Induction of osteoclast-like cell formation by leptin-induced soluble intercellular adhesion molecule secreted from cancer cells

Abstract

Background: Leptin is considered a tumorigenic adipokine, suggested to promote tumorigenesis and progression in many cancers. On the other hand, intercellular adhesion molecule-1 (ICAM-1) shows altered expression in a variety of benign and malignant diseases. Histologically, ICAM-1 expression is reported as proportional to cancer stage and considered as a potential diagnosis biomarker. The altered expressions of ICAM-1 and its soluble form in malignant diseases have gained interests in recent years. Material and methods: The expression of ICAM-1 and its regulatory signaling were examined by Western blot or flow cytometry. The effect of soluble ICAM-1 on osteoclast formation was investigated by tartrate-resistance acid phosphatase staining of RAW cells and tumor-induced osteolysis in vivo. Results: In our study, we found that leptin enhanced soluble ICAM-1 production but not surface ICAM-1 expression in lung and breast cancer cells, and this effect was regulated through leptin receptor (ObR), while silencing ObR abrogated leptin-induced soluble ICAM-1 expression. In addition, we revealed that leptin administration provoked the JAK1/2, STAT3, FAK, ERK, and GSK3αβ signaling cascade, leading to the elevation of ICAM-1 expression. Moreover, soluble ICAM-1 secreted by leptin-stimulated cancer cells synergize with the receptor activator of nuclear factor kappa-B ligand (RANKL) in inducing osteoclast formation. Soluble ICAM also enhanced tumor-induced osteolysis in vivo. Conclusion: These findings suggest that soluble ICAM-1 produced under leptin treatment enhances osteoclast formation and is involved in tumor-induced osteolysis. Leptin plays an important role in physiology in health and diseases. Leptin affects immune responses that may induce inflammation and carcinogenesis. Leptin is also considered as a tumorigenic adipokine suggested to promote tumorigenesis and progression in many cancers. On the other hand, intercellular adhesion molecule-1 (ICAM-1) shows altered expression in a variety of benign and malignant diseases. Histologically, ICAM-1 expression is reported to be proportional to cancer stage and considered as a potential diagnosis biomarker. It has been reported that soluble ICAM-1 allows tumor cells to escape from immune recognition and stimulates angiogenesis and tumor growth. The altered expressions of ICAM-1 and its soluble form in malignant diseases have gained interests in recent years. In our study, we found that leptin enhanced soluble ICAM-1 production but not surface ICAM-1 expression in lung and breast cancer cells, and this effect was regulated through leptin receptor (ObR), while silencing ObR abrogated leptin-induced soluble ICAM-1 expression. In addition, we revealed that leptin administration provoked the JAK1/2, STAT3, FAK, ERK, and GSK3αβ signaling cascade, leading to the elevation of ICAM-1 expression. Moreover, soluble ICAM-1 secreted by leptin-stimulated cancer cells synergize with receptor activator of nuclear factor-kappa B ligand in inducing osteoclast formation. Soluble ICAM also enhanced tumor-induced osteolysis in vivo. These findings suggest that soluble ICAM-1 produced under leptin treatment is possibly involved in lung and breast cancer bone metastasis.

Leptin, Adiponectin, and Sam68 in Bone Metastasis from Breast Cancer

“…Injection of ICAM-neutralizing antibody reduced the osteolytic process in tumour-bearing mice. These findings led the authors to speculate that sICAM could be a potential therapeutic target or diagnostic tool for bone metastases from lung and breast cancer [81].…”

Adipocyte-Derived Leptin Promotes PAI-1-Mediated Breast Cancer Metastasis in a STAT3/miR-34a Dependent Manner

“…In this study, we screened for secreted proteins in the co-cultured cancer cells and confirmed leptin as a positive regulator of PAI-1. Other secreted-proteins, such as MPS-1, ICAM-1, and PLOD2, have also been validated as critical downstream effectors of leptin in cancers [ 16 , 55 , 56 ]. MPS-1 was demonstrated to promote the leptin-induced growth of colorectal cancer via activating the JNK/c-Jun pathway [ 55 ].…”

“…MPS-1 was demonstrated to promote the leptin-induced growth of colorectal cancer via activating the JNK/c-Jun pathway [ 55 ]. Another study revealed that leptin provoked the JAK1/2, STAT3, FAK, ERK, and GSK3αβ signaling cascade to stimulate the production of soluble ICAM-1 in cancer cells, which induced osteoclast formation and enhanced tumor-induced osteolysis in vivo [ 56 ]. On the other hand, leptin-induced non-secreted proteins, such as OBR, PKM2, ACAT2, and SREBP-1, are also important for breast cancer evolution [ 57 , 58 , 59 , 60 ].…”

Focal Adhesion Kinase Fine Tunes Multifaced Signals toward Breast Cancer Progression

“…Besides, both FAK and c-Src signaling stimulated the leptin-invadopodia of MCF10A normal breast epithelial cells and the migratory abilities of both MCF-7 and MDA-MB 231 breast cancer cells [ 189 ]. In addition, leptin-dependent activation of JAK1/2/STAT3/FAK/ERK/GSK3αβ signaling cascade in breast tumor cells enhanced the production of intercellular adhesion molecule 1 (ICAM-1), toward the development of breast cancer bone metastasis [ 190 ].…”