Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis

Abstract

Management of bone metastasis remains clinically challenging and requires the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Galectin-3 (Gal-3) has been implicated as a secreted factor that alters the bone tumor microenvironment. Proteolytic cleavage of Gal-3 may also contribute to malignant cellular behaviors, but has not been addressed in cancer metastasis. Here, we report that Gal-3 modulates the osteolytic bone tumor microenvironment in the presence of RANKL. Gal-3 was localized on the osteoclast cell surface, and its suppression by RNAi or a specific antagonist markedly inhibited osteoclast differentiation markers, including TRAP, and reduced the number of mature osteoclasts. Structurally, the 158–175 amino acid sequence in the carbohydrate recognition domain (CRD) of Gal-3 was responsible for augmented osteoclastogenesis. During osteoclast maturation, Gal-3 interacted and co-localized with myosin-2A along the surface of cell-cell fusion. Pathologically, bone metastatic cancers expressed and released an intact form of Gal-3, mainly detected in breast cancer bone metastases, as well as a cleaved form, more abundant in prostate cancer bone metastases. Secreted intact Gal-3 interacted with myosin-2A, leading to osteoclastogenesis, whereas a shift to cleaved Gal-3 attenuated the enhancement in osteoclast differentiation. Thus, our studies demonstrate that Gal-3 shapes the bone tumor microenvironment through distinct roles contingent on its cleavage status, and highlight Gal-3 targeting through the CRD as a potential therapeutic strategy for mitigating osteolytic bone remodeling in the metastatic niche.

AllergoOncology – the impact of allergy in oncology: EAACI position paper

“…Depending on the nature and distribution of IgE receptors, different functions might be envisaged. Galectin‐3 is well recognized for its contribution to tumour progression and metastasis development , while galectin‐9 seems to have antiproliferative effects . The trimeric FcεRI(αγ2) showed membranous and cytoplasmic expression in intestinal epithelial cells and a prominent FcεRI α‐chain expression was also found in the Paneth cells of patients with cancer of the proximal colon.…”

Galectin-3 type-C self-association on neutrophil surfaces; The carbohydrate recognition domain regulates cell function

“…17,19,25 Galectin-3C is unable to induce cell activity 4,21 and has been described as a dominant-negative form of galectin-3, 26,27 since it can inhibit galectin-3-induced angiogenesis, 28 affect galectin-3 maintenance of the glycocalyx barrier function at the ocular surface, 29 suppress the contribution of galectin-3 to plateletinduced COX-2 overexpression in HT29 cells, 30 supress breast cancer in vivo, 27 and attenuate galectin-3-induced osteoclastogenesis. 31 The dominant negative galectin-3C has also been shown to reduce motility and invasion in ovarian cancer cells. 32 So far, the inhibitory functions of galectin-3C have not been investigated with respect to neutrophil activation, but its presence in inflamed/infected human tissue is inferred, based on that galecin-3 increases during inflammation, 33,34 neutrophils release (galectin-3-cleaving) proteases during inflammatory processes 21 and protease-positive bacteria release proteases during infection.…”

Quantitative proteomics reveal the anti-tumour mechanism of the carbohydrate recognition domain of Galectin-3 in Hepatocellular carcinoma

“…In the bone remodelling process during skeletal metastasis of breast and prostate cancers, secreted intact Galectin-3 could induce osteoclastogenesis, whereas Gal3C could inhibit osteoclast differentiation, indicated that Gal3C may play an opposing role 40 . Gal3C inhibited tumour growth and metastasis in orthotopic nude mouse models of human breast cancer and in a murine model of human multiple myeloma 41, 42 .…”