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.
Highlights
Prostate cancer is the second most common cancer in men, and represents a significant cause of mortality worldwide [1]
To delineate the galectin expression profile during prostate cancer progression, we first examined the galectin-transcriptional pattern of several human prostate cancer cell lines, which are representative of different stages of the disease
As angiogenesis relies on the expression of hypoxia-regulated genes and Gal-1 is regulated by hypoxia in different tumor types [26, 33, 34], we examined the effects of hypoxia on the galectin expression profile of human prostate cancer
Summary
Prostate cancer is the second most common cancer in men, and represents a significant cause of mortality worldwide [1]. A family of glycan-binding proteins, play pivotal roles as regulators of tumor biology by directly influencing tumor transformation, invasiveness, angiogenesis, and tumor-immune escape [6, 7] These lectins are defined by a common structural fold and a conserved carbohydrate recognition domain (CRD) that recognizes N- and O-glycans expressing the disaccharide N-acetyllactosamine (Gal-b(1–4)-GlcNAc), differences in glycan-binding preferences of individual members of the family have been reported [7]. Gal-1 is uniquely expressed at high levels in human prostate cancer and contributes to tumor progression by promoting neovascularization. These results underscore the importance of Gal-1 as an attractive therapeutic target in advanced stages of prostate cancer
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