The Animal Lectin Galectin-8 Promotes Cytokine Expression and Metastatic Tumor Growth in Mice

Yehiel Zick

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Galectin-8 (gal-8) belongs to a family of widely expressed animal lectins that modulate cell adhesion, cell proliferation, apoptosis and immune responses (1). Our interest in gal-8 began 25 years ago, when we were the first to clone this protein (2). Since then, about 200 publications were devoted to gal-8, still, it remains relatively an understudied member of the galectin family. To better understand its mode of action we generated two mouse models: whole body gal-8 transgenic mice (gal-8-Tg) and gal-8 knockout animals (gal-8-KO). Interestingly, we could show that gal-8-Tg mice exhibited accelerated osteoclasts activity and bone turnover, which culminated in reduced bone mass (3), while the opposite was true for the gal-8-KO animals (4). These phenotypes could be attributed to a direct action of gal-8 on osteoblasts that secrete the osteoclastogenic factor RANKL upon binding of gal-8 (3). 

Due to the fact that RANKL is a member of the cytokine family, the obvious question was whether gal-8 affects the expression of other cytokines and chemokines. Indeed, we could show in the present work https://rdcu.be/b3SWf that gal-8 induces the expression and secretion of a number of cytokines and chemokines such as SDF-1 and MCP-1. Accordingly, the mRNA levels of these cytokines were significantly reduced (80-95%) in gal-8-KO mice, while gal-8-Tg mice presented the mirror image.

Given that tumor growth and metastasis are regulated by chemokines and pro-inflammatory cytokines it was obvious to determine whether gal-8 promotes chemoattraction of cancer cells toward target tissues via its effects on SDF-1 and MCP-1 secretion. Indeed, we could show that cytokine and chemokine secretion, induced by gal-8, promotes migration of cancer cells toward cells treated with this lectin. Accordingly, gal-8 KO mice experienced reduced tumor size and smaller and fewer metastatic lesions when injected with cancer cells. 

These results suggest the existence of a 'vicious cycle' (Fig. 1) whereby gal-8 secreted both by tumor and naïve cells present in the tumor microenvironment, promotes in an autocrine and paracrine manner the secretion of chemokines, cytokines, and additional proteins (e.g. MMP9, GAS6) that support tumor growth and induce recruitment of cancer cells to the metastatic niche. The recruited tumor cells that secrete gal-8, further propagate this ‘vicious cycle’. 

A final twist to our story emerges from understanding that ‘cytokine storm’ is a key contributor to poor prognosis of COVID-19 patients (5). Given that gal-8 is a potent stimulator of cytokine expression, as shown in the present work, it is tempting to speculate that gal-8 inhibitors (6) might also be considered as potential new drugs in the combat of COVID-19 and its adverse outcomes.

 References

1.         Johannes, L., Jacob, R., and Leffler, H. (2018) Galectins at a glance. J Cell Sci 131

2.         Hadari, Y. R., Paz, K., Dekel, R., Mestrovic, T., Accili, D., and Zick, Y. (1995) Galectin-8. A new rat lectin, related to galectin-4. J Biol Chem 270, 3447-3453

3.         Vinik, Y., Shatz-Azoulay, H., Vivanti, A., Hever, N., Levy, Y., Karmona, R., Brumfeld, V., Baraghithy, S., Attar-Lamdar, M., Boura-Halfon, S., Bab, I., and Zick, Y. (2015) The mammalian lectin galectin-8 induces RANKL expression, osteoclastogenesis, and bone mass reduction in mice. eLife 4, 19

4.         Vinik, Y., Shatz-Azoulay, H., Hiram-Bab, S., Kandel, L., Gabet, Y., Rivkin, G., and Zick, Y. (2018) Ablation of the mammalian lectin galectin-8 induces bone defects in mice. FASEB J 32, 2366-2380

5.         Vaninov, N. (2020) In the eye of the COVID-19 cytokine storm. Nat Rev Immunol 20, 277

6.         Bohari, M. H., Yu, X., Kishor, C., Patel, B., Go, R. M., Eslampanah Seyedi, H. A., Vinik, Y., Grice, I. D., Zick, Y., and Blanchard, H. (2018) Structure-Based Design of a Monosaccharide Ligand Targeting Galectin-8. ChemMedChem13, 1664-1672

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Yehiel Zick

Scientist, Weizmann Institute of Science

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