Abstract 2650: Age-dependent association between protein expression of the embryonic stem cell marker Cripto-1 and survival of glioblastoma patients.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Aggressive tumor cells can show characteristics similar to normal embryogenic progenitor cells, and de-regulated embryonic developmental signaling networks have been linked to cancer initiation and progression. Thus, cell fate regulation in embryonic development and cell transformation during oncogenesis may share common signaling pathways. Several tumor types have been suggested to be initiated from stem-like cells. Exploring in tumors, the re-emergence of embryonic signaling pathways involved in stem cell self-renewal can produce new insight into the initiation and progression of cancer and may lead to development of new therapeutic strategies. The Nodal pathway is required for maintenance of undifferentiated embryonic stem cells. Nodal is a morphogen that belongs to the TGF-beta family. Its signaling can be regulated by co-factors such as the Epidermal Growth Factor - like member, Cripto-1 and another TGF-beta member, Lefty. Nodal and Cripto-1 are critical in embryonic development and is generally poorly detected in differentiated tissues. However, an increased expression has been detected in different human tumor types. The dismal prognosis of glioblastomas calls for increased biological knowledge and novel therapeutic targets. Gene expression studies in a glioblastoma xenograft model, where multicellular spheroids from glioblastoma patient biopsies were generated and implanted intracranially in nude rats and where highly infiltrative non-angiogenic tumors can switch to angiogenic tumors upon in vivo intracranial passaging, has revealed importance of gene ontology categories connected to development and negative regulators of differentiation. In this model we detected several significant overrepresented morphogenesis categories, and we hypothesized that increased activity in Nodal signaling also could be found in human glioblastomas. We assessed the gene expression of Nodal, Cripto-1 and Lefty in microarrays of infiltrative and angiogenic xenograft samples developed from four glioblastoma patients. The genes were expressed both in the infiltrative and angiogenic xenografts. Further we examined Nodal, Cripto-1 and Lefty expression in 199 primary glioblastomas by immunohistochemistry, and assessed their potential clinical relevance by analyzing the association between their protein expression and patient survival. A weak to moderate protein expression of Nodal and Lefty and a stronger expression of Cripto-1 was found in the patient samples. Interestingly a significant association between patient age, Cripto-1 expression and survival was demonstrated, where higher Cripto-1 scores were associated with poorer survival in younger patients. These findings suggest that Cripto-1 may represent a novel negative prognostic marker in younger glioblastoma patients and also a potential therapeutic target in this patient group. Citation Format: Berit B. Tysnes, Hege AA Saetran, Sverre J. Mork, Naira V. Margaryan, Geir E. Eide, Rolf Bjerkvig, Luigi Strizzi, Mary J.C. Hendrix. Age-dependent association between protein expression of the embryonic stem cell marker Cripto-1 and survival of glioblastoma patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2650. doi:10.1158/1538-7445.AM2013-2650