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 tumor-associated 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.

• Authors: Ute Distler, Jamal Souady, Marcel Hülsewig, Irena Drmić-Hofman, Jörg Haier, Axel Denz, Robert Grützmann, Christian Pilarsky, Norbert Senninger, Klaus Dreisewerd, Stefan Berkenkamp, M Alexander Schmidt, Jasna Peter-Katalinic, Johannes Müthing
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 8 Pg. 2464-75 (Aug 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18723492 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neoplasm
• Antigens, CD
• Antineoplastic Agents
• Biomarkers, Tumor
• Gangliosides
• Recombinant Proteins
• Ribosome Inactivating Proteins, Type 2
• Toxins, Biological
• mistletoe lectin I
• Sialyltransferases
• ST6GAL1 protein, human

Topics

• Adenocarcinoma (drug therapy)
• Antibodies, Neoplasm (blood)
• Antigens, CD (immunology)
• Antineoplastic Agents (therapeutic use)
• Biomarkers, Tumor (antagonists & inhibitors, immunology)
• Chemotherapy, Adjuvant
• Chromatography, Thin Layer
• Gangliosides (antagonists & inhibitors, immunology)
• Humans
• Immunohistochemistry
• Microscopy, Fluorescence
• Pancreatic Neoplasms (drug therapy)
• Recombinant Proteins (therapeutic use)
• Ribosome Inactivating Proteins, Type 2 (therapeutic use)
• Sialyltransferases (antagonists & inhibitors, immunology)
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
• Toxins, Biological (therapeutic use)