Cancer research: new findings for more effective skin tumour therapy
(Vienna, 27 Jan. 2010) Research findings of the Cancer Research Institute at MedUni Vienna enable more effective therapy for skin tumours. The work of Beate Lichtenberger from Maria Sibilia's team has been published in the renowned American specialist journal "Cell".
For the treatment of tumours, the influence of the two factors "growth" and "survival" of the malignant structures is essential. Based on this approach, the Vienna scientists under Univ. Prof. Dr. Maria Sibilia from the research unit "Cellular and Molecular Tumour Biology" managed back in 2000 to develop a mouse model which forms epithelial carcinomas by overactivating a signal pathway (RAS). Here the vascular endothelial growth factor (VEGF) activates receptors (VEGFR) on blood vessel cells, stimulates these to grow and therefore ensures there are enough nutrients for the tumour to continue to grow.
In the existing further research as part of an EU-funded project it has now been shown that the growth factor VEGF influences the growth of tumour cells themselves as well as angiogenesis. The researchers also discovered that, unlike originally believed, the receptors are not only found on the cell surface but also inside the cells. This is relevant because although antibody treatment is effective for suppressing the receptors on the cell surface it is not effective inside the cells. These findings shed new light in particular on how and when cancer drugs should be combined in order to more effectively tackle the growth of solid epithelial tumours which are often difficult to treat with therapy; this is very important for modern targeted and personalised cancer therapy.
The data is now available because of the study of skin tumours in cooperation with Univ. Prof. Dr. Peter Petzelbauer (Department of Dermatology). Since VEGF receptors have also been described on other human tumour cells, however, the authors are confident that in further studies these effects could also be described for other tumours and the successes will be comprehensible in clinical trials. "This research is an outstanding example of our translational research strategy at the Cancer Research Institute where we want to convert the basic research as quickly as possible into successful treatment," explains Maria Sibilia.
In a K5-SOS-dependent skin tumour model in a mouse in which the Ras signal pathway is hyperactivated it has been shown that the VEGF produced by the tumour cells has a role not dependent on the angiogenesis in the proliferation of epithelial tumour cells. The expression of VEGF is greater in SOS-dependent tumours and the deletion in epidermal cells does not only delay tumour growth with regression of blood vessels but also by inhibiting the proliferation of cancer cells. This is also reduced by the knock-down of VEGF receptors Flt1 and Neuropilin-1 in vitro in tumour cells. The deletion of Flt1 in the epidermis of mice also reduces SOS-dependent tumour growth and the proliferation of cancer cells, which shows that the VEGF/Flt1 signal pathway regulates tumour development independent of the angiogenesis. Surprisingly the deletion of VEGF in mice with mutant epidermal growth factor receptor (EGFR) leads to complete inhibition of tumour formation. This indicates that VEGFR and EGFR signal transduction work together in neoplastic cells in order to stimulate tumour growth. Similar results were found with pharmacological inhibition of EGFR and VEGFR using drugs which are currently used in tumour therapy for people. Mechanistically it was shown that K5-SOS up-regulates the expression of VEGF and its receptors Flt1 and Neuropilin-1 via Erk, which activates an autocrine proliferation loop, while the EGFR functions as a survival factor for the tumour cells. Flt1 is also expressed in most human squamous cell carcinomas and the knock-down of Flt1 in squamous cell carcinoma cell lines reduces their proliferation, which underlines the medical relevance of this study. This is why VEGF, apart from its classic function as one of the most important angiogenesis factors, must also be seen as a very potent growth factor for epidermal tumours.
» Autocrine VEGF Signaling Synergizes with EGFR in Tumor Cells to Promote Epithelial Cancer Development Beate M. Lichtenberger, Poi Kiang Tan, Heide Niederleithner, Napoleone Ferrara, Peter Petzelbauer, Maria Sibilia Cell, Volume 140, Issue 2, 268-279, 22 January 2010
» Photo: Cross-section of a tumour - in red the blood vessels, in green the cell nuclei of the proliferating tumour cells.