Spontaneous lung metastasis formation of human Merkel cell carcinoma cell lines transplanted into scid mice

TY - JOUR

T1 - Spontaneous lung metastasis formation of human Merkel cell carcinoma cell lines transplanted into scid mice

AU - Knips, Jillian

AU - Czech-Sioli, Manja

AU - Spohn, Michael

AU - Heiland, Max

AU - Moll, Ingrid

AU - Grundhoff, Adam

AU - Schumacher, Udo

AU - Fischer, Nicole

N1 - © 2017 UICC.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Merkel cell carcinoma (MCC) is an aggressive skin cancer entity that frequently leads to rapid death due to its high propensity to metastasize. The etiology of most MCC cases is linked to Merkel cell polyomavirus (MCPyV), a virus which is monoclonally integrated in up to 95% of tumors. While there are presently no animal models to study the role of authentic MCPyV infection on transformation, tumorigenesis or metastasis formation, xenograft mouse models employing engrafted MCC derived cell lines (MCCL) represent a promising approach to study certain aspects of MCC pathogenesis. Here, the two MCPyV positive MCC cell lines WaGa and MKL-1 were subcutaneously engrafted in scid mice. Engraftment of both MCC cell lines resulted in the appearance of circulating tumor cells and metastasis formation, with WaGa-engrafted mice showing a significantly shorter survival time as well as increased numbers of spontaneous lung metastases compared to MKL-1 mice. Interestingly, explanted tumors compared to parental cell lines exhibit an upregulation of MCPyV sT-Antigen expression in all tumors, with WaGa tumors showing significantly higher sT-Antigen expression than MKL-1 tumors. RNA-Seq analysis of explanted tumors and parental cell lines furthermore revealed that in the more aggressive WaGa tumors, genes involved in inflammatory response, growth factor activity and Wnt signaling pathway are significantly upregulated, suggesting that sT-Antigen is the driver of the observed differences in metastasis formation. This article is protected by copyright. All rights reserved.

AB - Merkel cell carcinoma (MCC) is an aggressive skin cancer entity that frequently leads to rapid death due to its high propensity to metastasize. The etiology of most MCC cases is linked to Merkel cell polyomavirus (MCPyV), a virus which is monoclonally integrated in up to 95% of tumors. While there are presently no animal models to study the role of authentic MCPyV infection on transformation, tumorigenesis or metastasis formation, xenograft mouse models employing engrafted MCC derived cell lines (MCCL) represent a promising approach to study certain aspects of MCC pathogenesis. Here, the two MCPyV positive MCC cell lines WaGa and MKL-1 were subcutaneously engrafted in scid mice. Engraftment of both MCC cell lines resulted in the appearance of circulating tumor cells and metastasis formation, with WaGa-engrafted mice showing a significantly shorter survival time as well as increased numbers of spontaneous lung metastases compared to MKL-1 mice. Interestingly, explanted tumors compared to parental cell lines exhibit an upregulation of MCPyV sT-Antigen expression in all tumors, with WaGa tumors showing significantly higher sT-Antigen expression than MKL-1 tumors. RNA-Seq analysis of explanted tumors and parental cell lines furthermore revealed that in the more aggressive WaGa tumors, genes involved in inflammatory response, growth factor activity and Wnt signaling pathway are significantly upregulated, suggesting that sT-Antigen is the driver of the observed differences in metastasis formation. This article is protected by copyright. All rights reserved.

KW - Journal Article

U2 - 10.1002/ijc.30723

DO - 10.1002/ijc.30723

M3 - SCORING: Journal article

C2 - 28380668

VL - 141

SP - 160

EP - 171

JO - INT J CANCER

JF - INT J CANCER

SN - 0020-7136

IS - 1

ER -