Publications by authors named "Daniel Wicklein"

45 Publications

Low expression of CD24 is associated with poor survival in colorectal cancer.

Biochimie 2021 Oct 9. Epub 2021 Oct 9.

Faculty of Biology and Biotechnology, HSE University, Moscow, Russia; SRC Bioclinicum, Moscow, Russia. Electronic address:

In this study we analyzed expression of CD24 in a cohort of colorectal cancer patients using immunohistochemistry staining of CD24. We found a significant association between absence or low expression of CD24 (10% of membranous and 55% of cytoplasmic staining) and shortened patient survival. Protein localization played a crucial role in the prognosis: membranous form was the major and prognostic one in primary tumors, while cytoplasmic expression was elevated in liver metastases compared to the primary tumors and contained prognostic information. Then, using The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) RNA-seq data, we showed that CD24 mRNA level was two-fold decreased in primary colorectal cancers compared to adjacent normal mucosa. Like the protein staining data, ten percent of patients with the lowest mRNA expression levels of CD24 in primary tumors had reduced survival compared to the ones with higher expression. To explain these findings mechanistically, shRNA-mediated CD24 knockdown was performed in HT-29 colorectal cancer cells. It resulted in the increase of cell migration in vitro, no changes in proliferation and apoptosis, and a slight decrease in cell invasion. As increased cell migration is a hallmark of metastasis formation, this finding corroborates the association of a decreased CD24 expression with poor prognosis. Differential gene expression analysis revealed upregulation of genes involved in cell migration in the group of patients with low CD24 expression, including integrin subunit α3 and α3, β3 subunits of laminin 332. Further co-expression analysis identified SPI1, STAT1 and IRF1 transcription factors as putative master-regulators in this group.
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http://dx.doi.org/10.1016/j.biochi.2021.10.004DOI Listing
October 2021

Integrin alpha-V is an important driver in pancreatic adenocarcinoma progression.

J Exp Clin Cancer Res 2021 Jun 26;40(1):214. Epub 2021 Jun 26.

Institute of Anatomy and Experimental Morphology, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Mesothelial E- and P-selectins substantially mediate the intraperitoneal spread of Pancreatic ductal adenocarcinoma (PDA) cells in xenograft models. In the absence of selectins in the host, the integrin subunit alpha-V (ITGAV, CD51) was upregulated in the remaining metastatic deposits. Here we present the first experimental study to investigate if ITGAV plays a functional role in PDA tumor growth and progression with a particular focus on intraperitoneal carcinomatosis.

Methods: Knockdown of ITGAV was generated using an RNA interference-mediated approach in two PDA cell lines. Tumor growth, intraperitoneal and distant metastasis were analyzed in a xenograft model. Cell lines were characterized in vitro. Gene expression of the xenograft tumors was analyzed. Patient samples were histologically classified and associations to survival were evaluated.

Results: The knockdown of ITGAV in PDA cells strongly reduces primary tumor growth, peritoneal carcinomatosis and spontaneous pulmonary metastasis. ITGAV activates latent TGF-β and thereby drives epithelial-mesenchymal transition. Combined depletion of ITGAV on the tumor cells and E- and P-selectins in the tumor-host synergistically almost abolishes intraperitoneal spread. Accordingly, high expression of ITGAV in PDA cells was associated with reduced survival in patients.

Conclusion: Combined depletion of ITGAV in PDA cells and E- and P-selectins in host mice massively suppresses intraperitoneal carcinomatosis of PDA cells xenografted into immunodeficient mice, confirming the hypothesis of a partly redundant adhesion cascade of metastasizing cancer cells. Our data strongly encourage developing novel therapeutic approaches for the combined targeting of E- and P-selectins and ITGAV in PDA.
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http://dx.doi.org/10.1186/s13046-021-01946-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235815PMC
June 2021

Effect of the Expression of and Genes on the Metastatic Potential of Breast Cancer Cells.

Front Genet 2021 2;12:662843. Epub 2021 Jun 2.

Faculty of Biology and Biotechnologies, National Research University Higher School of Economics, Moscow, Russia.

Breast cancer (BC) is the leading cause of death from malignant neoplasms among women worldwide, and metastatic BC presents the biggest problems for treatment. Previously, it was shown that lower expression of and genes is associated with a higher risk of the formation of distant metastases in BC. In this work, we studied the change in phenotypical traits, as well as in the transcriptomic and proteomic profiles of BC cells as a result of the stable knockdown of and genes. The knockdown of and genes was found to lead to a strong increase in the expression of the matrix metalloproteinase (MMP) . These results were in good agreement with the correlation analysis of gene expression in tumor samples from patients and were additionally confirmed by zymography. The knockdown of and genes was also discovered to change the expression of a group of genes involved in the formation of intercellular contacts. In particular, the expression of the gene was markedly reduced, which also complies with the correlation analysis. The spheroid formation assay showed that intercellular adhesion decreased as a result of the knockdown of the and genes. Thus, the obtained data indicate that malignant breast tumors with reduced expression of the and genes can metastasize with a higher probability due to a more efficient invasion of tumor cells.
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http://dx.doi.org/10.3389/fgene.2021.662843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206645PMC
June 2021

Xenograft-derived mRNA/miR and protein interaction networks of systemic dissemination in human prostate cancer.

Eur J Cancer 2020 09 1;137:93-107. Epub 2020 Aug 1.

Institute of Anatomy and Experimental Morphology, University Medical Center, Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany.

Background: Distant metastasis formation is the major clinical problem in prostate cancer (PCa) and the underlying mechanisms remain poorly understood. Our aim was to identify novel molecules that functionally contribute to human PCa systemic dissemination based on unbiased approaches.

