Placental Galectins in Cancer: Why We Should Pay More Attention

Abstract

The first studies suggesting that abnormal expression of galectins is associated with cancer were published more than 30 years ago. Today, the role of galectins in cancer is relatively well established. We know that galectins play an active role in many types of cancer by regulating cell growth, conferring cell death resistance, or inducing local and systemic immunosuppression, allowing tumor cells to escape the host immune response. However, most of these studies have focused on very few galectins, most notably galectin-1 and galectin-3, and more recently, galectin-7 and galectin-9. Whether other galectins play a role in cancer remains unclear. This is particularly true for placental galectins, a subgroup that includes galectin-13, -14, and -16. The role of these galectins in placental development has been well described, and excellent reviews on their role during pregnancy have been published. At first sight, it was considered unlikely that placental galectins were involved in cancer. Yet, placentation and cancer progression share several cellular and molecular features, including cell invasion, immune tolerance and vascular remodeling. The development of new research tools and the concomitant increase in database repositories for high throughput gene expression data of normal and cancer tissues provide a new opportunity to examine the potential involvement of placental galectins in cancer. In this review, we discuss the possible roles of placental galectins in cancer progression and why they should be considered in cancer studies. We also address challenges associated with developing novel research tools to investigate their protumorigenic functions and design highly specific therapeutic drugs.

Keywords: cancer; galectins; placenta.

Figure 1

Three-dimensional structures of placental galectins. The dimeric structures of human GAL-13 and GAL-14 are shown respectively in purple/pink (GeneID UniProt Q9UHV8) and blue/cyan (GeneID UniProt Q8TCE9). GAL-13 is a prototype member stabilized by forming two disulfide bridges at the dimer interface [29]. In contrast, GAL-14 adopts a swapped dimer architecture, whereby terminal β-strands S5 and S6 of one monomer interact with the core structure of the opposite monomer (and vice versa) to form the canonical CRD ‘jelly-roll’ fold [30]. GAL-16 is shown in green (GeneID UniProt A8MUM7). Although prototype galectins typically crystallize as dimers, GAL-16 adopts a distinct monomeric structure [21].

Figure 2

Comparison of placental galectins’ expression in normal and cancer tissues. (A) mRNA expression levels of placental galectins in normal tissues. Data were obtained from the Human Protein Atlas datasets. Normalized transcripts per million (nTPM) units are relative to normalized transcript expression values. (B) mRNA expression levels of placental galectins in cancer tissues. Data were obtained from the Human Protein Atlas datasets. FPKM units refer to fragments per kilobase of transcript per million mapped reads. The darker-colored histogram bars represent the mRNA expression levels of galectin, while the lightly colored histogram bars represent the percentage of patients with detectable expression levels.

Figure 3

Kaplan-Meier survival curves of patients according to placental galectin levels. Data were extracted from Nagy et al. Pancancer survival analysis of cancer hallmark genes was performed using data from 2021 [62]. The log-rank test was used to detect significant differences between survival curves.

Figure 4

Venn diagram of genes co-expressed with placental galectins. The data were generated using the Human Protein Atlas datasets based on RNA-Seq expression data. The figure illustrates genes among the 15 closest neighboring genes associated with placental functions and cancer progression.

Figure 5

Structural and sequence homology between placental galectins. (A) Multiple sequence alignment between GAL-14, GAL-13, and GAL-16. The bottom consensus sequence was defined with a global score similarity threshold of 70%. Overall sequence identity is 68% between GAL-13 and GAL-14, 61% between GAL-14 and GAL-16, and 76% between GAL-13 and GAL-16. All sequences are numbered on top according to the consensus. Strictly conserved residues are highlighted in white font in red boxes. Conservation of residues Asn, Asp, Gln, Glu (#) and Ile, Val (!) are labeled in the consensus. The multiple sequence alignment was performed using Clustal Omega and visualized using ESPript 3.0. (B) Overlay between GAL-13 (purple cartoon) and GAL-16 (green cartoon) CRDs illustrates strong structural similarity (76% sequence identity). Electron density representation highlights surface positions that are conserved (white surface) or distinct (red surface) between both galectins. Since GAL-13 and GAL-16 share strong sequence homology, many residues form similar three-dimensional white surface epitopes that likely explain antibody cross-reactivity.

Figure 6

Recapitulative summary of the recent findings on placental galectins and potential future directions for further investigations.