Oncostatin M Promotes Mammary Tumor Metastasis to Bone and Osteolytic Bone Degradation

Abstract

Oncostatin M (OSM) is an interleukin-6 (IL-6) family cytokine that has been implicated in a number of biological processes including inflammation, hematopoiesis, immune responses, development, and bone homeostasis. Recent evidence suggests that OSM may promote breast tumor invasion and metastasis. We investigated the role of OSM in the formation of bone metastases in vivo using the 4T1.2 mouse mammary tumor model in which OSM expression was knocked down using shRNA (4T1.2-OSM). 4T1.2-OSM cells were injected orthotopically into Balb/c mice, resulting in a greater than 97% decrease in spontaneous metastasis to bone compared to control cells. Intratibial injection of these same 4T1.2-OSM cells also dramatically reduced the osteolytic destruction of trabecular bone volume compared to control cells. Furthermore, in a tumor resection model, mice bearing 4T1.2-OSM tumors showed an increase in survival by a median of 10 days. To investigate the specific cellular mechanisms important for OSM-induced osteolytic metastasis to bone, an in vitro model was developed using the RAW 264.7 preosteoclast cell line co-cultured with 4T1.2 mouse mammary tumor cells. Treatment of co-cultures with OSM resulted in a 3-fold induction of osteoclastogenesis using the TRAP assay. We identified several tumor cell-induced factors including vascular endothelial growth factor, IL-6, and a previously uncharacterized OSM-regulated bone metastasis factor, amphiregulin (AREG), which increased osteoclast differentiation by 4.5-fold. In addition, pretreatment of co-cultures with an anti-AREG neutralizing antibody completely reversed OSM-induced osteoclastogenesis. Our results suggest that one mechanism for OSM-induced osteoclast differentiation is via an AREG autocrine loop, resulting in decreased osteoprotegerin secretion by the 4T1.2 cells. These data provide evidence that OSM might be an important therapeutic target for the prevention of breast cancer metastasis to bone.

Transcriptional regulation of adrenomedullin by oncostatin M in human astroglioma cells: Implications for tumor invasion and migration

“…In addition to these genes, our present results provide additional confirmation that ADM is one of the downstream targets of STAT-3, which contributes to tumor invasion. Previous reports showed that OSM promotes tumor invasion in cervical cancer and osteosarcoma, mainly through STAT-31920. Consistent with these findings, our study demonstrated that OSM enhanced migration of CRT-MG cells, which was abrogated by co-treatment with AG490 (Fig.…”

Oncostatin M binds to extracellular matrix in a bioactive conformation: Implications for inflammation and metastasis

“…Oncostatin M (OSM) is a member of the interleukin-6 (IL-6) cytokine family, which signals cancer cells primarily through STAT3 to promote a metastatic phenotype via effects on tumor cell proliferation, attachment to substratum, migration, invasion, metastasis and the epithelial-to-mesenchymal transition (EMT) (1–8). OSM is expressed as a 26 kDa MW protein (full-length) that can be proteolytically processed into 24 kDa OSM via proteolytic cleavage of eighteen C-terminal amino acids, as well as a 22 kDa form via removal of an additional thirteen C-terminal amino acids by a trypsin-like protease (9).…”

Osteoimmunology: oncostatin M as a pleiotropic regulator of bone formation and resorption in health and disease

“…25 The influence of OSM in driving osteoclast formation was the focus of much early work in osteoclast biology, particularly in the context of osteolytic bone disease. Indeed, OSM participates significantly in osteoclast formation in the context of breast cancer invasion of bone, 26 and may also be involved in the increased bone destruction associated with inflammatory arthritis. 27,28 The low osteoclast numbers observed in the OSMR-null mice also suggested a role for OSM in normal physiological levels of resorption in the process of bone remodeling.…”