Epithelial to mesenchymal transition markers are associated with an increased metastatic risk in primary cutaneous squamous cell carcinomas but are attenuated in lymph node metastases.
BACKGROUND
Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy in humans and approximately 5% metastasize, usually to regional lymph nodes. Epithelial to mesenchymal transition (EMT) is a process involving loss of intercellular adhesion, acquisition of a mesenchymal phenotype and enhanced migratory potential; epithelial markers, such as E-cadherin, are down-regulated and mesenchymal proteins (Vimentin), increased.


OBJECTIVE
To investigate the expression of EMT markers in metastatic SCC (MSCC) and their corresponding metastases, and to correlate them with clinico-pathological factors associated with an increased risk of metastasis.


METHODS
We performed a retrospective study that included 146 cSCC samples (51 primary non-metastatic, 56 primary metastatic, 39 lymphatic metastases). Immunohistochemistry for E-cadherin, Vimentin, Snail, beta-catenin, Twist, Zeb1 and Podoplanin was performed.


RESULTS
Loss of membranous E-cadherin was observed in 77% cSCCs, with no differences between MSCC and non-MSCC. Among the transcriptional factors controlling EMT, no significant Snail1 expression was detected. Twist, Zeb1, Vimentin, beta-catenin and Podoplanin were significantly overexpressed in MSCCs. Twist ectopic expression in SCC13 cells induced Zeb1, Vimentin and Podoplanin expression and E-cadherin delocalization. These changes resulted in a scattered migration pattern in vitro. Expression of EMT markers was decreased in the metastases when compared with the corresponding primary tumors.


CONCLUSIONS
These results suggest that a partial EMT, characterized by the expression of Twist but without a total E-cadherin depletion, is involved in the acquisition of invasive traits by cSCC, but the process is downregulated in lymph node metastases.
Servei de Dermatologia, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain; Cancer Research Program, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain. Electronic address: atoll@parcdesalutmar.cat.
Agustí
A
Toll
Emili
E
Masferrer
M E
ME
Hernández-Ruiz
Carla
C
Ferrandiz-Pulido
Mireia
M
Yébenes
Ane
A
Jaka
Anna
A
Tuneu
Anna
A
Jucglà
Javier
J
Gimeno
Teresa
T
Baró
Beatriz
B
Casado
Alberto
A
Gandarillas
Irmgard
I
Costa
Sergi
S
Mojal
Raul
R
Peña
Antonio García
AG
de Herreros
Vicenç
V
García-Patos
Ramon M
RM
Pujol
Inmaculada
I
Hernández-Muñoz
D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008562:Membrane Glycoproteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D012189:Retrospective Studies; D012306:Risk; D012878:Skin Neoplasms / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin / Q000378:metabolism; D000098853:Podoplanin
D015703:Antigens, CD; D014408:Biomarkers, Tumor; D015820:Cadherins; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D014746:Vimentin; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; C117468:PDPN protein, human; D000098853:Podoplanin; C000604407:SNAI1 protein, human; C103173:TWIST1 protein, human; C486307:ZEB1 protein, human
Cutaneous squamous cell carcinoma; E-cadherin; Epithelial to mesenchymal transition; Metastasis; Twist; Vimentin