| dc.contributor.advisor | Schön, Michael P. Prof. Dr. | |
| dc.contributor.author | Koßmann, Eugen Franz Josef | |
| dc.date.accessioned | 2021-04-09T09:23:45Z | |
| dc.date.available | 2021-05-04T00:50:20Z | |
| dc.date.issued | 2021-04-09 | |
| dc.identifier.uri | http://hdl.handle.net/21.11130/00-1735-0000-0008-57E6-3 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-8536 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 610 | de |
| dc.title | Vascular Cell Adhesion Molecule-1 (VCAM-1) modulates plasticity of human melanoma cells | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Schön, Michael P. Prof. Dr. | |
| dc.date.examination | 2021-04-27 | |
| dc.description.abstracteng | Malignant melanoma is by far the type of skin cancer with the highest mortality. As is the case for most cancers, metastasis is the major limiting factor determining therapeutic options and survival of the patients. Despite recent promising immunomodulatory therapies, the prognosis for patients with metastasized disease remains poor. The process of metastasis of solid tumors can generally be divided into a cascade consisting of local invasion around the primary tumor, intravasation, circulation in the bloodstream and finally extravasation with metastasis formation in distant organs. The interaction between VLA-4 on the melanoma cell and VCAM-1 on the endothelium has been implicated in extravasation. VCAM-1, physiologically important on activated endothelium for leukocyte diapedesis, is considered a rather pro-metastatic factor but so far, little is known about its exact impact on melanoma cells on the biophysical level.
Thus, the aim of this study was to investigate the interaction between melanoma cells and VCAM-1 in a new biophysical approach in order to evaluate its influence upon melanoma cell behavior and morphogenesis.
This project was based on an innovative in vitro method, in which glass matrices produced by micellar block copolymer nanolithography enabled the directed presentation of VCAM-1 on a single molecular plane in assumingly physiologic relevant distances from 70 to 670 ligands/μm2 and the concomitant presentation of cell-stimulating RGD. In the initial experiments the successful biofunctionalization of the glass matrices with VCAM-1 has been established and verified by physical measurement and indirect immunofluorescence microscopy.
The following cell experiments revealed that the increasing density of VCAM-1 influences the spreading behavior of melanoma cells. A high VCAM-1 density of 670 ligands/μm2 led to a significant cytoskeletal inhibition of melanoma cells (relative cell surface average 48.30%, SD ±9.09%) despite simultaneous stimulating RGD presence, whereas melanoma cells on a decreasing VCAM-1 density lower than 280 ligands/μm2 (relative cell surface average 66.54%, SD ±16.8%) showed a significant and increasing cell spreading (relative cell surface average 80.69%, SD
55
±13.03% on 120 ligands/μm2 and 102.56%, SD ±12.02%, p=0.0005 on 70 ligands/μm2) similar to the control surface with pure RGD stimulation (reference 100%, SD ±9.76%, p=0.0001).
An increasing VCAM-1 density also had an impact on melanoma cells’ formation of focal adhesions in number and size. Melanoma cells on the highest VCAM-1 density of 670 formed few (8.29 focal adhesions on average per cell, SD ±1.39) but large focal adhesions (mean size 0.91 μm2, SD ±0.12 μm2), whereas those cells on the lowest VCAM-1 density of 70 ligands/μm2 formed many (32.82 focal adhesions on average per cell, SD ±5.67, p=0.0005) but small focal adhesions (mean size 0.57 μm2, SD ±0.1 μm2, p=0.0201)
Overall, VCAM-1 seems to have an important specific functional role on melanoma cells leading to cytoskeletal inhibition, a visible reduction of stress fibers and a reduction of focal adhesions in number but an increase in size. These effects upon the cell size can be interpreted as quite relevant along the metastatic cascade concerning a tumor’s capability of immune escape or cell migration through the endothelium in the course of extravasation and metastasis. | de |
| dc.contributor.coReferee | Wienands, Jürgen Prof. Dr. | |
| dc.contributor.thirdReferee | Oppermann, Martin Prof. Dr. | |
| dc.subject.eng | melanoma | de |
| dc.subject.eng | VLA-4 | de |
| dc.subject.eng | VCAM-1 | de |
| dc.subject.eng | nano structured ligand presentation | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-21.11130/00-1735-0000-0008-57E6-3-0 | |
| dc.affiliation.institute | Medizinische Fakultät | de |
| dc.subject.gokfull | Dermatologie / Venerologie - Allgemein- und Gesamtdarstellungen (PPN619876174) | de |
| dc.description.embargoed | 2021-05-04 | |
| dc.identifier.ppn | 175359894X | |