establishment-human-multiple-myeloma-xenograft-model-chicken-to-study

Establishment of a Human Multiple Myeloma Xenograft Model in the Chicken to Study Tumor Growth, Invasion and Angiogenesis

Multiple myeloma (MM), a malignant plasma cell disease, remains incurable and novel drugs are required to improve the prognosis of patients. Due to the ...

Innsbruck Medical University

Karolinska Institute

Recently, EpCAM has attracted major interest as a target for antibody- and vaccine-based cancer immunotherapies. In breast cancer, the EpCAM antigen is overexpressed in 30-40% of all cases and this increased expression correlates with poor prognosis. The use of EpCAM-specific monoclonal antibodies is a promising treatment approach in these patients.

Effects of EpCAM overexpression on human breast cancer cell lines.

Dickkopf (dkk) genes belong to the family of secreted wnt-inhibitors with conserved cysteine-rich domains. In contrast to the prototype dkk1, dkk3 does not modulate canonical Wnt/β-catenin signalling. Until now, neither functions nor interaction partners of dkk3 in lower vertebrates have been described. In this study we cloned two dkk3 homologues dkk3a(dkk3l) and dkk3b(dkk3) and a dkk1 homologue dkk1a of the zebrafish and studied their expression patterns during embryonic development in comparison to the known dkk1b gene. Moreover, mutants with defects in hedgehog signalling (smo), notch (mib) signalling, nodal signalling (Zoep) or retinoic acid synthesis (neckless) were analyzed for changes in dkk3 gene expression. In situ hybridization analyses showed a dynamic expression of dkk1a and dkk1b primarily in epidermal structures of the otic vesicle, lens, branchial arches and fin folds. While dkk1a was expressed mainly in deep tissues, dkk1b expression was mainly found in protrusions at the outer surface of the branchial arch epidermis. In contrast, dkk3 genes showed expression in different tissues. Strong signals for dkk3a(dkk3l) were present in various neuronal structures of the head, whereas dkk3b(dkk3) expression was restricted mainly to endocrine cells of the pancreas and to the brachial arches. In summary, both dkk3 genes display a unique and distinct expression pattern in late embryonic development, pointing to a specific role during neuronal and pancreatic cell differentiation.

Distinct expression patterns of dickkopf genes during late embryonic development of Danio rerio.

The epithelial cell adhesion molecule (EpCAM) has been shown to be overexpressed in breast cancer and stem cells and has emerged as an attractive target for immunotherapy of breast cancer patients. This study analyzes the effects of EpCAM on breast cancer cell lines with epithelial or mesenchymal phenotype.

Phenotype-dependent effects of EpCAM expression on growth and invasion of human breast cancer cell lines.

The Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. However, effects of EpCAM overexpression on normal breast epithelial cells have never been studied before. Therefore, we analyzed effects of transient adenoviral overexpression of EpCAM on proliferation, migration and differentiation of primary human mammary epithelial cells (HMECs).

EpCAM overexpression prolongs proliferative capacity of primary human breast epithelial cells and supports hyperplastic growth.

Epithelial cell adhesion molecule (EpCAM) is a widely used immunohistochemical marker for epithelial human malignancies. Antibodies to target EpCAM are usually directed against its ectodomain (EpEX), but do not detect the intracellular domain (EpICD). The aim of this study was to compare membranous EpEX versus EpICD expression by immunohistochemistry.

Loss of membranous expression of the intracellular domain of EpCAM is a frequent event and predicts poor survival in patients with pancreatic cancer.

Diastereomeric and geometric analogs of calcipotriol, PRI-2202 and PRI-2205, were synthesized as advanced intermediates from vitamin D C-22 benzothiazoyl sulfones and side-chain aldehydes using our convergent strategy. Calcitriol, calcipotriol (PRI-2201) and tacalcitol (PRI-2191) were used as the reference compounds. Among a series of tested analogs the diastereomeric analog PRI-2202 showed the strongest antiproliferative activity on the human breast cancer cell line MCF-7, whereas the geometric analog PRI-2205 was the weakest. Both analogs were less potent in antiproliferative activity against HL-60 cells compared to the reference compounds. The ability to potentiate antiproliferative effect of cisplatin or doxorubicin against HL-60 cells or that of tamoxifen against the MCF-7 cell line was observed at higher doses of PRI-2202 or PRI-2205 than those of the reference compounds. The proapoptotic activity of tamoxifen, expressed as the diminished mitochondrial membrane potential, as well as the increased phosphatidylserine expression, was partially attenuated by calcitriol, PRI-2191, PRI-2201 and PRI-2205. The treatment of the MCF-7 cells with tamoxifen alone resulted in an increase in VDR expression. Moreover, a further increase in VDR expression was observed when the analogs PRI-2201 or PRI-2205, but not PRI-2191, were used in combination with tamoxifen. This observation could partially explain the potentiation of the antiproliferative effect of tamoxifen by vitamin D analogs.

Synthesis and Biological Activity of Diastereomeric and Geometric Analogs of Calcipotriol, PRI-2202 and PRI-2205, Against Human HL-60 Leukemia and MCF-7 Breast Cancer Cells.

Article	Year
Effects of EpCAM overexpression on human breast cancer cell lines. BMC cancer\| PubMed ID: 21281469	2011
Distinct expression patterns of dickkopf genes during late embryonic development of Danio rerio. Gene expression patterns : GEP\| PubMed ID: 21889616	2011
Phenotype-dependent effects of EpCAM expression on growth and invasion of human breast cancer cell lines. BMC cancer\| PubMed ID: 23110550	2012
EpCAM overexpression prolongs proliferative capacity of primary human breast epithelial cells and supports hyperplastic growth. Molecular cancer\| PubMed ID: 23758908	2013
Loss of membranous expression of the intracellular domain of EpCAM is a frequent event and predicts poor survival in patients with pancreatic cancer. Histopathology\| PubMed ID: 24117877	2014
Synthesis and Biological Activity of Diastereomeric and Geometric Analogs of Calcipotriol, PRI-2202 and PRI-2205, Against Human HL-60 Leukemia and MCF-7 Breast Cancer Cells. Cancers\| PubMed ID: 24202449	2013

Agnieszka Martowicz

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