A Unique Galectin Signature in Human Prostate Cancer Progression Suggests Galectin-1 as a Key Target for Treatment of Advanced Disease

Abstract

Galectins, a family of glycan-binding proteins, influence tumor progression by modulating interactions between tumor, endothelial, stromal, and immune cells. Despite considerable progress in identifying the roles of individual galectins in tumor biology, an integrated portrait of the galectin network in different tumor microenvironments is still missing. We undertook this study to analyze the "galectin signature" of the human prostate cancer microenvironment with the overarching goal of selecting novel-molecular targets for prognostic and therapeutic purposes. In examining androgen-responsive and castration-resistant prostate cancer cells and primary tumors representing different stages of the disease, we found that galectin-1 (Gal-1) was the most abundantly expressed galectin in prostate cancer tissue and was markedly upregulated during disease progression. In contrast, all other galectins were expressed at lower levels: Gal-3, -4, -9, and -12 were downregulated during disease evolution, whereas expression of Gal-8 was unchanged. Given the prominent regulation of Gal-1 during prostate cancer progression and its predominant localization at the tumor-vascular interface, we analyzed the potential role of this endogenous lectin in prostate cancer angiogenesis. In human prostate cancer tissue arrays, Gal-1 expression correlated with the presence of blood vessels, particularly in advanced stages of the disease. Silencing Gal-1 in prostate cancer cells reduced tumor vascularization without altering expression of other angiogenesis-related genes. Collectively, our findings identify a dynamically regulated "galectin-specific signature" that accompanies disease evolution in prostate cancer, and they highlight a major role for Gal-1 as a tractable target for antiangiogenic therapy in advanced stages of the disease. Cancer Res; 73(1); 86-96. Ó2012 AACR.

Towards molecular mechanisms regulating the expression of galectins in cancer cells under microenvironmental stress conditions

“…For instance, the monocytic differentiation of HL-60 cells was accompanied by the upregulation of galectin-3 and the down-regulation of galectin-9 mRNA expression, while no changes or expression were detected with galectins -1, -2, -4, -7, and -8 [33]. This conceptual point has also readily been demonstrated in studies with prostate carcinoma tissues, showing that, as the cancer progressed toward more aggressive stages, the level of galectin-1 increased, the levels of galectins -3, -4, -9, and -12 gradually decreased, and galectin-8 remained stably expressed [34]. As such, many fundamental questions about the cell stress biology of galectin proteins remain insufficiently answered, leaving a number of unresolved issues and limiting the practical application of galectin-based therapies.…”

Galectin-1 drives lymphoma CD20 immunotherapy resistance: validation of a preclinical system to identify resistance mechanisms

“…Elevated serum Gal-1 levels correlate with disease severity in patients with CLL, 50 B lymphoblastic leukemia, 51 classic Hodgkin lymphoma, 52,53 prostate tumors, 54 and Kaposi sarcoma 55 and were symptomatic of lymphoma burden in mice with BL3750…”

Studies on the role of goat heart galectin-1 as a tool for detecting post-malignant changes in glycosylation pattern

“…Oxidative stress has been reported to enhance endothelial binding of lectins and activate the lectin complement pathway (Collard et al, 2001;Laderach et al, 2013), thus proclaiming an interesting correlation between lectins and oxidative stress. We thus investigated the effect of GHG-1 on pyrogallol induced free radical damage to erythrocyte membrane.…”