Methods: We compared mRNA, microRNA (miR) and protein expression levels in established human PCa xenograft tumours with high (PC-3), moderate (VCaP) or weak (DU-145) spontaneous micrometastatic potential. By focussing on those mRNAs, miRs and proteins that were differentially regulated among the xenograft groups and known to interact with each other we constructed dissemination-related mRNA/miR and protein/miR networks. Next, we clinically and functionally validated our findings.

Results: Besides known determinants of PCa progression and/or metastasis, our interaction networks include several novel candidates. We observed a clear role of epithelial-to-mesenchymal transition (EMT) pathways for PCa dissemination, which was additionally confirmed by an independent human PCa model (ARCAP-E/-M). Two converging nodes, CD46 (decreasing with metastatic potential) and DDX21 (increasing with metastatic potential), were used to test the clinical relevance of the networks. Intriguingly, both network nodes consistently added prognostic information for patients with PCa whereas CD46 loss predicted poor outcome independent of established parameters. Accordingly, depletion of CD46 in weakly metastatic PCa cells induced EMT-like properties in vitro and spontaneous micrometastasis formation in vivo.

Conclusions: The clinical and functional relevance of the dissemination-related interaction networks shown here could be successfully validated by proof-of-principle experiments. Therefore, we suggest a direct pro-metastatic, clinically relevant role for the multiple novel candidates included in this study; these should be further exploited by future studies.
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http://dx.doi.org/10.1016/j.ejca.2020.06.025DOI Listing
September 2020

Systematic analysis of the human tumor cell binding to human vs. murine E- and P-selectin under static vs. dynamic conditions.

Glycobiology 2020 08;30(9):695-709

Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.

Endothelial E- and P-selectins promote metastasis formation by interacting with sialyl-Lewis X and A (sLeX/sLeA) on circulating tumor cells. This interaction precedes extravasation and can take place under dynamic and static conditions. Metastasis formation is often studied in xenograft models. However, it is unclear whether species differences exist in the ligand specificity of human (h) vs. murine (m) selectins and whether different ligands are functional under dynamic vs. static conditions. We systematically compared the h vs. m E- and P-selectin (ESel/PSel) binding of a range of human tumor cells under dynamic vs. static conditions. The tumor cells were categorized by their sLeA/X status (sLeA+/sLeX+, sLeA-/sLeX+ and sLeA-/sLeX-). The general biological nature of the tumor-selectin interaction was analyzed by applying several tumor cell treatments (anti-sLeA/X blockade, neuraminidase, pronase and inhibition of O/N-glycosylation). We observed remarkable differences in the static vs. dynamic interaction of tumor cells with h vs. m ESel/PSel depending on their sLeA/X status. The tumor cell treatments mostly affected either static or dynamic as well as either h- or m-selectin interaction. mESel showed a higher diversity of potential ligands than hESel. Inhibition of O-GalNAc-glycosylation also affected glycosphingolipid synthesis. Summarized, different ligands on human tumor cells are functional under static vs. dynamic conditions and for the interaction with human vs. murine ESel/PSel. Non-canonical selectin ligands lacking the sLeA/X glycan epitopes exist on human tumor cells. These findings have important implications for the current development of glycomimetic, antimetastatic drugs and encourage the development of immunodeficient mice with humanized selectins.
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http://dx.doi.org/10.1093/glycob/cwaa019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443332PMC
August 2020

-Regulating miR-4274 and Its Host Gene Play a Role in -Dependent Effects on Phenotype of Basal-Like Breast Cancer.

Front Mol Biosci 2019 8;6:122. Epub 2019 Nov 8.

Faculty of Biology and Biotechnologies, Higher School of Economics, Moscow, Russia.

Specificity of RNAi to selected target is challenged by off-target effects, both canonical and non-canonical. Notably, more than half of all human microRNAs are co-expressed with hosting them proteincoding genes. Here we dissect regulatory subnetwork centered on gene, which is associated with low proliferative state and high migratory activity of basal-like breast cancer. We inhibited expression of gene in a model cell line for basal-like breast carcinoma MDA-MB-231, then traced secondary and tertiary effects of this knockdown to , a laminin encoding gene that contributes to the phenotype of triple-negative breast cancer. -regulating miRNA miR-4274 and its host gene were highlighted as intermediate regulators of the expression levels of , which correlated in a basal-like breast carcinoma sample subset of TCGA to the levels of negatively. Overall, our study points that the secondary and tertiary layers of regulatory interactions are certainly underappreciated. As these types of molecular event may significantly contribute to the formation of the cell phenotypes after RNA interference based knockdowns, further studies of multilayered molecular networks affected by RNAi are warranted.
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http://dx.doi.org/10.3389/fmolb.2019.00122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857517PMC
November 2019

The Actin Binding Protein Plastin-3 Is Involved in the Pathogenesis of Acute Myeloid Leukemia.

Cancers (Basel) 2019 Oct 26;11(11). Epub 2019 Oct 26.

Department of Oncology, Hematology and Bone Marrow Transplantation with Division of Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Leukemia-initiating cells reside within the bone marrow in specialized niches where they undergo complex interactions with their surrounding stromal cells. We have identified the actin-binding protein Plastin-3 (PLS3) as potential player within the leukemic bone marrow niche and investigated its functional role in acute myeloid leukemia. High expression of PLS3 was associated with a poor overall and event-free survival for AML patients. These findings were supported by functional in vitro and in vivo experiments. AML cells with a PLS3 knockdown showed significantly reduced colony numbers in vitro while the PLS3 overexpression variants resulted in significantly enhanced colony numbers compared to their respective controls. Furthermore, the survival of NSG mice transplanted with the PLS3 knockdown cells showed a significantly prolonged survival in comparison to mice transplanted with the control AML cells. Further studies should focus on the underlying leukemia-promoting mechanisms and investigate PLS3 as therapeutic target.
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http://dx.doi.org/10.3390/cancers11111663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895973PMC
October 2019

Immunohistochemical Analysis of Transcription Factors and Markers of Epithelial-Mesenchymal Transition (EMT) in Human Tumors.

