The presence of a vicious cycle
The presence of a “vicious cycle” established between tumor proliferation and paratumor osteolysis plays a crucial role in the development of primary bone tumors . Cancer cells produce soluble factors that activate directly or indirectly via osteoblasts, osteoclast differentiation and maturation , . In turn, during bone degradation, osteoclasts release tumor supportive growth factors stocked in the mineralized bone matrix . Studies about the cellular mechanisms underlying the rapid bone resorption in ES indicate that ES cells activate osteoclast activity . According with these findings, we demonstrated that the increase in bone volume observed after Cx43 overexpression in ES cells is due in large part to inhibition of osteoclast activity rather than to stimulation of osteoblast activity. The decrease of TRAP activity at the level of the growth plate, that is, not in direct contact with the tumor, suggests that the overexpression of Cx43 affects the ability of the tumor cells to produce a soluble factor able to regulate osteoclast activity, such as RANKL or M-CSF. This hypothesis is supported by previous reports demonstrating that ES cells support osteoclast formation by a RANKL- and M-CSF-dependent mechanism .
In conclusion, this report provides new insights regarding the role of the tumor suppressor gene Cx43 in the first stage of ES development, specifically during the primary bone tumor growth. We specifically demonstrated: 1) that Cx43 gene expression affects tumor growth by a blockade of the dpp-iv inhibitors in G0/G1 phase consistent with an increase of p27 level, and 2) that Cx43 gene expression plays a crucial role in the “vicious cycle” established between tumor proliferation and paratumor osteolysis by its ability to decrease osteoclast activity. The role of Cx43 in the more late stage of ES development like metastatic dissemination remains to be elucidated. Indeed, the role of connexins in invasion and metastasis seems to be even more complex, and several reports suggest that connexins might facilitate invasion, intravasation, extravasation and metastasis .
The following are the supplementary data related to this article.
Conflict of interest
Introduction Sarcomas are a heterogeneous group of mesenchymal tumors that occur in a higher proportion in children compared to adults, with 11% of all childhood cancers being sarcomas compared with 1% in the adult population . Approximately 80% arise in soft tissue, while the 20% remainders originate in bone . Rhabdomyosarcoma (RMS), synovial sarcoma (SS) and Ewing sarcoma (ES) are some of the pediatric sarcomas carrying specific chromosome translocations  and associated fusion genes, which have diagnostic and, in some cases, prognostic value . Moreover, fusion proteins resulting from chromosome translocations are oncogenic . The consistent association of these gene fusions with specific sarcoma subtypes has facilitated the development of molecular diagnostic assays such as FISH (Fluorescence in-situ hybridization) and RT-PCR (Polymerase Chain Reaction with Reverse Transcription) . RMS, the most common soft tissue sarcoma of childhood, is a family of sarcomas which are derived from mesenchymal cells related to skeletal muscle lineage . Two main histopathologic variants have been described, embryonal (ERMS), the most prevalent, and alveolar (ARMS). The subtype ARMS is often diagnosed in adolescents, with primary tumors localized in extremities and trunk, while subtype ERMS generally is diagnosed in young children with primary tumors localized in sites such as the head and neck, genitourinary tract and retroperitoneum , . Between ERMS and ARMS subtypes, there are clinical and genetic differences. The ERMS subtype has no specific chromosomes gains or losses. However, these tumors have showed a loss of heterozygosity at 11p15.5, which may lead to an increased expression of IGF2 gene . Otherwise, the majority of (80–85%) ARMS characterized chromosome translocations: t(2;13)(q35;q14) or, less commonly, t(1;13)(p36;p14), giving rise of fusion genes PAX3–FOXO1 (55–70%) or PAX7–FOXO1 (10–22%), respectively.