Tumor-associated CD75s- and iso-CD75s-gangliosides are potential targets for adjuvant therapy in pancreatic cancer

Abstract

Pancreatic adenocarcinoma confers one of the highest mortality rates in malignant human tumors with very poor prognosis. Because as yet no treatments are available that produce a substantial survival benefit for this fatal neoplasia, new therapeutic concepts are urgently required to support cancer standard treatment. In search of tumorassociated gangliosides with therapeutic background, we probed a random collection of cancerous and adjacent normal postoperative tissue samples from 38 patients for the expression of CD75s-and iso-CD75s-gangliosides. We exhaustively analyzed the expression of CD75s-1-ganglioside (IV 6 Neu5Ac-nLc4Cer) and structurally closely related iso-CD75s-1-ganglioside (IV 3 Neu5Ac-nLc4Cer) by means of immunohistology of cryosections and semiquantitative TLC of tissue lipid extracts combined with mass spectrometry. CD75s-1-and iso-CD75s-1-ganglioside showed an elevated expression in 42% and 66% of the tumors, respectively, indicating a significant association with neoplastic transformation (P = 0.001). Thus, increased expression of CD75s-1-and iso-CD75s-1-gangliosides renders these cell surface molecules promising candidates for oncologic applications. Further statistical analysis revealed a significant enhancement of CD75s-1-ganglioside in the group of less differentiated tumors (grade >2) suggesting this ganglioside as a potential marker for poor differentiation. The CD75s-specific antitumor drug rViscumin, which represents the recombinant counterpart of the ribosome-inactivating lectin viscumin, has successfully passed clinical phase I trials and provides an opportunity for treating pancreatic cancer. Consequently, if an enhanced expression is existent in malignant tissues, we propose the targeting of CD75s-gangliosides with rViscumin as a novel potential strategy in adjuvant treatment of pancreatic malignancies. [Mol Cancer Ther 2008;7(8):2464 -75]

Advances on the compositional analysis of glycosphingolipids combining thin-layer chromatography with mass spectrometry

“…As a potential anticancer drug rViscumin has entered clinical trials (Habeck, 2003) and has successfully passed clinical phase I toxicity studies (Schöffski et al, 2004(Schöffski et al, , 2005. In a very recent publication we reported the elevated expression of the ganglioside IV 6 Neu5Ac-nLc4Cer in a cohort of clinically characterized pancreatic cancer cases (Distler et al, 2008b). Moreover, the enhanced expression of the isomeric ganglioside IV 3 Neu5Ac-nLc4Cer in the majority of pancreatic tumors suggests a further potential target structure that could help oncologists tailor treatment to individual patients suffering from pancreatic cancer.…”

“…We will highlight as a medical important approach its application to the identification of cancer-associated neutral GSLs and gangliosides in human tumors, which are currently under clinical investigation as targets for anti-cancer therapies (Distler et al, 2008b).…”

Immunomodulatory Effects of <i>Viscum album</i> Extracts on Natural Killer Cells: Review of Clinical Trials

“…ML I was found to bind to terminal a2-6-sialylated structures on glycolipids and on glycoproteins, and gangliosides with a CD75s terminus were defined as lectin receptors [113,114]. Their role in mediating lectin-related immune responses, however, is not fully resolved [115], since these structures are not only expressed on immune cells such as monocytes, macrophages, granulocytes, dendritic cells [115] and lymphocytes [116] and on tumor cells [117,118] but also on CD8 + suppressor T cells with negative regulatory function [119], and furthermore, they are also detectable in serum.…”

Assessment of the Molecular Expression and Structure of Gangliosides in Brain Metastasis of Lung Adenocarcinoma by an Advanced Approach Based on Fully Automated Chip-Nanoelectrospray Mass Spectrometry

“…Some of these alterations are intrinsic to the neoplastic tumor cells and others are associated with the invasion of tumor-infiltrating host cells. Therefore, changes in their composition and structure during neoplastic transformation have been studied and demonstrated for more than two decades [19][20][21][22][23].…”