Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewGalectin expression in cancer diagnosis and prognosis: A systematic review☆
Graphical abstract
Introduction
Galectins are part of the lectin superfamily and they exert their main biological functions by interacting with specific glycoconjugates, i.e. carbohydrate structures linked to proteins, peptides and lipids. This way, galectins decipher the information encoded by the glycosylation machinery and translate this information into cellular functions. The interactions between galectins and glycoconjugates are mediated via a conserved carbohydrate recognition domain (CRD) of approximately 14 kD which shows binding affinity – albeit not exclusively – for β-galactosides [1], [2]. Based on structural features, galectins can be classified into three subgroups, i.e. prototype galectins, tandem repeat galectins and chimeric galectins [3](Fig. 1A). An important feature of galectins is their ability to homodimerize and oligomerize which increases the glycan binding valency and allows galectins to simultaneously interact with multiple glycoconjugates [4], [5]. As a result, galectins can mediate homo- and heterotypic interactions between cells, facilitate the binding of cells to extracellular matrix components and modulate signaling pathways and cellular behavior by e.g. receptor clustering [6], [7](Fig. 1B).
Galectins also engage in direct protein-protein interactions, thereby influencing cell signaling, cell-cycle progression, apoptosis and even pre-mRNA splicing [8], [9]. In line with this functional diversity, galectin dysfunction or altered expression has frequently been associated with disease, including cancer [10], [11], [12]. In the last two decades it has been shown that galectins contribute to many hallmarks of cancer [13], including sustained proliferative signaling, resistance to cell death signals, evasion of immune surveillance, induction of angiogenesis, and activation of the metastatic potential [2], [9], [14], [15], [16]. Consequently, efforts are being made to develop galectin-targeting compounds, ranging from competing carbohydrate ligands to small non-carbohydrate binding molecules and blocking antibodies [2], [17]. Several of these compounds have been shown to possess anti-tumor activity in vitro as well as to hamper tumor progression in pre-clinical cancer models in vivo [18], [19], [20], [21], [22], [23]. Currently, several clinical trials with different galectin-targeting agents are ongoing (Table 1). This marks the coming of age of galectin-based cancer therapies which is further exemplified by different patent applications for galectin inhibitors [24]. However, to successfully implement such inhibitors in future therapies it is pivotal to identify the patients that are likely to benefit most from these agents, i.e. patients in which galectins are associated with disease outcome. To facilitate this, we performed a systematic review of studies that reported on galectin expression in human cancer patients. We evaluated the diagnostic and prognostic value of galectin expression in tumor tissues as well as of circulating galectins. This not only resulted in a timely overview of the current knowledge but also identified the areas that require further investigation. This will help ongoing efforts that aim to implement galectin-targeted therapies in the clinic for the treatment of cancer patients.
Section snippets
Galectin expression in cancerous vs. normal tissues
Over 200 original studies were identified that reported on galectin expression in cancer patients, covering most tissues and cancer types (Fig. 2A). The median number of patients was 73 (range 4–2978) and 83 studies included 100 or more patients. The majority of the studies, i.e. > 70%, focused on galectin-1 and galectin-3 while tumors of the digestive tract and the reproductive system were the best studied cancer types, accounting for a little over 50% (Fig. 2B + C). To get more insight in the
Galectin expression and prognosis.
Apart from comparing galectin expression between normal and malignant tissues, many studies explored the prognostic value of galectin expression in cancer. From these studies, it has become apparent that galectins can be linked to patient outcome. For example, there is ample evidence that increased galectin-1 expression is associated with poor overall survival (OS) and disease free survival (DFS), irrespective of the cancer type (Supplementary Table 1). The opposite picture is emerging for
Circulating galectins as diagnostic biomarkers
As evident from the previous paragraphs, cancerous tissue is frequently characterized by altered galectin expression. Since galectins are known to be secreted it has been anticipated that changes in the levels of circulating galectins might reveal the presence of malignant tissue. Indeed, in thyroid cancer, increased levels of circulating galectin-1 and galectin-3 have been reported [146], [147], which corroborates with the observed increase in tissue expression. Also for other cancer types,
Circulating galectins as biomarkers of prognosis and therapeutic efficacy
Despite some discrepancies, there is ample evidence that circulating galectins can provide valuable patient information. This extends beyond diagnostic purposes as e.g. circulating galectin-1 levels correlate well with the clinical stage and other prognostic markers in Hodgkin lymphoma [179] and circulating galectin-3 was found to have prognostic value in stage III/IV melanoma patients [180]. In addition, there are reports linking altered galectin serum levels to metastatic disease. Iurisci et
Conclusions and future perspectives
Since their recognition as a distinct protein family twenty years ago [1], galectins have emerged as versatile glycan-binding proteins that facilitate a wide range of cellular functions and biological processes. Consequently, deregulated galectin expression has often been associated with aberrant cellular behavior, most notably in cancer. Indeed, over 130 studies have described alterations in galectin expression when comparing malignant tissues with normal tissues. Furthermore, altered galectin
Literature survey and data collection
Citations were managed using SENTE 6 (version 6.6.5, Third Street Software). Within SENTE, a library was generated following a search of the Pubmed database with the search string 'GALECTIN AND CANCER'. Within this library further searches were performed combining a specific 'GALECTIN' with 'PROGNOSIS', 'SERUM' and/or 'PATIENT'. From each study, the following information was retrieved (if available): galectin type, tumor type (including sub classification), number of patients, number of
Financial disclosures
None.
The following is the supplementary data related to this article.
Transparency Document
Acknowledgements
Despite the thorough and systematic literature screening approach, it is possible that some relevant studies were missed. The authors apologize for these unintentional omissions.
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Funding: The work presented here was supported by a research grant from the Dutch Cancer Society (VU2009-4358).