Anticancer Res 2019 Oct;39(10):5437-5448

Institute of Anatomy and Experimental Morphology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background/aim: Epithelial-mesenchymal transition (EMT) is a key multi-step process which enables cancer cells to detach from the epithelial primary tumor mass and allows them to metastasize to distant organs. We immunohistochemically analyzed the expression of the transcription factors (TWIST-1, SLUG, ZEB1, ZEB2) and components of the extracellular matrix (laminin-5, fibronectin) which influence the EMT.

Materials And Methods: Primary human breast (MDA-MB-231), colon (HT29, HCT116), ovarian (SKOV3, OVCAR3) and head and neck squamous cell carcinoma cell lines (UTSCC2, UTSCC24A) grown as xenografts were immunohistochemically analyzed in vitro and in vivo.

Results: A high SLUG expression was observed in every cancer entity both in vitro and in vivo. ZEB1 and ZEB2 showed a high in vivo expression especially in SKOV3 and in in vitro grown MDA-MB-231 cells.

Conclusion: SLUG expression showed the highest expression in all cancer entities investigated. Hence, it presumably represents the master regulator of EMT in these metastatic tumor entities.
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http://dx.doi.org/10.21873/anticanres.13737DOI Listing
October 2019

Redistribution, homing and organ-invasion of neoplastic stem cells in myeloid neoplasms.

Semin Cancer Biol 2020 02 10;60:191-201. Epub 2019 Aug 10.

Institute of Anatomy and Experimental Morphology, University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The development of a myeloid neoplasm is a step-wise process that originates from leukemic stem cells (LSC) and includes pre-leukemic stages, overt leukemia and a drug-resistant terminal phase. Organ-invasion may occur in any stage, but is usually associated with advanced disease and a poor prognosis. Sometimes, extra-medullary organ invasion shows a metastasis-like or even sarcoma-like destructive growth of neoplastic cells in local tissue sites. Examples are myeloid sarcoma, mast cell sarcoma and localized blast phase of chronic myeloid leukemia. So far, little is known about mechanisms underlying re-distribution and extramedullary dissemination of LSC in myeloid neoplasms. In this article, we discuss mechanisms through which LSC can mobilize out of the bone marrow niche, can transmigrate from the blood stream into extramedullary organs, can invade local tissue sites and can potentially create or support the formation of local stem cell niches. In addition, we discuss strategies to interfere with LSC expansion and organ invasion by targeted drug therapies.
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http://dx.doi.org/10.1016/j.semcancer.2019.07.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115853PMC
February 2020

CEACAM1 promotes melanoma metastasis and is involved in the regulation of the EMT associated gene network in melanoma cells.

Sci Rep 2018 08 8;8(1):11893. Epub 2018 Aug 8.

Institute of Anatomy and Experimental Morphology, University Cancer Center, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany.

We investigated the functional role of CEACAM1 in a spontaneous metastasis xenograft model of human melanoma in scid mice using BRAF wildtype MeWo cells with and without RNAi mediated knockdown of CEACAM1. Tumors from the xenograft model were subjected to whole genome expression analysis and metastasis was quantified histologically. Results and identified markers were verified using tissue samples of over 100 melanoma patients. Knockdown of CEACAM1 prolonged the animals' survival by significantly reducing subcutaneous growth of MeWo tumors and spontaneous lung metastasis. Microarray analysis revealed a strong influence of CEACAM1 knockdown on the network of EMT associated genes in the xenograft tumors (e.g. downregulation of BRAF, FOSL1, NRAS and TWIST). IGFBP7 and Latexin (highest up- and downregulated expression in microarray analysis) were found to be associated with longer and shorter survival, respectively, of melanoma patients. High FOSL1 and altered TWIST1 expression were found to be correlated with shortened survival in the cohort of melanoma patients. After a stepwise selection procedure combining above markers, multivariate analysis revealed IGFBP7, Latexin and altered TWIST to be prognostic markers for death. CEACAM1 could be a target for melanoma therapy as an alternative to (or in combination with) immune checkpoint and BRAF inhibitors.
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http://dx.doi.org/10.1038/s41598-018-30338-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082866PMC
August 2018

CD44 is a RAS/STAT5-regulated invasion receptor that triggers disease expansion in advanced mastocytosis.

Blood 2018 11 17;132(18):1936-1950. Epub 2018 Jul 17.

Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria.

The Hermes receptor CD44 is a multifunctional adhesion molecule that plays an essential role in the homing and invasion of neoplastic stem cells in various myeloid malignancies. Although mast cells (MCs) reportedly express CD44, little is known about the regulation and function of this receptor in neoplastic cells in systemic mastocytosis (SM). We found that clonal CD34/CD38 stem cells, CD34/CD38 progenitor cells, and CD117/CD34 MCs invariably express CD44 in patients with indolent SM (ISM), SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia (MCL). In addition, all human MCL-like cell lines examined (HMC-1, ROSA, and MCPV-1) displayed cytoplasmic and cell-surface CD44. We also found that expression of CD44 in neoplastic MCs depends on RAS-MEK and STAT5 signaling and increases with the aggressiveness of SM. Correspondingly, higher levels of soluble CD44 were measured in the sera of patients with advanced SM compared with ISM or cutaneous mastocytosis and were found to correlate with overall and progression-free survival. To investigate the functional role of CD44, a xenotransplantation model was employed using severe combined immunodeficient (SCID) mice, HMC-1.2 cells, and a short hairpin RNA (shRNA) against CD44. In this model, the shRNA-mediated knockdown of CD44 resulted in reduced MC expansion and tumor formation and prolonged survival in SCID mice compared with HMC-1.2 cells transduced with control shRNA. Together, our data show that CD44 is a RAS-MEK/STAT5-driven MC invasion receptor that correlates with the aggressiveness of SM. Whether CD44 can serve as therapeutic target in advanced SM remains to be determined in forthcoming studies.
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http://dx.doi.org/10.1182/blood-2018-02-833582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382065PMC
November 2018

Knockdown of L1CAM significantly reduces metastasis in a xenograft model of human melanoma: L1CAM is a potential target for anti-melanoma therapy.

