Elsevier

European Journal of Cancer

Volume 40, Issue 15, October 2004, Pages 2324-2330
European Journal of Cancer

Galectin-3 – an emerging prognostic indicator in advanced head and neck carcinoma

https://doi.org/10.1016/j.ejca.2004.06.025Get rights and content

Abstract

Galectin-3, is a multifunctional effector. It is the only chimera-type member of the galectin family of endogenous lectins, which share specificity with β-galactosides and have a jelly-roll-like folding pattern. It’s activity profile includes modulation of cell–cell and cell–extracellular matrix interactions and the regulation of proliferation and apoptosis/anoikis. While lectin histochemistry with plant/invertebrate proteins is routine practice and immunohistochemical analysis of endogenous lectins has been thoroughly examined, the application of an endogenous lectin as a marker is presently primarily a promising concept. The aims of our study were to test galectin-3 as a technical probe and to correlate staining by the tissue lectin, localising accessible ligands in situ, to clinicopathological characteristics and the prognosis of patients (relapse-free and overall survival) in advanced head and neck squamous cell cancer. We measured galectin-3-dependent staining in 53 surgically resected oropharyngeal and laryngeal cancer specimens (stage III or IV). Patients were divided into two groups based on a threshold of 5% positivity in the tumour cell population. The patient’s degree of positivity was significantly correlated with their level of differentiation and keratinisation and lack of lymph node involvement (P = 0.0001, P = 0.0007 and P = 0.0224, respectively). Periods of relapse-free and overall survival were significantly shortened when the tumour population failed to meet the positivity criterion, i.e. to harbour ligands for the endogenous lectin (P = 0.0039 and P = 0.0259, respectively). We conclude that (a) studies with an endogenous lectin as a marker are technically feasible and (b) detection of accessible galectin-3-specific ligands is an independent prognostic marker in advanced head and neck squamous cell cancer with therapeutic potential. Of note, histochemical application of an endogenous effector after its purification and labelling may bear relevance beyond the galectins.

Introduction

Head and neck squamous cell carcinomas (HNSCC) represent 14% of all new cancer cases in males and 6% in females worldwide. The incidence of tumour occurrence is influenced by life-style parameters, because tobacco smoking and alcohol consumption figure prominently as important risk factors [1]. The clinical course of HNSCC can depend on various tumour and host factors, tumour site, vascularity, lymphatic drainage, differentiation grade, TNM stage, host immune response, patient’s age, gender, and nutritional status being on the list of known variables. The search for biochemical markers aims to relate clinical parameters to distinct effectors with potential therapeutic application [2], [3], [4]. Ideally, reliable identification of ‘high-risk’ patients will enable tailored therapeutic regimens, and hopefully, improve the predicted unfavourable prognosis of this subgroup. It is in this context that we focused our study on testing an endogenous protein. Instead of performing immunohistochemical monitoring, we used a tissue protein as a probe to visualise the expression of accessible binding sites in tumour cells. Based on the assumption that a molecular interaction with suitable binding partners will be essential to effect responses on the cellular level, this approach is suitable to measure the extent of in situ potential for biorecognition. In general terms, the presented approach, if successful, could find many other applications beyond this test system.

Besides proteins and nucleic acids, glycans of cellular glycoconjugates are gaining attention as a biochemical code system for information storage. In fact, cell–cell/cell–matrix interactions and modulation of cell growth have been delineated to be regulated by glycan determinants serving as ligands for endogenous receptors, such as lectins [5], [6], [7]. The presence of these tissue lectins has rekindled interest in lectin histochemistry, because distinct changes in glycan presentation (glycome) might become interpretable in functional terms, when evidence for the involvement of tissue lectins as receptors can be provided [8], [9]. Prompted by the lectins’ various functional roles in situ, immunohistochemical staining for the presence of lectins has suggested they may be a potential new class of human markers [10], [11], [12], [13]. Focusing on the family of galectins, the only member of the chimera-type subgroup, i.e. galectin-3 (Gal-3), is being increasingly studied due to its role in cancer metastasis, apoptosis regulation and pre-mRNA splicing [14], [15], [16]. Following the initial assessment of Gal-3-related parameters in head and neck cancer and the emergence of their correlation with a low degree of differentiation [17], [18], [19], [20], [21], [22], it was imperative for us to determine whether the extent of Gal-3 binding might be used as a prognostic marker. To this end, we monitored tumour specimens from 53 patients suffering from advanced squamous cell carcinoma of the larynx and oropharynx, to assess its staining pattern in tumour cell populations in order to test whether it was of prognostic relevance.

Section snippets

Patients and histological specimens

Specimens used for the galectin histochemical analysis were obtained from 53 advanced head and neck squamous cell cancer patients who had initially undergone surgery (resection of the primary tumour with neck dissection) and further postoperative radiotherapy, without any prior treatment at the Department of Otorhinolaryngology and Head Neck Surgery, 1st Faculty of Medicine, Charles University, Faculty Hospital Motol, Prague, from October 1998 to March 2000. 31 tumours were of oropharyngeal and

Results

The analysis with a labelled marker depends critically on the lack of impairment of binding activity by the inevitable chemical modification needed to accomplish label incorporation. To ascertain the absence of a negative effect, we first checked the biotinylated lectin for retention of its binding activity by solid-phase assays using the glycoprotein asialofetuin as a matrix and by fluorescent activated cell sorting (FACS) can analysis of colon/ovarian/B lymphoma cell lines using glycoclusters

Discussion

The aims of our study were to test a tissue protein after labelling as a marker (conceptual/technical aim) and to then proceed to answer the question as to whether the reactivity of tumour cells to the endogenous lectin Gal-3, a cell adhesion molecule and growth regulator, might be of prognostic relevance. The results obtained from analysis of data from 53 patients suffering from advanced squamous carcinoma of the larynx and oropharynx revealed that positivity of tumour cells is positively and

Conflict of Interest

None.

Acknowledgements

This study was supported by the Grant Agency of the Czech Republic, project No. 304/02/0463 and 304/03/P027 and the Verein zur Förderung des biologisch-technologischen Fortschritts in der Medizin e. V. Authors are grateful to Mrs. Eva Vancová for her excellent technical assistance.

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