Galectin-3 in bone tumor microenvironment: a beacon for individual skeletal metastasis management

Abstract

The skeleton is frequently a secondary growth site of disseminated cancers, often leading to painful and devastating clinical outcomes. Metastatic cancer distorts bone marrow homeostasis through tumor-derived factors, which shapes different bone tumor microenvironments depending on the tumor cells' origin. Here, we propose a novel insight on tumor-secreted Galectin-3 (Gal-3) that controls the induction of an inflammatory cascade, differentiation of osteoblasts, osteoclasts, and bone marrow cells, resulting in bone destruction and therapeutic failure. In the approaching era of personalized medicine, the current treatment modalities targeting bone metastatic environments are provided to the patient with limited consideration of the cancer cells' origin. Our new outlook suggests delivering individual tumor microenvironment treatments based on the expression level/activity/functionality of tumor-derived factors, rather than utilizing a commonly shared therapeutic umbrella. The notion of "Gal-3-associated bone remodeling" could be the first step toward a specific personalized therapy for each cancer type generating a different bone niche in patients afflicted with non-curable bone metastasis.

Keywords: Bone metastasis; Bone tumor microenvironment; Galectin-3; Personalized medicine.

Fig. 1

Gal-3 interacting molecules in cancer metastasis. Gal-3 localizes to four biological compartments, i.e., nucleus, cytoplasm, extracellular space, and circulation, and plays unique roles through interaction with numerous proteins. Due to nuclear translocation, secretion, and internalization, Gal-3 can circulate among the nucleus, cytoplasm, extracellular space, and blood stream. The figure was produced using Servier Medical Art on www.servier.com with permission. Inset: protein structures of the Galectin family, which is classified into three molecular types: (1) prototypical, (2) tandem repeat, and (3) chimeric structure. Gal-3 is the only chimera protein, and its monomers are linked through their N-terminal domain, establishing pentameric structures. This complex of multivalent interactions modulates the extracellular function of Gal-3 in the tumor microenvironment. After exposure to proteolytic enzymes (MMP and/or PSA), intact Gal-3 is cleaved at the site of collagen α-like sequence, which leads to the disruption of pentameric structures and the production of cleaved Gal-3

Fig. 2

Roles of Gal-3 in the bone microenvironment. In breast cancer bone metastasis, intact Gal-3 is the predominant form. Cancer-secreted Gal-3 exhibits dual properties in bone metastasis: (1) secreted Gal-3 mediates osteoclast fusion and (2) suppresses osteoblast differentiation, leading effectively to osteolytic bone remodeling. Consequently, in breast cancer bone metastasis, Gal-3 drives osteolytic bone remodeling along with other osteoclast stimulators such as PTHrP and IL-8, inducing intracellular signaling for osteoclast differentiation/maturation, e.g. cFOS, NF-κB, and NFATc1. On the other hand, in prostate cancer bone metastasis, cleaved Gal-3 is the major form, which reduces the potent function of intact Gal-3 and gives priority to other secretory factors controlling the bone tumor microenvironment such as osteoblast stimulators, BMP, Wnt, and FGF. In prostate cancer bone metastasis, osteoblast stimulation is generally predominant in the context of complex tumor/environment-derived factors, leading to osteoblastic signal activation such as SMAD (in BMP signaling), β-catenin, δPKC (in Wnt signaling), and MAPK (in FGF signaling), which induce osteoblast differentiation and bone matrix production. Consequently, these events result in osteosclerotic bone remodeling. The figure was produced using Servier Medical Art on www.servier.com with permission

Fig. 3

Comparative pathology of the bone tumor microenvironment in bone-related tumors. Tumor cells control their bone microenvironment differently, depending on the tumor type and the tumor-derived factors. Consequently, bone niches respond with different signal activations. The figure was produced using Servier Medical Art on www.servier.com with permission. a Breast cancer bone metastasis. b Prostate cancer bone metastasis. c Osteosarcoma. d Multiple myeloma. e Oral squamous cell carcinoma. f Giant cell tumor of the bone

Fig. 4

Clinical presentation of bone metastases. a A full-body bone scan in a breast cancer patient using technetium-99m shows multiple bone metastatic lesions in the spine, pelvis, and femur (red circles). b CT hip images demonstrate distinct differences in bone metastasis patterns based on the origin of cancer cells. Osteolytic remodeling is seen in a breast cancer bone metastasis (left, green arrowhead), whereas osteosclerotic remodeling is seen in prostate cancer bone metastases (right, green arrowheads). c A gross specimen shows an example of osteolytic remodeling in renal cell carcinoma with cortical erosion and loss of cancellous bone (left, white arrowheads). Osteosclerotic remodeling in prostate cancer (right, asterisks) is marked by bone production in the lesser trochanter (right, white arrowhead) and a pathologic femoral neck fracture (right, red arrow). Clinical images were approved to present in this article by the Institutional Review Board in Gunma University Hospital on October 7, 2015 (Registration no. 15-58)

Fig. 5

Current therapeutic concepts for bone metastasis. In bone marrow, metastatic tumor cells proliferate and disturb the normal homeostasis and cross talk among the niches of bone cells, immune cells, stem cells, and hematopoietic cells. These interactions lead to abnormal bone remodeling and enhance tumor progression. Hence, current therapeutic concepts to treat patients with bone metastasis are classified into two categories, (1) treatments against cancer cells and (2) treatments targeting bone tumor microenvironments. As for treatment against cancer cells, the therapeutic modalities include radiation, surgery/ablation, chemotherapy, hormone therapy, and radiopharmaceuticals. In the clinical setting, the treatment options are selected based on cancer characteristics, e.g., detected number and location of bone metastatic lesions, hormone sensitivity, chemotherapeutic sensitivity, and radiation sensitivity. With respect to treatment targeting bone tumor microenvironments, the therapeutic modalities include bisphosphonates and anti-RANKL therapy for the purpose of suppression of activated osteoclasts. Although bone tumor microenvironment contains various cells, specific therapeutic approaches are clinically not established, except for osteoclasts. In the future, personalized approaches may be necessary based on different statuses of tumor-derived factors affecting the bone tumor microenvironments