PLoS One 2018 12;13(2):e0192525. Epub 2018 Feb 12.

Institute of Anatomy and Experimental Morphology, University Cancer Center, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany.

Finding additional functional targets for combination therapy could improve the outcome for melanoma patients. In a spontaneous metastasis xenograft model of human melanoma a shRNA mediated knockdown of L1CAM more than sevenfold reduced the number of lung metastases after the induction of subcutaneous tumors for two human melanoma cell lines (MeWo, MV3). Whole genome expression arrays of the initially L1CAM high MeWo subcutaneous tumors revealed unchanged or downregulated genes involved in epithelial to mesenchymal transition (EMT) except an upregulation of Jagged 1, indicating a compensatory change in Notch signaling especially as Jagged 1 expression showed an increase in MeWo L1CAM metastases and Jagged 1 was expressed in metastases of the initially L1CAM low MV3 cells as well. Expression of 17 genes showed concordant regulation for L1CAM knockdown tumors of both cell lines. The changes in gene expression indicated changes in the EMT network of the melanoma cells and an increase in p53/p21 and p38 activity contributing to the reduced metastatic potential of the L1CAM knockdowns. Taken together, these data make L1CAM a highly interesting therapeutic target to prevent further metastatic spread in melanoma patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192525PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809060PMC
April 2018

Intracellular and extracellular microRNA: An update on localization and biological role.

Prog Histochem Cytochem 2016 11 25;51(3-4):33-49. Epub 2016 Jun 25.

Hertsen Moscow Oncology Research Institute, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, 125284, Moscow, Russian Federation. Electronic address:

MicroRNA (miRNA) is a class of small non-coding RNAs which mediate post-transcriptional gene silencing (PTGS) by sequence-specific inhibition of target mRNAs translation and/or lowering their half-lives in the cytoplasm. Together with their binding partners, Argonaute (AGO) proteins, miRNAs form cores of RNA-induced silencing complexes (RISC). Despite a substantial progress in understanding RISC structure, until recently little was known about its localization in the cell. This review is aimed to provide an overview of the emerging picture of miRNA and RISC localization and function both in the intracellular space and outside of the cell. In contrast to the common assumption that PTGS occurs in the cytoplasm, it was found to operate mainly on the membranes of the endoplasmic reticulum (ER). Besides ER membranes miRNAs were found in all main cellular compartments including nucleus, nucleolus and mitochondria where they regulate various processes including transcription, translation, alternative splicing and DNA repair. Moreover, a certain pool of miRNAs may not be associated with RISC and carry completely different functions. Finally, the discovery of cell-free miRNAs in all biological fluids suggests that miRNAs might also act as signaling molecules outside the cell, and may be utilized as biomarkers for a variety of diseases. In this review we discuss miRNA secretion mechanisms and possible pathways of cell-cell communication via miRNA-containing exosomes in vivo.
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http://dx.doi.org/10.1016/j.proghi.2016.06.001DOI Listing
November 2016

L1CAM: Cell adhesion and more.

Prog Histochem Cytochem 2016 08 24;51(2):25-32. Epub 2016 May 24.

Hertsen Federal Medical Research Centre of the Ministry of Health of the Russian Federation, Koroleva str 4, 249036 Obninsk, Russia; Moscow State University, Leninskie Gory, 119991 Moscow, Russia. Electronic address:

L1CAM is a cell adhesion molecule of the immunoglobulin superfamily which was originally discovered as a major player in the development of the nervous system. L1CAM was demonstrated to have prognostic value in different cancers and to be a promising target for anti-cancer therapy. Here we overview the present data on L1CAM structure and function, regulation of its expression, role in cancer and therapeutic potential.
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http://dx.doi.org/10.1016/j.proghi.2016.05.001DOI Listing
August 2016

Establishment and Characterization of a Pair of Patient-derived Human Non-small Cell Lung Cancer Cell Lines from a Primary Tumor and Corresponding Lymph Node Metastasis.

Anticancer Res 2016 Apr;36(4):1507-18

Institute of Anatomy and Experimental Morphology, University Cancer Center Hamburg, University of Hamburg, Hamburg, Germany.

Background: Non-small lung cancer is the leading cause of cancer-related mortality worldwide. For a deeper understanding of tumor biology, we established a pair of cell lines derived from a primary tumor and a corresponding lymph node metastasis.

Material And Methods: The cell line BC4323 from the primary tumor (PT) and a mediastinal lymph node metastasis (LN) were derived from an adenocarcinoma (pT2, pN2, G3, UICC stage IIIa) in a 47-year-old female patient. Comparative characterization was performed by in vitro analysis. A murine xenograft was established for analysis of in vivo behavior.

Results: Chromosomal aberrations were detected in multiple chromosomal sections throughout the entire genome, with only a few differences between PT and LN cells. High-level Kirsten ras oncogene homolog (KRAS) mutation and amplification were seen based on a chromosomal translocation and novel assembled chromosome. In contrast to the genomic level, at the mRNA and protein levels, multiple differences were detectable, in particular in markers for cell adhesion [e.g. epithelial cell adhesion molecule (EpCAM), CD44, P-selectin binding, epidermal growth factor receptor (EGFR) and integrin alphaV] and the epithelial-mesenchymal transition. Due to accelerated tumor growth in vivo by the PT cells, a shortened overall survival was seen (60 vs. 101 days, p=0.005).

