In search of a novel target — Phosphatidylserine exposed by non-apoptotic tumor cells and metastases of malignancies with poor treatment efficacy

Abstract

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.

Pseudorabies Virus US3 Protein Kinase Protects Infected Cells from NK Cell-Mediated Lysis via Increased Binding of the Inhibitory NK Cell Receptor CD300a

“…Our findings may also have relevance for cancer therapy, since several types of cancer have been associated with upregulated group I PAK activity and nonapoptotic PS exposure (82)(83)(84). Our observation that noninfected primary epithelial cells are substantially recognized by the PS-binding antibody 1H6 may indicate that perhaps caution should be exercised in targeting PS for anticancer or antiviral therapy (82).…”

Analysis of Renal Cell Carcinoma as a First Step for Developing Mass Spectrometry-Based Diagnostics

“…Of particular importance, PESI is very good at detecting the lipid components in human tissues and living animals [10]. Taking into account the fact that cancer calls display changes in lipid composition [13], such as phospholipids [14], sphingolipids [15,16], and cholesterol sulfates [17], we focused on determining the differences in lipid composition in cancer tissue for diagnoses of human renal cell carcinoma (RCC). We were able to delineate clear differences in spectral patterns with special references to lipids.…”

Annexin-directed β-glucuronidase for the targeted treatment of solid tumors

“…For cell lines where both A5-mβG and A1-mβG exhibited remarkable stability, A1-mβG did show markedly higher stability initially; however, by Day 3 differences in bound protein were no longer significant. Differences in fusion protein binding stability between cell lines have been consistently observed ( Krais et al, 2013) and likely result from the high diversity of phosphatidylserine expression between cell lines of different cancer types (Riedl et al, 2011) and even between cell lines of the same cancer type (Chu et al, 2013). The lack of evidence for enhanced stability of A1 fusions compared with A5 fusions, paired with the lower K d and higher activity seen in A5 fusions, strongly favors further investigation of the A5-mβG construct.…”

“…However, malignant cells and their metastases, the tumor vasculature and cultured tumor cells all explicitly and significantly externalize phosphatidylserine. Phosphatidylserine expression results from a loss of lipid asymmetry that occurs without cell damage or external activators present, making outer leaflet phosphatidylserine a promising malignant cell fingerprint (Riedl et al, 2011). Further, the feasibility of phosphatidylserine targeting has been validated by the clinical success of Bavituximab, a phosphatidylserine binding antibody (Tabagari et al, 2009).…”