Highlights► Outlined the need of novel strategies for cancer therapies that can counteract problems arising particularly in chemotherapy due to resistance to current drugs and their low specificity. ► Elaborated the differences in membrane composition and properties between cancer and non-cancer cells, the basis for the use of anticancer peptides derived from host defense peptides as new weapons against cancer. ► Described the current knowledge on the mode of action of these peptides and the status of in vivo studies. ► Summarized the challenges and perspectives for the development of host defense peptides as novel anticancer agents.

This study was performed in the aim to identify potential targets for the development of novel therapy to treat cancer with poor outcome or treatment efficacy. We show that the negatively charged phospholipid phosphatidylserine (PS) is exposed in the outer leaflet of their plasma membrane not only in tumor cell lines, but also in metastases and primary cultures thereof, which contrasts with a lack of PS exposure by differentiated non-tumorigenic counterparts. Studied tumor cell lines were derived from non-tumorigenic and malignant melanomas, prostate- and renal cancer, glioblastoma and a rhabdomyosarcoma. Importantly, also metastases of melanoma expose PS and there is a correlation between malignancy of melanoma cell lines from different stages of tumor progression and PS exposure. The PS exposure we found was neither of apoptotic nor of experimental artificial origin. Finally potentially malignant and non-malignant cells could be differentiated by sorting of a primary cell culture derived from a glioblastoma based on PS exposure, which has so far not been possible within one culture due to lack of a specific marker. Our data provide clear evidence that PS could serve as uniform marker of tumor cells and metastases as well as a target for novel therapeutic approaches based on e.g. PS-specific host defense derived peptides.

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