Paradoxical effects of T-cadherin on squamous cell carcinoma: up- and down-regulation increase xenograft growth by distinct mechanisms

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Abstract

Mechanisms underlying cutaneous squamous cell carcinoma (SCC) tumour growth and invasion are incompletely understood. Our previous pathological andin vitrostudies suggest that cell surface glycoprotein T-cadherin (T-cad) might be a controlling determinant of the behaviour of SCC. Here we used a murine xenograft model to determine whether T-cad modulates SCC tumour progressionin vivo.Silencing or up-regulation of T-cad in A431 (shTcad or Tcad+, respectively) both resulted in increased tumour expansionin vivo. To explain this unanticipated outcome, we focused on proliferation, apoptosis and angiogenesis/lymphangiogenesis, which are important determinants of the progression of solid tumoursin vivo. shTcad exhibited enhanced proliferation potentialin vitroandin vivo,and their signalling response to EGF was characterized by a higher Erk1/2:p38MAPK activity ratio, which has been correlated with more aggressive tumour growth. T-cad over-expression did not affect proliferation but staining for cleaved caspase 3 revealed a minimal occurrence of extensive apoptosis in Tcad+ tumours. Immunofluoresence staining of xenograft sections revealed increased intra-tumoural total microvessel (CD31+) and lymphatic vessel (LYVE-1+) densities in Tcad+ tumours. shTcad tumours exhibited decreased microvessel and lymphatic densities. Tcad+ expressed higher levels of transcripts forVEGF-A, VEGF-CandVEGF-D in vitroandin vivo. Culture supernatants collected from Tcad+ enhanced sprout outgrowth from spheroids composed of either microvascular or lymphatic endothelial cells, and thesein vitroangiogenic and lymphangiogenic responses were abrogated by inclusion of neutralizing VEGF antibodies. We conclude that T-cad can exert pleiotropic effects on SCC progression; up- or down-regulation of T-cad can promote SCC tumour expansionin vivobut through distinct mechanisms, namely enhancement of angio/lymphangiogenic potential or enhancement of proliferation capacity. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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