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

Abstract

Mechanisms underlying cutaneous squamous cell carcinoma (SCC) tumour growth and invasion are incompletely understood. Our previous pathological and in vitro studies 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 progression in vivo. Silencing or up-regulation of T-cad in A431 (shTcad or Tcad(+) , respectively) both resulted in increased tumour expansion in vivo. To explain this unanticipated outcome, we focused on proliferation, apoptosis and angiogenesis/lymphangiogenesis, which are important determinants of the progression of solid tumours in vivo. shTcad exhibited enhanced proliferation potential in vitro and in 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 for VEGF-A, VEGF-C and VEGF-D in vitro and in vivo. Culture supernatants collected from Tcad(+) enhanced sprout outgrowth from spheroids composed of either microvascular or lymphatic endothelial cells, and these in vitro angiogenic 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 expansion in vivo but through distinct mechanisms, namely enhancement of angio/lymphangiogenic potential or enhancement of proliferation capacity.

T‐cadherin in prostate cancer: relationship with cancer progression, differentiation and drug resistance

“…As these cells give rise to transient amplifying cells and differentiated keratinocytes which move upward towards the skin surface to create new strata layers, T-cadherin expression decreases and is eventually completely lost. In skin tumours its expression level varies depending on tumour type and cell of origin: it is strongly expressed in basal cell carcinoma [55], but downregulated in squamous cell carcinoma and leads to increased tumour growth, invasion and metastasis [51,57,58], Together, these observations suggest that T-cadherin may be involved in coordination of epithelial differentiation and structural organisation of polarised tissues. Whilst the relationship between prostate cell types is still debated, lineage tracing studies [8][9][10] and the identification of cells with an intermediate phenotype (transit-amplifying cells) expressing both basal and luminal markers [59] support that basal cells serve as precursors for luminal cells.…”

T-Cadherin Is an Auxiliary Negative Regulator of EGFR Pathway Activity in Cutaneous Squamous Cell Carcinoma: Impact on Cell Motility

“…Analysis of T-cad expression in relation to histological classification of degree of differentiation revealed that T-cad loss in cutaneous SCC was not ubiquitous but occurred locally in association with histological features of a potentially more malignant and invasive phenotype (Pfaff et al, 2010). In vitro studies using HSC-1 or A431 SCC cell lines collectively demonstrated that T-cad silencing increased migratory, invasive, and proliferation potential, whereas the converse was true for T-cad overexpression (Mukoyama et al, 2005;Pfaff et al, 2010Pfaff et al, , 2011. However, in a murine xenograft model, either gain or loss of T-cad in A431 increased tumor expansion in vivo (Pfaff et al, 2011).…”

EGFR and IGF‐1R in regulation of prostate cancer cell phenotype and polarity: opposing functions and modulation by T‐cadherin

“…Down‐regulation of T‐cadherin in highly invasive hepatocellular carcinoma cells inhibited cell motility and did not influence proliferation (50). Silencing of T‐cadherin in cutaneous squamous cell carcinoma cells promoted the growth of tumor xenografts, but so did T‐cadherin overexpression through its ability to promote intratumoral angiogenesis (48).…”

“…Allelic loss of chromosome bands 16q24.1-q24.2, reduced expression of T-cadherin, and hypermethylation of the remaining allele have been detected in many human cancers including breast, colon, lung, hepatic, skin carcinomas, neuroblastoma, and others (9). Most studies showed that introduction of T-cadherin cDNA inhibited tumor cell growth, whereas T-cadherin silencing, conversely, stimulated proliferation, invasion, and metastasis in several in vitro and in vivo models (9,18,(47)(48)(49). Other data, however, show that T-cadherin does not obligatorily act as a tumor suppressor.…”