Galectins are a family of carbohydrate-binding proteins with an affinity for beta-galactosides. Galectin-1 (Gal-1) is differentially expressed by various normal and pathological tissues and appears to be functionally polyvalent, with a wide range of biological activity. The intracellular and extracellular activity of Gal-1 has been described. Evidence points to Gal-1 and its ligands as one of the master regulators of such immune responses as T-cell homeostasis and survival, T-cell immune disorders, inflammation and allergies as well as host-pathogen interactions. Gal-1 expression or overexpression in tumors and/or the tissue surrounding them must be considered as a sign of the malignant tumor progression that is often related to the long-range dissemination of tumoral cells (metastasis), to their dissemination into the surrounding normal tissue, and to tumor immune-escape. Gal-1 in its oxidized form plays a number of important roles in the regeneration of the central nervous system after injury. The targeted overexpression (or delivery) of Gal-1 should be considered as a method of choice for the treatment of some kinds of inflammation-related diseases, neurodegenerative pathologies and muscular dystrophies. In contrast, the targeted inhibition of Gal-1 expression is what should be developed for therapeutic applications against cancer progression. Gal-1 is thus a promising molecular target for the development of new and original therapeutic tools.

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Galectin-1: A Small Protein with Major Functions

REVIEW Galectin-1: a small protein with major functions

Galectins and cancer.

The expression patterns of 7075 genes were analyzed in four conventional (clear cell) renal cell carcinomas (RCC), one chromophobe RCC, and two oncocytomas using cDNA microarrays Expression profiles were compared among tumors using various clustering algorithms, thereby separating the tumors into two categories consistent with corresponding histopathological diagnoses Specifically, conventional RCCs were distinguished from chromophobe RCC/oncocytomas based on large-scale gene expression patterns Chromophobe RCC/oncocytomas displayed similar expression profiles, including genes involved with oxidative phosphorylation and genes expressed normally by distal nephron, consistent with the mitochondrion-rich morphology of these tumors and the theory that both lesions are related histogenetically to distal nephron epithelium Conventional RCCs underexpressed mitochondrial and distal nephron genes, and were further distinguished from chromophobe RCC/oncocytomas by overexpression of vimentin and class II major histocompatibility complex-related molecules Novel, tumor-specific expression of four genes—vimentin, class II major histocompatibility complex-associated invariant chain (CD74), parvalbumin, and galectin-3—was confirmed in an independent tumor series by immunohistochemistry Vimentin was a sensitive, specific marker for conventional RCCs, and parvalbumin was detected primarily in chromophobe RCC/oncocytomas In conclusion, histopathological subtypes of renal epithelial neoplasia were characterized by distinct patterns of gene expression Expression patterns were useful for identifying novel molecular markers with potential diagnostic utility

Expression profiling of renal epithelial neoplasms: a method for tumor classification and discovery of diagnostic molecular markers.

Purpose: Knowledge about galectin expression by human tumor cells is mainly restricted to galectins-1 and -3. This study was conducted to define the gene expression pattern of all presently known human galectins in tumor cell lines of various histogenetic origin (galectinomics). Methods: The presence of mRNAs for human galectins-1, -2, -3, -4, -7, -8, and -9 was monitored by RT-PCR analyses in a panel of 61 human tumor cell lines of different origin (breast, colon, lung, brain, skin, kidney, urogenital system, hematopoietic system). Results: The validity of the technique was first confirmed by comparison of RT-PCR data with those obtained by Western blotting and cytofluorometry for galectins-1 and -3 in 18 cell lines. The following detection of a complex pattern of gene expression beyond commonly studied galectins-1 and -3 underscored the need for this fingerprinting. The most abundantly expressed message for a member of this lectin family was galectin-8 with 59 positive cell lines. With the exception of the tested lung tumors, galectin-1 and -3 transcripts were frequently expressed in the cell line panel with differences between individual cases. Positivity for galectins-2 and -4 was confined to a significant fraction of colorectal and neural tumors. Signals for galectin-9, the third known human tandem-repeat-type galectin besides -4 and -8, appeared in colorectal carcinoma cell lines with a frequency similar to that of galectin-4 but with inter-line differences. Its expression was restricted to lines of this tumor type, of the tested ovarian carcinoma, and hematopoietic malignancies. Conclusions: The results clearly demonstrate that human tumor cells express more mRNA species for galectins than those for galectins-1 and -3. To derive unequivocal diagnostic and prognostic information by immunohistochemistry on galectins with antagonistic impact on growth control and significant influence on cell adhesion, additional monitoring of these so far insufficiently studied family members is essential.

Comprehensive galectin fingerprinting in a panel of 61 human tumor cell lines by RT-PCR and its implications for diagnostic and therapeutic procedures

We studied 2 families of molecules whose role remains uncharacterized or obscure in the progress of renal cell carcinoma (RCC): galectins, a major class of glycoproteins, and the Thomsen-Friedenreich (T) antigen. We characterized the level of expression of galectin-1 and galectin-3 and their respective binding sites in a series of 74 RCCs. We also characterized the level of expression of laminin, a natural ligand for galectins. Finally, we characterized the level of T antigen expression and the T antigen binding sites. All levels of expression were quantitatively determined by using computer-assisted microscopy on immunohistochemically or glycohistochemically stained slides. A small concentration of galectin-1 binding sites or a large concentration heterogeneity of galectin-3 can be associated with unfavorable prognoses for patients with grade II or III RCCs. In contrast, T antigen and T antigen binding sites revealed no change across the 2 RCC groups that exhibited different clinical outcomes. We established discriminant scores that permitted a clear distinction between the 2 RCC groups analyzed. Modifications to the expression of galectin-1 and galectin-3, but not of T antigen, parallel an increase in RCC aggressiveness. Galectins represent a family of molecules with a meaningful role in RCC progression.

Galectin-1 and galectin-3 binding pattern expression in renal cell carcinomas.

The present work aims to refine prognosis in cases of renal cell carcinoma (RCC) by integrating a variety of parameters with the prognostic information provided by histopathological grading and clinical staging, carried out on a series of 97 RCCs. To this end, Feulgen-stained RCC cell nuclei were characterized by means of 38 variables describing nuclear DNA ploidy levels and morphology. All of these data were subjected to a principal components analysis. On the basis of this multivariate analysis, Fuhrman grade II was subdivided into grades II- and II+, and Fuhrman grade III into grade III- and III+. The same kind of subcategorization was performed in the case of the T2 and T3 clinical stages. The results show that the classification into grade II- and III- RCCs correspond to a more favourable prognosis than grade II+ and III+, to which shorter survival periods were attributable. Similar results were obtained for the subcategorization of the T2 and T3 clinical stages. Very simple biological characterizations of these grade- or stage-related RCC groups were obtained by means of a decision tree approach applied to the cytometry-generated variables. The resulting classification rules were validated on a new series of 18 patients and enabled very accurate predictions of survival.

Olivier De Lathouwer

Papers

Galectin-1 and galectin-3 binding pattern expression in renal cell carcinomas.

Improving the prognostic value of histopathological grading and clinical staging in renal cell carcinomas by means of computer-assisted microscopy.