Conclusion: We provide detailed analysis of a cell line derived from a primary tumor and a corresponding LN metastasis. This unique feature allows further investigative analysis of the differences and regulatory processes underlying the metastatic process during tumor progression in non-small cell lung cancer.
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April 2016

Carcinoembryonic antigen-related cell adhesion molecules (CEACAM) 1, 5 and 6 as biomarkers in pancreatic cancer.

PLoS One 2014 19;9(11):e113023. Epub 2014 Nov 19.

Institute of Anatomy and Experimental Morphology and University Cancer Center Hamburg (UCCH), University Medical-Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Aim of this study was to assess the biological function in tumor progression and metastatic process carcinoembryonic antigen-related cell adhesion molecules (CEACAM) 1, 5 and 6 in pancreatic adenocarcinoma (PDAC).

Experimental Design: CEACAM knock down cells were established and assessed in vitro and in a subcutaneous and intraperitoneal mouse xenograft model. Tissue and serum expression of patients with PDAC were assessed by immunohistochemistry (IHC) and by enzyme linked immunosorbent assays.

Results: Presence of lymph node metastasis was correlated with CEACAM 5 and 6 expression (determined by IHC) and tumor recurrence exclusively with CEACAM 6. Patients with CEACAM 5 and 6 expression showed a significantly shortened OS in Kaplan-Meier survival analyses. Elevated CEACAM6 serum values showed a correlation with distant metastasis and. Survival analysis revealed a prolonged OS for patients with low serum CEACAM 1 values. In vitro proliferation and migration capacity was increased in CEACAM knock down PDAC cells, however, mice inoculated with CEACAM knock down cells showed a prolonged overall-survival (OS). The number of spontaneous pulmonary metastasis was increased in the CEACAM knock down group.

Conclusion: The effects mediated by CEACAM expression in PDAC are complex, though overexpression is correlated with loco-regional aggressive tumor growth. However, loss of CEACAM can be considered as a part of epithelial-mesenchymal transition and is therefore of rather importance in the process of distant metastasis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0113023PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237406PMC
July 2015

Serum EpCAM expression in pancreatic cancer.

Anticancer Res 2014 Sep;34(9):4741-6

Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Aim of the study was to assess the diagnostic and prognostic impact of serum EpCAM levels in patients with pancreatic adenocarcinoma (PDAC).

Materials And Methods: For quantitative measurement of preoperative serum EpCAM levels, a sandwich enzyme immunoassay kit was used (ELISA). Sixty-six patients with PDAC were included in the study and for comparison 43 patients with chronic pancreatitis and 104 healthy blood donors without any clinical evidence of cancer were analyzed as well.

Results: Serum EpCAM levels differed significantly between the groups. The average value for patients with PDAC was 0.240±0.833 ng/ml, in patients with CP 0.192±0.590 ng/ml and 0.626±1.164 ng/ml in normal blood donor sera. With a cut-off level of 0.422 ng/ml EpCAM, the calculated sensitivity of detecting PDAC was 66.7% with corresponding specificity of 77.5%. A correlation with clinico-pathological data (pT, pN, M, R-status, grading, UICC stage) was not found and in addition there was no difference in overall survival between patients with high- and low-preoperative serum EpCAM levels.

Conclusion: EpCAM can be detected in the serum in patients with PDAC though the sensitivity for detecting PDAC is low and a correlation with clinical parameters was not found.
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September 2014

Molecular changes in pre-metastatic lymph nodes of esophageal cancer patients.

PLoS One 2014 21;9(7):e102552. Epub 2014 Jul 21.

Department of Clinical Chemistry, Center for Diagnostic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Lymph node metastasis indicates poor prognosis in esophageal cancer. To understand the underlying mechanisms, most studies so far focused on investigating the tumors themselves and/or invaded lymph nodes. However they neglected the potential events within the metastatic niche, which precede invasion. Here we report the first description of these regulations in patients on transcription level. We determined transcriptomic profiles of still metastasis-free regional lymph nodes for two patient groups: patients classified as pN1 (n = 9, metastatic nodes exist) or pN0 (n = 5, no metastatic nodes exist). All investigated lymph nodes, also those from pN1 patients, were still metastasis-free. The results show that regional lymph nodes of pN1 patients differ decisively from those of pN0 patients--even before metastasis has taken place. In the pN0 group distinct immune response patterns were observed. In contrast, lymph nodes of the pN1 group exhibited a clear profile of reduced immune response and reduced proliferation, but increased apoptosis, enhanced hypoplasia and morphological conversion processes. DKK1 was the most significant gene associated with the molecular mechanisms taking place in lymph nodes of patients suffering from metastasis (pN1). We assume that the two molecular profiles observed constitute different stages of a progressive disease. Finally we suggest that DKK1 might play an important role within the mechanisms leading to lymph node metastasis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102552PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105535PMC
April 2015

Antibody directed against human YKL-40 increases tumor volume in a human melanoma xenograft model in scid mice.

PLoS One 2014 21;9(4):e95822. Epub 2014 Apr 21.

