ABSTRACT
Intraabdominal tumor dissemination is a major hallmark of epithelial ovarian cancer (EOC), but the underlying mechanisms have not been fully elucidated. The CXCR3 chemokine receptor supports migration of tumor cells to metastatic sites, but its role in ovarian cancer metastasis is largely unknown. Herein, we first screened two independent cohorts of high-grade serous ovarian cancers (HGSCs, discovery set n=60, validation set n=117) and 102 metastatic lesions for CXCR3 expression. In primary tumors, CXCR3 was particularly overexpressed by tumor cells at the invasive front. In intraabdominal metastases, tumor cells revealed a strong CXCR3 expression regardless of its expression in the corresponding primary tumor, suggesting a selection of CXCR3-overexpressing cancer cells into peritoneal niches. In support of this, CXCR3 mediated the migration of tumor cell lines OVCAR3 and SKOV3 toward malignant ascites, which was inhibited by a monoclonal anti-CXCR3 antibody in vitro. These results were prospectively validated in ascites-derived tumor cells from EOC patients ex vivo (n=9). Moreover, tumor cell-associated overexpression of CXCR3 in advanced ovarian cancer patients was associated with a reduced progression-free survival (PFS) and overall survival (OS), which remained independent of optimal debulking, age, FIGO stage and lymph node involvement (PFS: hazard ratio (HR) 2.11, 95% confidence interval (CI) 1.30-3.45, P=0.003; OS: HR 2.36, 95% CI 1.50-3.71, P<0.001). These results in ovarian cancer patients identify CXCR3 as a potential new target to confine peritoneal spread in ovarian cancer after primary cytoreductive surgery.
ABSTRACT
INTRODUCTION: Afterbirth tissues, which include the umbilical cord, placenta, amnion, and cord blood, are usually discarded. Recent progress in regenerative medicine suggests that we re-evaluate these tissues and assess their therapeutic potential. METHODS: Firstly the unique properties of afterbirth tissues and their current use in regenerative medicine are summarised. Then we introduce the cooperation of our institutions and our experiences regarding the collection and utilisation of afterbirth tissues. RESULTS: A literature survey suggests that besides the well-known transplantation of hematopoietic stem cells from cord blood, afterbirth tissues were also used as a source of stem cells, progenitor cells, differentiated cells, and blood vessels for tissue engineering purposes. According to our own experience, the two participating OB/GYN departments and the blood donation service were able to organise a sufficient supply of umbilical cords for research purposes. The yield correlated with incentives for the midwives. A total of more than 4,300 cords was collected for experiments designed to create small caliber vessel grafts. The contamination rate was low. Birth mode significantly affected umbilical vein function, whereas ischaemia for up to 40 h did not have any deleterious effects. Umbilical veins were cryopreserved with a moderate loss of function. Fresh umbilical veins were endothelium-denuded and reseeded with endothelial cells harvested from coronary artery disease patients to generate an autologous surface. CONCLUSIONS: Afterbirth tissues have unique properties which make them ideally suited for regenerative medicine. These tissues can be procured and utilised in research facilities even in the absence of an in-house birthing centre.
Subject(s)
Amnion , Fetal Blood , Placenta , Regenerative Medicine/methods , Umbilical Cord , Umbilical Veins , Cooperative Behavior , Cord Blood Stem Cell Transplantation , Endothelial Cells , Female , Germany , Hematopoietic Stem Cell Transplantation , Humans , Infant, Newborn , Interdisciplinary Communication , Pregnancy , Research , Stem Cells , Tissue Donors , Tissue Engineering/methods , Tissue Preservation/methodsABSTRACT
AIMS: The aim of our study was to develop and optimize methods for relative and absolute protein quantifications in formalin-fixed and paraffin-embedded (FFPE) tissues with special emphasis on HER mediated pathways in breast cancer. METHODS: Using a recently developed technology for extraction of full-length proteins from FFPE tissues, we evaluated >50 commercial antibodies for specificity using Western blots and protein microarrays. Purified HER receptor proteins were used to determine absolute protein concentrations. RESULTS: We confirmed specificity of 23 commercially available phosphospecific and non-phosphospecific antibodies using Western blots with protein extracts from cell lines and tissue extracts from breast cancer patients. Spiking known amounts of purified HER receptor proteins in HER receptor negative tissue extracts allowed us to precisely measure abundances of HER-receptors. CONCLUSIONS: Our results will provide a basis for the development of diagnostic techniques for the quantitative analysis of deregulated HER receptors and downstream signalling proteins in typical clinical tissues.
