Untersuchung der Rolle von L1CAM bei der Entstehung des Ovarialkarzinoms
Zusammenfassung der Projektergebnisse
L1CAM is a relatively large cell adhesion molecule that is over-expressed in various types of human cancers, including High Grade Serous Ovarian Cancer (HGSOC). Many studies have shown that the expression of L1CAM (CD171) is associated with malignant characteristics like chemoresistance, the epithelial to mesenchymal transition (EMT), proliferation, migration, invasion and survival. In HGSOC, it was shown that high expression of L1CAM is associated with poor overall survival and may confer chemoresistance in this setting. It was further shown that L1CAM expression in ovarian carcinomas and the present of its soluble form in patient ascites correlates with shorter patients survival. However, nothing is known about the role of L1CAM during the initiation or the early stages of ovarian cancer and how L1CAM might contribute to the transition to an increasingly malignant phenotype. During our investigations we showed that L1CAM contributes to the dissemination of malignant cells from STIC lesions. We could further demonstrate that L1CAM triggers the formation of three dimensional spheres that increase the chance of the cells to surviv under anchorageindependent culture conditions by reducing anoikis in primary fallopian tube cells as well as ovarian cancer cells. Additionally, we found that L1CAM contributed to this process by regulating the recruitment of fibronectin to build an effective basement membrane. Those data indicate that L1CAM expression in precursor lesions may be necessary for the tumor to metastasize to other sites of the fallopian tube, the ovary or the peritoneal cavity. Furthermore we found a strong link between the non-canonical WNT pathway and L1CAM expression which might explain the high L1CAM expression at the apical side of the STIC lesions. However, further studies must be performed to analyze which factors regulate the gradient expression of L1CAM and whether the inhibition of those factors or L1CAM itself, delay the onset of the malignant disease.
Projektbezogene Publikationen (Auswahl)
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Elafin: a double agent in breast and ovarian cancer. Oncoscience. 2015 Sep 17;2(10):793-4
Feng Y, Doberstein K, Drapkin R
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L1CAM in human cancer. Int J Cancer. 2016 Apr 1;138(7):1565-76
Altevogt, Doberstein, Fogel
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CCNE1 amplification and centrosome number abnormality in serous tubal intraepithelial carcinoma: further evidence supporting its role as a precursor of ovarian high-grade serous carcinoma. Mod Pathol. 2016 Oct;29(10):1254-61
Kuhn E, Wang TL, Doberstein K, Bahadirli-Talbott A, Ayhan A, Sehdev AS, Drapkin R, Kurman RJ, Shih IeM