Institute of Anatomy and Experimental Morphology, University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Induced overexpression of the secretory protein YKL-40 promotes tumor growth in xenograft experiments. We investigated if targeting YKL-40 with a monoclonal antibody could inhibit tumor growth. YKL-40 expressing human melanoma cells (LOX) were injected subcutenously in Balb/c scid mice. Animals were treated with intraperitoneal injections of anti-YKL-40, isoptype control or PBS. Non-YKL-40 expressing human pancreatic carcinoma cell line PaCa 5061 served as additional control. MR imaging was used for evaluation of tumor growth. Two days after the first injections of anti-YKL-40, tumor volume had increased significantly compared with controls, whereas no effects were observed for control tumors from PaCa 5061 cells lacking YKL-40 expression. After 18 days, mean tumor size of the mice receiving repeated anti-YKL-40 injections was 1.82 g, >4 times higher than mean tumor size of the controls (0.42 g). The effect of anti-YKL-40 on the increase of tumor volume started within hours after injection and was dose dependent. Intratumoral hemorrhage was observed in the treated animals. The strong effect on tumor size indicates important roles for YKL-40 in melanoma growth and argues for a careful evaluation of antibody therapy directed against YKL-40.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095822PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994147PMC
June 2015

L1CAM promotes enrichment of immunosuppressive T cells in human pancreatic cancer correlating with malignant progression.

Mol Oncol 2014 Jul 2;8(5):982-97. Epub 2014 Apr 2.

Group Inflammatory Carcinogenesis, Institute for Experimental Medicine, UKSH Campus Kiel, Arnold-Heller-Str. 3, Building 17, 24105 Kiel, Germany. Electronic address:

Regulatory T cell (T-reg) enrichment in the tumor microenvironment is regarded as an important mechanism of tumor immune escape. Hence, the presence of T-regs in highly malignant pancreatic ductal adenocarcinoma (PDAC) is correlated with short survival. Likewise, the adhesion molecule L1CAM is upregulated during PDAC progression in the pancreatic ductal epithelium also being associated with poor prognosis. To investigate whether L1CAM contributes to enrichment of T-regs in PDAC, human CD4(+)CD25(+)CD127(-)CD49d(-) T-regs and CD4(+)CD25(-) T-effector cells (T-effs) were isolated by magnetic bead separation from blood of healthy donors. Their phenotype and functional behavior were analyzed in dependence on human premalignant (H6c7) or malignant (Panc1) pancreatic ductal epithelial cells, either exhibiting or lacking L1CAM expression. T cells derived from blood and tumors of PDAC patients were analyzed by flow cytometry and findings were correlated with clinical parameters. Predominantly T-regs but not T-effs showed an increased migration on L1CAM expressing H6c7 and Panc1 cells. Whereas proliferation of T-regs did not change in the presence of L1CAM, T-effs proliferated less, exhibited a decreased CD25 expression and an increased expression of CD69. Moreover, these T-effs exhibited a regulatory phenotype as they inhibited proliferation of autologous T cells. Accordingly, CD4(+)CD25(-)CD69(+) T cells were highly abundant in PDAC tissues compared to blood being associated with nodal invasion and higher grading in PDAC patients. Overall, these data point to an important role of L1CAM in the enrichment of immunosuppressive T cells in particular of a CD4(+)CD25(-)CD69(+)-phenotype in PDAC providing a novel mechanism of tumor immune escape which contributes to tumor progression.
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http://dx.doi.org/10.1016/j.molonc.2014.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528528PMC
July 2014

Selectins mediate small cell lung cancer systemic metastasis.

PLoS One 2014 3;9(4):e92327. Epub 2014 Apr 3.

Department of Anatomy and Experimental Morphology, University Medical Center Hamburg- Eppendorf, Hamburg, Germany; Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg- Eppendorf, Hamburg, Germany.

Metastasis formation is the major reason for the extremely poor prognosis in small cell lung cancer (SCLC) patients. The molecular interaction partners regulating metastasis formation in SCLC are largely unidentified, however, from other tumor entities it is known that tumor cells use the adhesion molecules of the leukocyte adhesion cascade to attach to the endothelium at the site of the future metastasis. Using the human OH-1 SCLC line as a model, we found that these cells expressed E- and P-selectin binding sites, which could be in part attributed to the selectin binding carbohydrate motif sialyl Lewis A. In addition, protein backbones known to carry these glycotopes in other cell lines including PSGL-1, CD44 and CEA could be detected in in vitro and in vivo grown OH1 SCLC cells. By intravital microscopy of murine mesenterial vasculature we could capture SCLC cells while rolling along vessel walls demonstrating that SCLC cells mimic leukocyte rolling behavior in terms of selectin and selectin ligand interaction in vivo indicating that this mechanism might indeed be important for SCLC cells to seed distant metastases. Accordingly, formation of spontaneous distant metastases was reduced by 50% when OH-1 cells were xenografted into E-/P-selectin-deficient mice compared with wild type mice (p = 0.0181). However, as metastasis formation was not completely abrogated in selectin deficient mice, we concluded that this adhesion cascade is redundant and that other molecules of this cascade mediate metastasis formation as well. Using several of these adhesion molecules as interaction partners presumably make SCLC cells so highly metastatic.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0092327PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974710PMC
January 2015

SDA, a DNA aptamer inhibiting E- and P-selectin mediated adhesion of cancer and leukemia cells, the first and pivotal step in transendothelial migration during metastasis formation.

PLoS One 2014 3;9(4):e93173. Epub 2014 Apr 3.

Hamburg University, MIN-Faculty, Chemistry Department, Institute for Biochemistry and Molecular Biology, Hamburg, Germany.

