Antagonistic Functions of Connexin 43 during the Development of Primary or Secondary Bone Tumors

Abstract

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.

Keywords: bone tumors; connexin 43; gap junction; metastatic process; primary tumor growth.

Figure 1

Gap junction. (A) Schematic representation of gap-junctional channel. (B) Schematic representation of homotypic and heterotypic gap-junctional channel. (C) Schematic representation of the connexin structure.

Figure 2

(A) Osteoblast differentiation. (B) Osteoclast differentiation. (C) Schematic representation of the gap junction communication (Gj) between bone cells.

Figure 3

Implication of connexin 43 in (A) primary bone tumors and (B) secondary bone tumor from prostate cancer.