Age-Dependent Association between Protein Expression of the Embryonic Stem Cell Marker Cripto-1 and Survival of Glioblastoma Patients

Abstract

Exploring the re-emergence of embryonic signaling pathways may reveal important information for cancer biology. Nodal is a transforming growth factor-β (TGF-β)-related morphogen that plays a critical role during embryonic development. Nodal signaling is regulated by the Cripto-1 co-receptor and another TGF-β member, Lefty. Although these molecules are poorly detected in differentiated tissues, they have been found in different human cancers. Poor prognosis of glioblastomas justifies the search for novel signaling pathways that can be exploited as potential therapeutic targets. Because our intracranial glioblastoma rat xenograft model has revealed importance of gene ontology categories related to development and differentiation, we hypothesized that increased activity of Nodal signaling could be found in glioblastomas. We examined the gene expressions of Nodal, Cripto-1, and Lefty in microarrays of invasive and angiogenic xenograft samples developed from four patients with glioblastoma. Protein expression was evaluated by immunohistochemistry in 199 primary glioblastomas, and expression levels were analyzed for detection of correlations with available clinical information. Gene expression of Nodal, Lefty, and Cripto-1 was detected in the glioblastoma xenografts. Most patient samples showed significant levels of Cripto-1 detected by immunohistochemistry, whereas only weak to moderate levels were detected for Nodal and Lefty. Most importantly, the higher Cripto-1 scores were associated with shorter survival in a subset of younger patients. These findings suggest for the first time that Cripto-1, an important molecule in developmental biology, may represent a novel prognostic marker and therapeutic target in categories of younger patients with glioblastoma.

MicroRNA-15b suppresses the growth and invasion of glioma cells through targeted inhibition of cripto-1 expression

“…Pilgaard et al (8) suggested that cripto-1 may be a prognostic biomarker for glioblastoma multiforme (GBM) with the potential of being a therapeutic target. Tysnes et al (9) observed that the majority of samples of patients with glioblastoma demonstrated significant levels of cripto-1, as it was detected by immunohistochemistry. Thus, numerous studies have demonstrated that cripto-1 may be a novel tumor-specific marker, and its value in early diagnosis of tumors, targeted treatment, drug resistance mechanisms and prognosis is of interest (3)(4)(5)(6)(7)(8)(9).…”

“…An in-vivo study demonstrated that the growth of human nasopharyngeal carcinoma CNE-2 cells was significantly inhibited in cripto-1 knockout mice compared with the control group (7). Previous studies have demonstrated elevated cripto-1 expression in gliomas (8,9). Pilgaard et al (8) suggested that cripto-1 may be a prognostic biomarker for glioblastoma multiforme (GBM) with the potential of being a therapeutic target.…”

Investigating the role of CRIPTO‐1 (TDGF‐1) in glioblastoma multiforme U87 cell line

“…10 In another work, it was observed that higher Cripto-1 scores were linked with reduced survival in younger GBM patient. 9 Cripto-1 is enriched in cancer cell subpopulations showing stem like cell characteristics. For example, in embryonal carcinoma (EC), Cripto-1 exists in two distinct subpopulations (low and high).…”

Identification of Cancer Stem Cells in Oral Squamous Cell Carcinoma Using Cripto-1.

“…Over the past years, a substantial number of studies on many solid tumors including glioblastoma (Tysnes et al, 2013), breast cancer (Al-Hajj et al, 2003), prostate cancer (Collins et al, 2005), pancreatic cancer (Hermann et al, 2007), colorectal cancer and OSCC However, most of these stem cell markers including CD133, CD44,...etc. used in the above studies were empirical and derived from normal stem cells which are known to be largely tissue specific which inturn had raised an important question regarding the specificity and reliability of such CSC markers (Baillie et al, 2017 andLiu et al, 2017).…”