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