title: 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 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 tartrate-resistant acid phosphatase, 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 colocalized 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.
authors.affiliation: Department of Oncology and Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors.forename: Kosei
authors.initials: K
authors.lastname: Nakajima
authors.affiliation: Department of Oncology and Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors.forename: Dhong Hyo
authors.initials: DH
authors.lastname: Kho
authors.affiliation: Department of Orthopedic Surgery, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yanagawa
authors.affiliation: Maxillofacial Surgery, Department of Maxillofacial Neck Reconstruction, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo, Tokyo, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Harazono
authors.affiliation: Department of Oncology and Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors.forename: Victor
authors.initials: V
authors.lastname: Hogan
authors.affiliation: Biostatistics Core, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan.
authors.forename: Rouba
authors.initials: R
authors.lastname: Ali-Fehmi
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.affiliation: Department of Oncology and Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan. raza@karmanos.org.
authors.forename: Avraham
authors.initials: A
authors.lastname: Raz
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000556:secondary; D016723:Bone Remodeling / Q000502:physiology*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D037502:Galectin 3 / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D009218:Myosins / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000473:pathology*; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D053245:RANK Ligand / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D037502:Galectin 3; D007527:Isoenzymes; D053245:RANK Ligand; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D009218:Myosins
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