Abstract 38: Galectin-9D5 is a prognostic marker in early stage non-small cell lung cancer.
Authors: Thijssen Victor L. , Schulkens Iris A. , Heusschen Roy , van den Boogaart Vivian , van Suylen Robert-Jan , Pham Thang V. , Dingemans Anne-Marie C. , Griffioen Arjan W. 
Published: August 2014

Background: Galectins are proteins with a conserved carbohydrate recognition domain and a high affinity for beta-galactosides on glycoconjugates. They are differentially expressed in many pathologies, including cancer. Recent findings suggest a prognostic potential of galectin-1 and -3 in lung cancer as increased expression is frequently associated with enhanced malignancy and poor patient survival. However, prognostic values of the other 13 members of the galectin family in lung cancer remain elusive. We performed extensive galectin expression profiling and determined the prognostic value of all known human galectins in early stage non-small cell lung cancer (NSCLC) patients.

Methods: A retrospective study was performed on primary tumors from 93 early stage NSCLC patients with a follow-up of at least 5 years. The mRNA expression levels of all human galectins in NSCLC tumor tissue were determined by qPCR and correlated with overall survival. Additionally, tissue microarrays (TMAs) comprising of both normal and tumor lung tissue were stained for galectin-9 and staining frequency was scored in epithelial cells and endothelial cells (EC).

Results: Galectin mRNA expression in NSCLC was shown to be confined to galectin-1, -3, -4, -7, -8, and -9. Patients with galectin-1 expression levels above median showed significant shorter overall survival (43.5 (95% CI 32.4-54.6) vs. 72.2 (59.3-89.0) months; p=0.039, HR=1.5). The expression of galectin-3 was not prognostic in our patient group. Only one other galectin was found to be of prognostic value, i.e. a splice variant of galectin-9 lacking exon 5 (galectin-9D5). Patients with galectin-9D5 expression levels below median have shorter overall survival (49.2 (34.1-64.2) vs. 67.3 (55.0-79.6) months; p=0.007, HR=2.2). Overall patient survival was even worse when patients with high galectin-1 and low galectin-9D5 levels were compared to all other patients (30.0 (16.2-43.9) vs. 70.8 (58.6-83.0) months; p=0.002, HR=4.6). Immunohistochemical staining of TMAs for total galectin-9 revealed no differences between epithelial cells of normal and tumor tissue. However, galectin-9 protein levels were significantly increased in tumor EC compared to normal EC.

Conclusion: Comprehensive galectin expression profiling identified a spice variant of galectin-9, i.e. galectin-9D5, as a novel prognostic marker in early stage NSCLC. Interestingly, whereas low galectin-9D5 mRNA expression levels predict poor patient survival, we observed an increased galectin-9 protein expression in tumor EC compared to normal EC. Further research is warranted to unravel role of galectin-9 in angiogenesis and immune regulation in NSCLC. Since it has been shown that adjuvant chemotherapy can improve the survival of patients with resected stage II-IIIa NSCLC, determining the galectin expression profile might serve as a tool in predicting prognosis and treatment selection for individual patients.

Citation Format: Victor L. Thijssen, Iris A. Schulkens, Roy Heusschen, Vivian van den Boogaart, Robert-Jan van Suylen, Thang V. Pham, Anne-Marie C. Dingemans, Arjan W. Griffioen. Galectin-9D5 is a prognostic marker in early stage non-small cell lung cancer. [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 38. doi:10.1158/1538-7445.AM2013-38