B-cell precursor acute lymphoblastic leukemia and stromal cells communicate through Galectin-3

Abstract

The molecular interactions between B-cell precursor acute lymphoblastic leukemia (pre-B ALL) cells and stromal cells in the bone marrow that provide microenvironmentally-mediated protection against therapeutic drugs are not well-defined. Galectin-3 (Lgals3) is a multifunctional galactose-binding lectin with reported location in the nucleus, cytoplasm and extracellular space in different cell types. We previously reported that ALL cells co-cultured with stroma contain high levels of Galectin-3. We here establish that, in contrast to more mature B-lineage cancers, Galectin-3 detected in and on the ALL cells originates from stromal cells, which express it on their surface, secrete it as soluble protein and also in exosomes. Soluble and stromal-bound Galectin-3 is internalized by ALL cells, transported to the nucleus and stimulates transcription of endogenous LGALS3 mRNA. When human and mouse ALL cells develop tolerance to different drugs while in contact with protective stromal cells, Galectin-3 protein levels are consistently increased. This correlates with induction of Galectin-3 transcription in the ALL cells. Thus Galectin-3 sourced from stroma becomes supplemented by endogenous Galectin-3 production in the pre-B ALL cells that are under continuous stress from drug treatment. Our data suggest that stromal Galectin-3 may protect ALL cells through auto-induction of Galectin-3 mRNA and tonic NFκB pathway activation. Since endogenously synthesized Galectin-3 protects pre-B ALL cells against drug treatment, we identify Galectin-3 as one possible target to counteract the protective effects of stroma.

Galectin 3 as a guardian of the tumor microenvironment

“…Possible mechanisms include membrane blebbing, use of autophagic vesicles, or exosomes (39). Galectin 3 has been found in exosomes derived from dendritic cells, bladder cancer cells, and leukemia cells (40)(41)(42). While it is unknown how Galectin 3 becomes cargo in exosomes, an unexplored possibility is that it associates with glycosphingolipids that can form exosomes independent of traditional cellular mechanisms (43,44).…”

“…Though Galectin 3 was detected in the cytoplasm and nucleus in melanoma samples, association of nuclear Galectin 3 was more significantly associated with good clinical outcome compared to cytoplasmic Galectin 3. and thus could contribute to drug resistance, angiogenesis, metastasis, immune suppression, or other functions that would benefit the tumor cell. In acute lymphoblastic leukemia (ALL) it appears that the stromal derived Galectin 3 is critical for chemoresistance (42). Changes in glycosylation patterns on receptors or membrane lipids could impact cellular function and immune recognition and thus impact tumorigenesis and drug resistance (57,(63)(64)(65).…”

“…As will be discussed, Galectin 3 expression in cancer cells is influenced by tumor niche support cells such as MSC and can be influenced by metabolic changes (e.g. hypoxia) that can occur in the malignant microenvironment(42,(66)(67)(68)(69)(70). Interestingly, Galectin 3 levels are seen to be increased in the bone marrow of aging mice (67).…”

“…Galectin 3 can also be secreted (though the mechanism is not clear) and the protein can have diverse effects on both cancer and support cells by (a) supporting cell:cell interactions, (b) regulating receptor activity on plasma membranes (acting as a rheostat to modulate receptor activity in some cases), (c) serving as a ligand that can inactivate or even kill T cells, (d) serving as a ligand to support survival signaling and (e) regulating the presence of surface proteins on the plasma membrane by influencing endocytosis of these molecules (19-21, 23, 29, 71-73). A diagram showing some of the reported functions of Galectin 3 in a representative tumor component of the tumor microenvironment in many types of cancers.Induction of Galectin 3 by the tumor microenvironmentRecent reports have shown that Galectin 3 is induced in leukemia cells after contact with support cells of the tumor microenvironment including MSC(42,(68)(69)(70). Initial studies on microenvironment effect on Galectin 3 expression were conducted in chronic myeloid leukemia (CML) cells(68,70).…”

“…However, the mechanism of Galectin 3 induction in the CML cells was not clear. In acute lymphoblastic leukemia (ALL) cells, it appears the induction of Galectin 3 is mediated at least in part transcriptionally by a mechanism involving the NF kappa B pathway(42). A recent study has found that co-culture of ALL cell lines bearing t(1,19) translocation with glioma derived U343 cells induces Galectin 3 expression(74).…”