Endothelial (E-) and platelet (P-) selectin mediated adhesion of tumor cells to vascular endothelium is a pivotal step of hematogenous metastasis formation. Recent studies have demonstrated that selectin deficiency significantly reduces metastasis formation in vivo. We selected an E- and P-Selectin specific DNA Aptamer (SDA) via SELEX (Systematic Evolution of Ligands by EXponential enrichment) with a K(d) value of approximately 100 nM and the capability of inhibiting the interaction between selectin and its ligands. Employing human colorectal cancer (HT29) and leukemia (EOL-1) cell lines we could demonstrate an anti-adhesive effect for SDA in vitro. Under physiological shear stress conditions in a laminar flow adhesion assay, SDA inhibited dynamic tumor cell adhesion to immobilized E- or P-selectin. The stability of SDA for more than two hours allowed its application in cell-cell adhesion assays in cell culture medium. When adhesion of HT29 cells to TNFα-stimulated E-selectin presenting human pulmonary microvascular endothelial cells was analyzed, inhibition via SDA could be demonstrated as well. In conclusion, SDA is a potential new therapeutic agent that antagonizes selectin-mediated adhesion during metastasis formation in human malignancies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093173PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974700PMC
January 2015

Cell adhesion molecules in metastatic neuroblastoma models.

Clin Exp Metastasis 2014 Apr 19;31(4):483-96. Epub 2014 Feb 19.

Center for Experimental Medicine, Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Several cell adhesion molecules (CAMs) including selectins, integrins, cadherins and immunoglobulin-like CAMs are involved in leukocyte adhesion especially at sites of inflammation. In cancer cells, these CAMs have been associated with the growth and metastatic behavior in several malignant entities. In this study adhesion of LAN 1 and SK-N-SH neuroblastoma cells to selectins, hyaluronan and endothelial cells were determined under flow conditions. Furthermore cells were injected subcutaneously into wildtype and selectin deficient scid mice and their growth and metastatic behavior were analyzed. Under shear stress SK-N-SH cells firmly adhered to E-selectin-Fc-fusion protein, hyaluronan and endothelial cells, while LAN 1 cells showed less or hardly any adhesive events by comparison. In the SK-N-SH xenograft model metastasis formation was slightly dependent on the expression of selectins, while LAN 1 cells developed metastases completely independent of selectin expression. The different adhesive and metastatic properties of LAN 1 and SK-N-SH cells are reflected by a different expression profile of several CAMs. The results indicate that endothelial selectins are not essential for metastasis formation of human LAN 1 and SK-N-SH cells. However, other CAMs namely CD44, N-cadherin, NCAM and integrins were upregulated or downregulated, respectively, in SK-N-SH and LAN 1 cells and are potential adhesion molecules involved in the metastatic cascade of these cells.
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http://dx.doi.org/10.1007/s10585-014-9643-8DOI Listing
April 2014

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

Clin Cancer Res 2014 Apr 13;20(7):1791-802. Epub 2014 Feb 13.

Authors' Affiliations: Institutes of Anatomy and Experimental Morphology and Pathology, University Cancer Center Hamburg, Department of General, Visceral and Thoracic Surgery, and Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-2308DOI Listing
April 2014

Activated leukocyte cell adhesion molecule (CD166): an "inert" cancer stem cell marker for non-small cell lung cancer?

Stem Cells 2014 Jun;32(6):1429-36

Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg Eppendorf, Hamburg, Germany.

Recently, the activated leukocyte cell adhesion molecule (CD166) was identified as an "inert" cancer stem cell (CSC) marker for non-small cell lung cancer (NSCLC). Few data exist regarding the clinical relevance of CD166 expression in NSCLC. We evaluated the expression of CD166 using immunohistochemistry in a large cohort of NSCLC patients (n = 1,910) on a tissue microarray basis. Expression was inversely associated with tumor size and lymph node status. Grading slightly failed to be significantly inversely associated, and survival analysis revealed no significant survival benefit of CD166-positive patients. Due to the results of this study, the theory of CD166 as a CSC marker for NSCLC must be questioned. The association of CD166 with smaller tumors and no nodal metastases does not make it a typical CSC marker. Further studies are required to investigate the functional role of CD166 in NSCLC.
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http://dx.doi.org/10.1002/stem.1665DOI Listing
June 2014

E- and p-selectins are essential for repopulation of chronic myelogenous and chronic eosinophilic leukemias in a scid mouse xenograft model.

PLoS One 2013 26;8(7):e70139. Epub 2013 Jul 26.

Institute of Anatomy and Experimental Morphology, University Cancer Center, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany.

In chronic myelogenous (CML) and chronic eosinophilic leukemia (CEL), neoplastic cells spread via the circulation into various extramedullary organs. As E- and P-selectin constitute the starting point for the leucocyte adhesion/invasion cascade, and CEL and CML cells share many properties with normal granulocytes, we investigated the role of these selectins in CEL and CML cell expansion and organ invasion in a xenotransplantation model using scid mice. Using two human leukemic cell lines (EOL-1 and K562), we were able to show that E- and P-selectins mediate leukemia cell tethering and adherence in a laminar flow assay. While E-selectin binding depended on sialylated carbohydrate moieties, P-selectin binding was completely (K562) or partially (EOL-1) independent of these carbohydrates indicating the involvement of non-canonical selectin ligands. In a xenograft model in scid mice, both cell lines invaded the bone marrow and other organs, formed chloromas, and ultimately produced an overt leukemia. In contrast, in E- and P-selectin knockout scid mice, the cells failed to show engraftment in 8 out of 10 animals and even if they did engraft, they produced only little organ invasion and chloroma formation. Together, these data suggest that E- and P-selectins play an important role in leukemic dissemination in CML and CEL.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070139PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724803PMC
April 2014

Interaction of magnetically labeled multipotent mesenchymal stromal cells and E-and P-selectins monitored by magnetic resonance imaging in mice.

