Aberrant presentation of HPA-reactive carbohydrates implies Selectin-independent metastasis formation in human prostate cancer

TY - JOUR

T1 - Aberrant presentation of HPA-reactive carbohydrates implies Selectin-independent metastasis formation in human prostate cancer

AU - Lange, Tobias

AU - Kupfernagel, Mareike

AU - Wicklein, Daniel

AU - Gebauer, Florian

AU - Maar, Hanna

AU - Brügge, Kathrin

AU - Müller, Imke

AU - Simon, Ronald

AU - Schlomm, Thorsten

AU - Sauter, Guido

AU - Schumacher, Udo

N1 - ©2014 AACR.

PY - 2014/4/1

Y1 - 2014/4/1

N2 - PURPOSE: To investigate the impact of prostate cancer cell surface glycosylation as part of the tumor cell-endothelial cell interaction in prostate cancer metastasis.EXPERIMENTAL DESIGN: Glycosyltransferase expression was profiled in metastasis-derived prostate cancer cell lines and compared with primary epithelium. Prostate cancer cells were examined for HPA- and selectin-binding and adhesion to endothelium. Spontaneous metastasis xenograft models were established to test the lectin HPA-binding sites as a marker of metastatic competence and to evaluate E-selectin-binding sites in vivo. The importance of selectins for metastasis formation was analyzed using Sele(-/-)/Selp(-/-) mice. The clinical relevance of HPA- and E-selectin-binding sites in prostate cancer was determined.RESULTS: Glycosyltransferases involved in the synthesis of common HPA-binding sites are downregulated in prostate cancer cells. An absence of HPA-reactive carbohydrates specifically indicates spontaneous metastatic spread of prostate cancer xenografts in vivo and a poor prognosis of patients with prostate cancer. HPA-binding sites decrease in lymph node metastases compared with corresponding primary tumors. Common selectin ligands are absent on prostate cancer cells, which do not adhere to recombinant selectins or endothelium under shear stress in vitro. Spontaneous metastasis formation is largely independent of selectins in vivo. E-selectin-binding sites are detectable in only 2% of patients with prostate cancer without prognostic significance.CONCLUSION: Prostate cancer is characterized by an inverse functional and prognostic importance of HPA-binding sites compared with other adenocarcinomas. Accordingly, this study surprisingly shows that the selectin-selectin ligand axis, which is essential for extravasation and thus metastasis formation in several malignancies, can be circumvented in prostate cancer.

AB - PURPOSE: To investigate the impact of prostate cancer cell surface glycosylation as part of the tumor cell-endothelial cell interaction in prostate cancer metastasis.EXPERIMENTAL DESIGN: Glycosyltransferase expression was profiled in metastasis-derived prostate cancer cell lines and compared with primary epithelium. Prostate cancer cells were examined for HPA- and selectin-binding and adhesion to endothelium. Spontaneous metastasis xenograft models were established to test the lectin HPA-binding sites as a marker of metastatic competence and to evaluate E-selectin-binding sites in vivo. The importance of selectins for metastasis formation was analyzed using Sele(-/-)/Selp(-/-) mice. The clinical relevance of HPA- and E-selectin-binding sites in prostate cancer was determined.RESULTS: Glycosyltransferases involved in the synthesis of common HPA-binding sites are downregulated in prostate cancer cells. An absence of HPA-reactive carbohydrates specifically indicates spontaneous metastatic spread of prostate cancer xenografts in vivo and a poor prognosis of patients with prostate cancer. HPA-binding sites decrease in lymph node metastases compared with corresponding primary tumors. Common selectin ligands are absent on prostate cancer cells, which do not adhere to recombinant selectins or endothelium under shear stress in vitro. Spontaneous metastasis formation is largely independent of selectins in vivo. E-selectin-binding sites are detectable in only 2% of patients with prostate cancer without prognostic significance.CONCLUSION: Prostate cancer is characterized by an inverse functional and prognostic importance of HPA-binding sites compared with other adenocarcinomas. Accordingly, this study surprisingly shows that the selectin-selectin ligand axis, which is essential for extravasation and thus metastasis formation in several malignancies, can be circumvented in prostate cancer.

U2 - 10.1158/1078-0432.CCR-13-2308

DO - 10.1158/1078-0432.CCR-13-2308

M3 - SCORING: Journal article

C2 - 24526735

VL - 20

SP - 1791

EP - 1802

JO - CLIN CANCER RES

JF - CLIN CANCER RES

SN - 1078-0432

IS - 7

ER -