Osteosarcomas are the most prevalent malignant primary bone tumors in children. Despite intensive efforts to improve both chemotherapeutics and surgical management, 40% of all osteosarcoma patients succumb to the disease. Specifically, the clinical outcome for metastatic osteosarcoma remains poor; less than 30% of patients who present metastases will survive five years after initial diagnosis. Treating metastatic osteosarcoma thus remains a challenge. One of the main characteristics of osteosarcomas is their ability to deregulate bone remodelling. The invasion of bone tissue by tumor cells indeed affects the balance between bone resorption and bone formation. This deregulation induces the release of cytokines or growth factors initially trapped in the bone matrix, such as transforming growth factor-β (TGF-β), which in turn promote tumor progression. Over the past years, there has been considerable interest in the TGF-β pathway within the cancer research community. This review discusses the involvement of the TGF-β signalling pathway in osteosarcoma development and in their metastatic progression.

Despite research and clinical advances during recent decades, bone cancers remain a leading cause of death worldwide. There is a low survival rate for patients with primary bone tumors such as osteosarcoma and Ewing’s sarcoma or secondary bone tumors such as bone metastases from prostate carcinoma. Gap junctions are specialized plasma membrane structures consisting of transmembrane channels that directly link the cytoplasm of adjacent cells, thereby enabling the direct exchange of small signaling molecules between cells. Discoveries of human genetic disorders due to genetic mutations in gap junction proteins (connexins) and experimental data using connexin knockout mice have provided significant evidence that gap-junctional intercellular communication (Gj) is crucial for tissue function. Thus, the dysfunction of Gj may be responsible for the development of some diseases. Gj is thus a main mechanism for tumor cells to communicate with other tumor cells and their surrounding microenvironment to survive and proliferate. If it is well accepted that a low level of connexin expression favors cancer cell proliferation and therefore primary tumor development, more evidence is suggesting that a high level of connexin expression stimulates various cellular process such as intravasation, extravasation, or migration of metastatic cells. If so, connexin expression would facilitate secondary tumor dissemination. This paper discusses evidence that suggests that connexin 43 plays an antagonistic role in the development of primary bone tumors as a tumor suppressor and secondary bone tumors as a tumor promoter.

Osteosarcoma, the main malignant primary bone tumor, affects a ‘young’ population composed of children and young adults. Current treatment consists of tumor resection associated with chemotherapy. Unfortunately in many cases, a lack of response to anti-tumor drugs is observed, leading to development of metastases and to the patient’s death. Because TGF-β promotes metastases from many solid epithelial tumors, we investigated the effect of inhibitory Smad7 overexpression on osteosarcoma behavior. In vitro, using three human osteosarcoma cell lines (HOS, SAOS2 and U2OS), we generated osteosarcoma cell clones constitutively expressing Smad7. By transfection of cells with (CAGA)₉-lux or -800PAI1-lux, by measuring the level of Smad3 phosphorylation, and by measuring the PAI-1, CTGF and COL1A1 expression by qPCR, we demonstrated that the overexpression of Smad7 inhibits the transcriptional response mediated by Smad3/4 in osteosarcoma cell lines. In addition, expression of Smad7 efficiently reduced the capacity of osteosarcoma cells to invade Matrigel in Boyden migration chambers. Gelatin zymography identified reduced MMP-2 secretion by Smad7-expressing osteosarcoma cells as compared with their control counterparts. In vivo, using a xenograft model of osteosarcoma induced by paratibial injection of HOS or SAOS2 cells overexpressing Smad7 in mice, we showed that inhibition of the TGF-β signaling pathway significantly slows primary tumor growth and increases mice survival. The microarchitectural parameters which were assessed by radiography and by microscanner analysis showed an increased trabecular bone volume when Smad7 was over-expressed. In addition, Smad7 overexpression in osteosarcoma cells inhibits the development of lung metastasis. These results suggest that the inhibition of TGF-β signaling pathway could be a new therapeutic strategy against the tumor progression of osteosarcoma.