Galectin-3 Determines Tumor Cell Adaptive Strategies in Stressed Tumor Microenvironments

Abstract

Galectin-3 is a member of the β-galactoside-binding lectin family, whose expression is often dysregulated in cancers. While galectin-3 is usually an intracellular protein found in the nucleus and in the cytoplasm, under certain conditions, galectin-3 can be secreted by an yet unknown mechanism. Under stressing conditions (e.g., hypoxia and nutrient deprivation) galectin-3 is upregulated, through the activity of transcription factors, such as HIF-1α and NF-κB. Here, we review evidence that indicates a positive role for galectin-3 in MAPK family signal transduction, leading to cell proliferation and cell survival. Galectin-3 serves as a scaffold protein, which favors the spatial organization of signaling proteins as K-RAS. Upon secretion, extracellular galectin-3 interacts with a variety of cell surface glycoproteins, such as growth factor receptors, integrins, cadherins, and members of the Notch family, among other glycoproteins, besides different extracellular matrix molecules. Through its ability to oligomerize, galectin-3 forms lectin lattices that act as scaffolds that sustain the spatial organization of signaling receptors on the cell surface, dictating its maintenance on the plasma membrane or their endocytosis. Galectin-3 induces tumor cell, endothelial cell, and leukocyte migration, favoring either the exit of tumor cells from a stressed microenvironment or the entry of endothelial cells and leukocytes, such as monocytes/macrophages into the tumor organoid. Therefore, galectin-3 plays homeostatic roles in tumors, as (i) it favors tumor cell adaptation for survival in stressed conditions; (ii) upon secretion, galectin-3 induces tumor cell detachment and migration; and (iii) it attracts monocyte/macrophage and endothelial cells to the tumor mass, inducing both directly and indirectly the process of angiogenesis. The two latter activities are potentially targetable, and specific interventions may be designed to counteract the protumoral role of extracellular galectin-3.

The roles of CSFs on the functional polarization of tumor‐associated macrophages

“…These observations supported a role of M‐CSF‐macrophages in tissue repair and in fibrosis . These mediators have also been involved in tumor progression .…”

Galectin-3, a Druggable Vulnerability for KRAS-Addicted Cancers

“…Galectin-3 can modulate the function of multiple cell types important during for progression [33, 41], and the early development of Galectin-3 inhibitors for cancer therapy focused on blocking the function of tumor-associated endothelial cells [42]. While we cannot rule out that the tumor growth inhibition observed for GCS-100 is exclusively due to its disruption of αvβ3 clustering on tumor cells, we do show a similar level of tumor growth inhibition in immune-compromised vs. immune-competent mice (Fig.…”

Consequências da exposição de células de melanoma ao shear stress para o remodelamento da microvasculatura intratumoral

“…Em outro exemplo, galectina-3 interage com a β-catenina, um componente downstream da via de sinalização Wnt (via responsável pela regulação da transcrição de diversos genes envolvidos em processos como diferenciação celular, proliferação e migração), promovendo a transcrição de genes como c-myc, ciclina D1, COX-2 (cyclooxygenase-2), MMP-7 (matrix metalloproteinase-7), entre outros (SHIMURA et al, 2004). Um das principais funções citoplasmáticas da galectina-3 é a regulação da apoptose através da interação com Bcl-2, e regulação da sobrevivência e proliferação celular através da interação com proteínas da via de sinalização das MAP quinases (AKAHANI et al, 1997;CARDOSO et al, 2016;HSU;LIU, 1996). (HUANG et al, 2018;NORTHCOTT et al, 2018; WIRTZ; KONSTANTOPOULOS; SEARSON, 2011).…”