Review
Galectin expression in cancer diagnosis and prognosis: A systematic review

https://doi.org/10.1016/j.bbcan.2015.03.003Get rights and content

Highlights

  • Galectin expression is frequently altered in malignant vs. normal tissues.

  • Galectin expression can serve as an independent prognostic marker.

  • The prognostic value depends on tumor type, tissue distribution and cellular localization.

  • Circulating galectins can serve as diagnostic biomarkers.

  • Circulating galectins can serve as biomarkers for prognosis and therapeutic efficacy.

Abstract

Galectins are a family of proteins that bind to specific glycans thereby deciphering the information captured within the glycome. In the last two decades, several galectin family members have emerged as versatile modulators of tumor progression. This has initiated the development and preclinical assessment of galectin-targeting compounds. With the first compounds now entering clinical trials it is pivotal to gain insight in the diagnostic and prognostic value of galectins in cancer as this will allow a more rational selection of the patients that might benefit most from galectin-targeted therapies. Here, we present a systematic review of galectin expression in human cancer patients. Malignant transformation is frequently associated with altered galectin expression, most notably of galectin-1 and galectin-3. In most cancers, increased galectin-1 expression is associated with poor prognosis while elevated galectin-9 expression is emerging as a marker of favorable disease outcome. The prognostic value of galectin-3 appears to be tumor type dependent and the other galectins require further investigation. Regarding the latter, additional studies using larger patient cohorts are essential to fully unravel the diagnostic and prognostic value of galectin expression. Furthermore, to better compare different findings, consensus should be reached on how to assess galectin expression, not only with regard to localization within the tissue and within cellular compartments but also regarding alternative splicing and genomic variations. Finally, linking galectin expression and function to aberrant glycosylation in cancer cells will improve our understanding of how these versatile proteins can be exploited for diagnostic, prognostic and even therapeutic purposes in cancer patients.

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.

. Number of studies reporting on associations between galectin expression and overall survival or disease free survival in different types of cancer.

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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.

References (261)

  • H.J. Kim et al.

    High galectin-1 expression correlates with poor prognosis and is involved in epithelial ovarian cancer proliferation and invasion

    Eur. J. Cancer

    (2012)
  • X. Sanjuán et al.

    Differential expression of galectin 3 and galectin 1 in colorectal cancer progression

    Gastroenterology

    (1997)
  • V. Mathieu et al.

    Galectin-1 in melanoma biology and related neo-angiogenesis processes

    J. Invest. Dermatol.

    (2012)
  • F.A. van den Brule et al.

    Expression of the 67-kD laminin receptor, galectin-1, and galectin-3 in advanced human uterine adenocarcinoma

    Hum. Pathol.

    (1996)
  • A. Bartolazzi et al.

    Thyroid Cancer Study Group. Application of an immunodiagnostic method for improving preoperative diagnosis of nodular thyroid lesions

    Lancet

    (2001)
  • Y. Wang et al.

    Regulation of prostate cancer progression by galectin-3

    Am. J. Pathol.

    (2009)
  • N. Kapucuoglu et al.

    Immunohistochemical galectin-3 expression in non-melanoma skin cancers

    Pathol. Res. Pract.

    (2009)
  • E.R. Brown et al.

    Association of galectin-3 expression with melanoma progression and prognosis

    Eur. J. Cancer

    (2012)
  • M.C. Clark et al.

    Galectin-3 binds to CD45 on diffuse large B-cell lymphoma cells to regulate susceptibility to cell death

    Blood

    (2012)
  • A. Mathieu et al.

    Nuclear galectin-3 expression is an independent predictive factor of recurrence for adenocarcinoma and squamous cell carcinoma of the lung

    Mod. Pathol.

    (2005)
  • A. Bauer et al.

    Identification of malignancy factors by analyzing cystic tumors of the pancreas

    Pancreatology

    (2009)
  • M. Demers et al.

    Overexpression of galectin-7, a myoepithelial cell marker, enhances spontaneous metastasis of breast cancer cells

    Am. J. Pathol.

    (2010)
  • S. Rorive et al.

    Changes in galectin-7 and cytokeratin-19 expression during the progression of malignancy in thyroid tumors: diagnostic and biological implications

    Mod. Pathol.

    (2002)
  • M.T. Elola et al.

