to activate Shc and to couple ␤ 6 signaling to the Raf-ERK/MAPK pathway. This pathway transcriptionally activated the matrix metalloproteinase-3 gene and promoted oral SCC cell proliferation and experimental metastasis in vivo. These findings indicate that integrin ␤ 6 signaling activates Fyn and thus promotes oral cancer progression.

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Section: Discussionsupporting

confidence: 49%

αvβ6-Fyn Signaling Promotes Oral Cancer Progression

Yang

et al. 2003

Journal of Biological Chemistry

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“…We have shown previously that over-expression of avb6 in oral SCC cells promotes cell migration, invasion and MMP-9 expression (Thomas et al, 2001b, c). Moreover, recent data from Xue et al (2001) demonstrated that inhibition of avb6 could significantly retard the growth of human SCC cells implanted orthotopically into athymic mice. These studies provide strong evidence that the activity of avb6 promotes development of SCC and that this integrin may represent a possible therapeutic target in the treatment of SCC.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to promoting cell migration and MMP-9 upregulation, we have demonstrated that increased expression of avb6 in squamous cell carcinoma cell lines produces a more invasive phenotype; such increased aggressive behaviour is avb6-dependent and is modulated through altered protease expression (Thomas et al, 2001b,c). A recent study has also shown that the progression of oral squamous carcinoma in vivo can be significantly retarded using inhibitory anti-avb6 antibodies (Xue et al, 2001).…”

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confidence: 99%

Binding of TGF-β1 latency-associated peptide (LAP) to αvβ6 integrin modulates behaviour of squamous carcinoma cells

et al. 2002

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The integrin avb6 is not detectable on normal keratinocytes in vivo but expression is increased significantly in oral squamous cell carcinoma where this heterodimer has been shown to play a role in cell migration, invasion and protease expression. Although regarded initially as a fibronectin receptor, avb6 may bind to arginine-glycine-aspartic acid sequences in other matrix molecules including tenascin and vitronectin. Interestingly, avb6 has also been shown to have high affinity for the TGF-b1 latency associated peptide and to participate in the activation of the TGF-b1 latent complex. Since TGF-b1 is present in squamous carcinomas, it is possible that latency associated peptide may modulate malignant keratinocyte behaviour independently from the classical TGF-b signalling pathways through its interaction with integrins. We show here that when latency associated peptide is immobilised onto a surface, it acts as an avb6-specific ligand for oral squamous carcinoma cells promoting adhesion and haptotactic migration in addition to avb6-dependent increase in pro-MMP-9 expression. In contrast, even very low concentrations of soluble latency associated peptide (0.1 mg ml 71) inhibited avb6-dependent adhesion, migration and invasion. Thus avb6-dependent processes of oral squamous cell carcinoma, is likely to be modulated, not only by the local concentration of latency associated peptide in the stroma, but also whether it is immobilised in the matrix or released as a soluble protein.

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“…Different integrins generate different signals and some of these integrins may have profound effects on the biologic behavior of tumors. Previous research has found that some integrins such as · 1 ß 1 , · 2 ß 1 , · 6 ß 1 , · 6 ß 4 , · 3 ß 1 , and · 7 ß 1 are involved in binding to laminin and that other integrins such as · v ß 6 , · 5 ß 1 , and · v ß 1 contribute to SCC cell migration (24)(25)(26). In the present study, downregulation of tumor cell expression of integrins · 3 , · 6 , · v , ß 1 , ß 3 , and ß 4 after S-1 therapy appeared to contribute to a reduction in spontaneous metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…We also found that tumor cells with downregulated FAK activity became less adherent to the ECM. FAK is associated with integrins within focal adhesions, and integrin activation by an ECM ligand is associated with increased tyrosine phosphorylation and kinase activity of FAK (26).…”

Section: Discussionmentioning

confidence: 99%

S-1 mediates the inhibition of lymph node metastasis in oral cancer cells

Sato

Hatori²,

Ando³

et al. 2009

Oncol Rep

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Abstract. S-1, an oral fluorouracil antitumor drug, is composed of three agents: tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo). Approximately 50% of oral squamous cell carcinomas (OSCC) exhibit cervical lymph node metastasis. The extent of lymph node involvement is a major determinant in both staging and prognosis of the majority of OSCC. The purpose of this study was to examine the effect of S-1 on the metastatic potential of OSCC cells. We used orthotopic green fluorescence protein (GFP) SAS-L1, in BALB/c nu/nu mice. Mice received oral doses of either 5% hydroxypropylmethylcellulose (HPMC) for control or S-1 (20 mg/kg) and were autopsied at 2 weeks. We also performed in vitro experiments using concomitant 5-fluorouracil (5-FU) and CDHP as a drug model of S-1 to determine the effect of S-1 on OSCC invasion and metastasis. Although 100% (11 of 11) of mice not treated with S-1 showed cervical lymph node metastasis, only 54.4% (6 of 11) of S-1 treated mice demonstrated metastasis. In in vitro experiments, OSCC cells treated with 5-FU and CDHP showed a marked reduction in invasiveness and in adhesion to laminin coated plates. Western blot analysis revealed that treatment with 5-FU and CDHP suppressed expression of integrins · v , · 3 , · 6 , ß 1 , ß 3 , ß 4 , ß 5 , and ß 6 . These results suggest that S-1 inhibits tumor proliferation and lymph node metastasis in OSCC cells. Moreover, expression of integrin subunits and the integrin signal transduction pathway may be closely related to metastasis suppression.

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Role of the αvβ6 Integrin in Human Oral Squamous Cell Carcinoma Growth in Vivo and in Vitro

Cited by 62 publications

References 44 publications

αvβ6-Fyn Signaling Promotes Oral Cancer Progression

αvβ6-Fyn Signaling Promotes Oral Cancer Progression

Binding of TGF-β1 latency-associated peptide (LAP) to αvβ6 integrin modulates behaviour of squamous carcinoma cells

S-1 mediates the inhibition of lymph node metastasis in oral cancer cells

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