Galectin-3 cleavage alters bone remodeling: Different outcomes in breast and prostate cancer skeletal metastasis.

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.

Cancer research. 2016 Feb 02 [Epub ahead of print]

Kosei Nakajima, Dhong Hyo Kho, Takashi Yanagawa, Yosuke Harazono, Victor Hogan, Wei Chen, Rouba Ali-Fehmi, Rohit Mehra, Avraham Raz

Department of Oncology and Pathology, Wayne State University School of Med. , Department of Oncology and Pathology, Wayne State University School of Med. , Orthopedic Surgery, Gunma University. , Maxillofacial Neck Reconstruction, Tokyo Medical and Dental University. , Department of Oncology and Pathology, Wayne State University School of Med. , Biostatistics, Wayne State University. , Department of Pathology, Wayne State University School of Med. , Pathology, University of Michigan. , Department of Oncology and Pathology, Wayne State University School of Med 

PubMed

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