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Novel tumor promoting function of TRAIL-R2, a family member of the otherwise apoptosis promoting TRAIL receptor family

Researchers of the Medical University of Vienna participated in a collaboration that clarified a novel and unexpected function of a TRAIL- receptor subtype.

(Vienna, May 21, 2015) Researchers from the Dept. of Thoracic Surgery and from the Surgical Research Labs participated in a collaboration that clarified a novel and unexpected function of a TRAIL- receptor subtype. TRAIL -receptors are one of the classical apoptosis (natural cell death) promoting receptor families. Those receptors are frequently detected on tumor cells. Therefore a number of preclinical and clinical studies currently aim to assess the potential of TRAIL or agonistic antibodies of the TRAIL receptors for cancer therapy, as those drugs should lead to apoptosis of the malignant cells.

Preclinical experiments performed by Henning Walczak’s group at the Centre for Cell Death, Cancer and Inflammation at the University College London Cancer Institute now indicated that asides of the known pro-apoptotic function of the TRAIL/TRAIL-R system there is a non-apoptotic function that supports tumor progression. They specifically deleted the murine TRAIL receptor in tumor cells and observed, that the murine TRAIL-R supported metastatic growth in tumor in model tumor. Further molecular dissection of the observed in-vivo effect indicated that the human TRAIL-receptor-2 (TRAIL-R2) mediated invasion and migration of tumor cells, when those cells harbored the oncogenic K-ras mutation. It should be noted that almost all human pancreatic cancer and 30% of human colon and lung adenocarcinoma carry such a mutation.

Balazs Hegedus and Michael Bergmann from the Anna Spiegel Translational Research Center initiated the clinical evaluation of this finding. Analyzing a cohort of patient with colorectal cancers lung metastases, which were treated at the Department of Thoracic Surgery, they could validate the preclinical findings. High expression of TRAIL-R2 but not of TRAIL-R1 was associated with a more dismal disease free survival in patients who suffered from a K-ras mutant tumor. This correlation was not observed in patients with K-ras wild type tumors.

The finding now depicts a more complex picture of the potential exploitation of TRAIL-receptor function. In KRAS mutant cancer, inhibiting, rather than triggering, human TRAIL-R2 should be explored as a therapeutic approach. Importantly, this study further emphasizes the necessity of subgroup analyses based on molecular markers when drugs are in clinical development and applied to cancer patients.

The study was published in April issue of the Top Journal Cancer Cell (http://www.ncbi.nlm.nih.gov/pubmed/25843002).