Mol Imaging 2013 Mar-Apr;12(2):100-10

Department of Diagnostic and Interventional Radiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The purpose of this study was to analyze the influence of E- and P-selectins on the migratory pattern of magnetically labeled multipotent mesenchymal stromal cells (MSCs) in mice using magnetic resonance imaging (MRI). Murine MSCs were labeled with fluorescent iron oxide microparticles and carboxyfluorescein succinidyl ester (CFSE). Expression of common MSC markers, CD44, CD90, CD105, and Sca-1, as well as of selectin ligands, CD15s and CD162, was assessed using flow cytometry and immunocytochemistry. Labeled MSCs were injected into E-/P-selectin-deficient and wild-type mice applying doses of 5 × 10(4) cells intracardially, 1 × 10(6) cells intravenously, and 5 × 10(6) cells intraperitoneally. After cell administration, mice underwent MRI repeatedly and histologic evaluation after 7 days. The results demonstrate that magnetically labeled murine MSCs retain their expression of the above-mentioned surface markers and their ability to interact with P-selectin. Furthermore, MRI examinations and histologic analysis revealed that E-/P-selectin deficiency in mice significantly alters the distribution of labeled MSCs after cell injection via different routes.
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August 2013

Influence of L1-CAM expression of breast cancer cells on adhesion to endothelial cells.

J Cancer Res Clin Oncol 2013 Jan 16;139(1):107-21. Epub 2012 Sep 16.

Department of Gynecology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Bldg. N27, 20246 Hamburg, Germany.

Purpose: Expression of the adhesion molecule L1-CAM (L1) has been shown to correlate with early recurrence in breast cancer. Here, we investigated whether L1-CAM expression of breast cancer cells might influence adherence to human pulmonary microvascular endothelial cells (HPMEC) and thus promote metastasis.

Methods: MDA-MB231-Fra2 breast cancer cells that express high levels of L1-CAM (L1(high) cells) were stably transfected to generate clones with strong L1-CAM downregulation. Adhesion to activated HPMEC was studied in dynamic cell flow and static assays. Potential binding partners on endothelial cells were identified by blocking experiments and adhesion assays after coating of the flow channels with recombinant proteins.

Results: Adhesion of L1(high) cells to activated HPMEC was significantly higher compared to L1l(ow) clones under flow conditions. Blocking experiments and adhesion assays with recombinant proteins identified activated leucocyte cell adhesion molecule (ALCAM) or L1 itself, but not ICAM-1, as potential binding partners on endothelial cells. E-selectin blocking antibodies strongly diminished the adherence of breast cancer cells irrespective of their L1-CAM expression.

Conclusions: Our experiments indicate that L1-CAM expression on breast cancer cells can promote adherence to activated endothelial cells by binding to endothelial L1-CAM or ALCAM. This mechanism might lead to increased metastasis and a poor prognosis in L1-CAM-positive carcinomas in vivo. Therefore, L1-CAM might be a suitable therapeutic target in breast cancers with a high L1-CAM expression.
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http://dx.doi.org/10.1007/s00432-012-1306-zDOI Listing
January 2013

RNAi technology to block the expression of molecules relevant to metastasis: the cell adhesion molecule CEACAM1 as an instructive example.

Authors:
Daniel Wicklein

Methods Mol Biol 2012 ;878:241-50

Centre for Experimental Medicine, Institute for Anatomy and Experimental Morphology, Hamburg, Germany.

Specific gene silencing using small hairpin RNA (shRNA) constructs offer researchers the possibility to study the influence of a single protein in the metastatic process. The role of the cellular adhesion molecule CEACAM1 on tumour formation and metastasis is of some interest. The human melanoma cell line FemX-1 was transfected with an shRNA construct directed against the CEACAM family. Stable clones were obtained and characterized via puromycin selection, single-cell dilution, and subsequent FACS analysis. The cell line showed a knock-down of CEACAM1 of more than 85%. This knock-down remained stable when examined in an SCID mouse xenograft experiment over 40 days.
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http://dx.doi.org/10.1007/978-1-61779-854-2_16DOI Listing
October 2012

Selectin binding is essential for peritoneal carcinomatosis in a xenograft model of human pancreatic adenocarcinoma in pfp--/rag2-- mice.

Gut 2013 May 5;62(5):741-50. Epub 2012 Apr 5.

Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.

Background And Objective: E- and P-selectins expressed on the luminal surface of mesodermally derived endothelial cells play a crucial role in the formation of haematogenous metastases in a number of malignancies. As peritoneal mesothelial cells are also derived form the mesoderm, it was hypothesised that selectins are also of importance in peritoneal tumour spread.

Methods: Immunohistochemistry was used to identify selectin expression on normal human peritoneum and isolated mesothelial cells. E- and P-selectin interactions with human pancreatic adenocarcinoma cells were investigated in dynamic flow assays and flow cytometry; the latter was also used to determine the main selectin ligands on pancreatic adenocarcinoma cell lines PaCa 5061, BxPC-3 and PaCa 5072, and selectin expression on human mesothelial cells. All cell lines were xenografted into the peritoneum of E- and P-selectin-deficient pfp/rag2 mice and selectin wild-type controls. Peritoneal carcinomatosis was quantified using MRI or a scoring system.

Results: E- and P-selectin were constitutively expressed on human mesothelial and endothelial cells in the peritoneum. PaCa 5061 and BxPC-3 cells interacted with E- and P-selectins in dynamic flow assays and flow cytometry, with CA19-9 (Sialyl Lewis a) being the main E-selectin ligand. For xenografted PaCa 5061 and BxPC-3 cells, peritoneal metastasis was significantly reduced in E- and P-selectin double knockout mice compared with wild-type pfp/rag2 animals. In contrast, PaCa 5072 cells were almost devoid of selectin binding sites and no intraperitoneal tumour growth was observed.

Conclusion: Interactions of tumour cells with peritoneal selectins play an important role in the peritoneal spread of pancreatic adenocarcinoma.
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http://dx.doi.org/10.1136/gutjnl-2011-300629DOI Listing
May 2013
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