    Galectins: matricellular glycan-binding proteins linking cell adhesion, migration, and survival

    Cell. Mol. Life Sci.

    (2007)
  • D. Compagno et al.

    Galectins: major signaling modulators inside and outside the cell

    Curr. Mol. Med.

    (2014)
  • F.T. Liu et al.

    Galectins in regulation of apoptosis

    Adv. Exp. Med. Biol.

    (2011)
  • V. Balan et al.

    Galectins as cancer biomarkers

    Cancers (Basel)

    (2010)
  • M. Giordano et al.

    Galectins in hematological malignancies

    Curr. Opin. Hematol.

    (2013)
  • F.T. Liu et al.

    Galectins as modulators of tumour progression

    Nat. Rev. Cancer

    (2005)
  • R.Y. Yang et al.

    Galectins: structure, function and therapeutic potential

    Expert. Rev. Mol. Med.

    (2008)
  • C.T. Oberg et al.

    Inhibition of galectins with small molecules

    Chimia (Aarau)

    (2011)
  • V.L. Thijssen et al.

    Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy

    Proc. Natl. Acad. Sci. U. S. A.

    (2006)
  • T. Dalotto-Moreno et al.

    Targeting galectin-1 overcomes breast cancer-associated immunosuppression and prevents metastatic disease

    Cancer Res.

    (2013)
  • D.O. Croci et al.

    Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi's sarcoma

    J. Exp. Med.

    (2012)
  • C.M. John et al.

    Truncated galectin-3 inhibits tumor growth and metastasis in orthotopic nude mouse model of human breast cancer

    Clin. Cancer Res.

    (2003)
  • L. Mirandola et al.

    Galectin-3C inhibits tumor growth and increases the anticancer activity of bortezomib in a murine model of human multiple myeloma

    PLoS One

    (2011)
  • H. Blanchard et al.

    Galectin-3 inhibitors: a patent review (2008-present)

    Expert Opin. Ther. Pat.

    (2014)
  • F.A. van den Brûle et al.

    Increased expression of galectin-1 in carcinoma-associated stroma predicts poor outcome in prostate carcinoma patients

    J. Pathol.

    (2001)
  • N. Kohrenhagen et al.

    Increased expression of galectin-1 during the progression of cervical neoplasia

    Int. J. Gynecol. Cancer

    (2006)
  • E.J. Jung et al.

    Galectin-1 expression in cancer-associated stromal cells correlates tumor invasiveness and tumor progression in breast cancer

    Int. J. Cancer

    (2007)
  • D. Spano et al.

    Galectin-1 and its involvement in hepatocellular carcinoma aggressiveness

    Mol. Med.

    (2010)
  • R. Chen et al.

    Stromal galectin-1 expression is associated with long-term survival in resectable pancreatic ductal adenocarcinoma

    Cancer Biol. Ther.

    (2012)
  • P.O. Berberat et al.

    Comparative analysis of galectins in primary tumors and tumor metastasis in human pancreatic cancer

    J. Histochem. Cytochem.

    (2001)
  • D. Tang et al.

    High expression of Galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer

    Int. J. Cancer

    (2012)
  • J. Shen et al.

    Protein expression profiles in pancreatic adenocarcinoma compared with normal pancreatic tissue and tissue affected by pancreatitis as detected by two-dimensional gel electrophoresis and mass spectrometry

    Cancer Res.

    (2004)
  • S. Abroun et al.

    Galectin-1 supports the survival of CD45RA(−) primary myeloma cells in vitro

    Br. J. Haematol.

    (2008)
  • N. D'Haene et al.

    The differential expression of Galectin-1 and Galectin-3 in normal lymphoid tissue and non-Hodgkin's and Hodgkin's lymphomas

    Int. J. Immunopathol. Pharmacol.

    (2005)
  • S.M. Koopmans et al.

    The involvement of Galectins in the modulation of the JAK/STAT pathway in myeloproliferative neoplasia

    Am. J. Blood Res.

    (2012)
  • L. Cindolo et al.

    galectin-1 and galectin-3 expression in human bladder transitional-cell carcinomas

    Int. J. Cancer

    (1999)
  • A. Gillenwater et al.

    A.K. el-Naggar, G.L. Clayman, R. Lotan, Expression of galectins in head and neck squamous cell carcinoma

    Head Neck

    (1996)
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