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?v?6 integrin promotes invasion of morphoeic basal cell carcinoma indirectly through stromal modulation

?v?6 integrin promotes invasion of morphoeic basal cell carcinoma indirectly through stromal modulation
?v?6 integrin promotes invasion of morphoeic basal cell carcinoma indirectly through stromal modulation
Basal cell carcinoma (BCC) is the most prevalent cancer in the Western world and its incidence is increasing. The pathogenesis of BCC involves deregulated sonic hedgehog signaling (shh), leading to activation of the Gli transcription factors. Most BCC have a nodular growth pattern, are indolent, slow-growing and considered 'low risk' lesions. In contrast, the 'high risk' morphoeic variant, which causes significant morbidity, has an infiltrative growth pattern, and is so-called because of its densely fibrous stroma. As ?v?6 is capable of promoting both carcinoma invasion and fibrosis, we examined expression of the integrin in BCCs and found that the morphoeic type showed significantly higher ?v?6 expression than the nodular type (p-=0.0009). In order to examine the function of ?v?6, we transfected the transcription factors Gli-1 or Gli-2 into NTERT, human keratinocytes to generate a BCC model. These cells expressed ?v?6 and were invasive, although inhibition of ?v?6 had no direct effect on cell invasion. However, the cells showed ?v?6-dependent activation of TGF-?1, which induced transdifferentiation of human fibroblasts into myofibroblasts. Paracrine secretion of HGF/SF by these myfibroblasts promoted c-Met-dependent tumor invasion in both Transwell and 3D-organotypic assays. These experimental in vitro findings were confirmed using human clinical samples where we showed that the stroma of morphoeic BCC is myofibroblast-rich compared with nodular BCC (p=0.0036), that myofibroblasts express HGF/SF, and that morphoeic BCCs are strongly c-Met-positive. These data suggest that ?v?6-dependent TGF-?1 activation induces both the infiltrative growth pattern and fibrotic stroma so characteristic of morphoeic BCC.
BCC, integrin, TGF-?, invasion, myofibroblast
0008-5472
3295-3303
Marsh, Daniel
eede5080-736a-4058-a4e1-a6b233651a35
Dickinson, Sarah
2ce95e22-e2a0-412f-a813-e2c35662d8c3
Neil, Graham W.
2144ec99-be88-409a-a92c-80a543865035
Marshall, John F.
1134b21f-7f23-4ee6-aaf5-c7580b73c10b
Hart, Ian R.
6a3728fc-5385-4dd4-a5e3-edd5168a0e8d
Thomas, Gareth J.
2ff54aa9-a766-416b-91ee-cf1c5be74106
Marsh, Daniel
eede5080-736a-4058-a4e1-a6b233651a35
Dickinson, Sarah
2ce95e22-e2a0-412f-a813-e2c35662d8c3
Neil, Graham W.
2144ec99-be88-409a-a92c-80a543865035
Marshall, John F.
1134b21f-7f23-4ee6-aaf5-c7580b73c10b
Hart, Ian R.
6a3728fc-5385-4dd4-a5e3-edd5168a0e8d
Thomas, Gareth J.
2ff54aa9-a766-416b-91ee-cf1c5be74106

Marsh, Daniel, Dickinson, Sarah, Neil, Graham W., Marshall, John F., Hart, Ian R. and Thomas, Gareth J. (2008) ?v?6 integrin promotes invasion of morphoeic basal cell carcinoma indirectly through stromal modulation. Cancer Research, 68 (9), 3295-3303. (doi:10.1158/0008-5472.CAN-08-0174).

Record type: Article

Abstract

Basal cell carcinoma (BCC) is the most prevalent cancer in the Western world and its incidence is increasing. The pathogenesis of BCC involves deregulated sonic hedgehog signaling (shh), leading to activation of the Gli transcription factors. Most BCC have a nodular growth pattern, are indolent, slow-growing and considered 'low risk' lesions. In contrast, the 'high risk' morphoeic variant, which causes significant morbidity, has an infiltrative growth pattern, and is so-called because of its densely fibrous stroma. As ?v?6 is capable of promoting both carcinoma invasion and fibrosis, we examined expression of the integrin in BCCs and found that the morphoeic type showed significantly higher ?v?6 expression than the nodular type (p-=0.0009). In order to examine the function of ?v?6, we transfected the transcription factors Gli-1 or Gli-2 into NTERT, human keratinocytes to generate a BCC model. These cells expressed ?v?6 and were invasive, although inhibition of ?v?6 had no direct effect on cell invasion. However, the cells showed ?v?6-dependent activation of TGF-?1, which induced transdifferentiation of human fibroblasts into myofibroblasts. Paracrine secretion of HGF/SF by these myfibroblasts promoted c-Met-dependent tumor invasion in both Transwell and 3D-organotypic assays. These experimental in vitro findings were confirmed using human clinical samples where we showed that the stroma of morphoeic BCC is myofibroblast-rich compared with nodular BCC (p=0.0036), that myofibroblasts express HGF/SF, and that morphoeic BCCs are strongly c-Met-positive. These data suggest that ?v?6-dependent TGF-?1 activation induces both the infiltrative growth pattern and fibrotic stroma so characteristic of morphoeic BCC.

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Published date: May 2008
Keywords: BCC, integrin, TGF-?, invasion, myofibroblast
Organisations: Cancer Sciences

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Local EPrints ID: 66682
URI: http://eprints.soton.ac.uk/id/eprint/66682
ISSN: 0008-5472
PURE UUID: 03cf5a5a-4ea3-4ab9-a556-cd9d3b36a412

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Date deposited: 10 Jul 2009
Last modified: 13 Mar 2024 18:28

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Contributors

Author: Daniel Marsh
Author: Sarah Dickinson
Author: Graham W. Neil
Author: John F. Marshall
Author: Ian R. Hart

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