CCN2 was abundantly produced by the tumor cells that had invaded the bone matrix
(Fig. 2D) of note, up-regulation of CCN2 in mandible oral squamous cell carcinoma was associated with increased bone destruction [33]. These data suggest that CCN2 can be considered a diagnostic marker and target for treatment in oral osteolytic mandibular squamous cell carcinoma. LEE011 Parathyroid hormone-related protein (PTHrP) plays a vital role in the development of the embryonic skeleton and other tissues. When it is produced in excess by cancers, it can cause hypercalcemia; and its local production by breast cancer cells has been implicated in the pathogenesis of bone metastasis in that disease. Localized production of PTHrP by cancer cells in such lesions was shown to promote the survival and proliferation of cancer cells and osteolysis in a mouse ZD6474 nmr model [42]. PTHrP induces both the production of RANKL and down-regulation of OPG production by osteoblasts, thereby stimulating osteoclastogenesis [43] and [44]. Type I PTH/PTHrP receptor (PTH1R) expression was specifically observed in cancer cells producing PTHrP and CCN2 invaded the bone marrow (Fig. 2B) and PTHrP strongly upregulated CCN2 in MDA-MB-231 cells in vitro [45]. CCN2 was critically involved in osteolytic metastasis and was induced by PKA- and PKC-dependent activation of ERK 1/2 signaling by PTHrP [45]. Transforming growth factor-β (TGF-β) is
by far the most abundant cytokine in bone, 200 μg/kg
tissue, and must be considered as a central player in bone turnover [46] and potentially able to couple bone resorption with bone formation [47] and [48]. Restricted to the bone environment, target cells include cancer cells as well as osteoblasts, osteoclasts, their precursors bone marrow and stromal cells [46] and [47]. TGF-β 3-mercaptopyruvate sulfurtransferase is a pleiotropic cytokine that plays a central role in maintaining epithelial homeostasis. In early carcinogenesis, TGF-β acts as a tumor suppressor by inhibiting cell proliferation [49] and [50]. However, several studies showed that primary tumor cells in the late stage could reprogram their response to TGF-β by dysregulation or mutational inactivation of various components of the TGF-β signaling pathway and through cross-interaction with other oncogenic pathways. Consequently, the TGF-β signal becomes a bone metastasis-promoting one [51], [52] and [53]. Blocking TGF-β signaling especially in advanced stages of cancer may result in beneficial therapeutic responses by inhibiting metastatic progression [54]. TGF-β is one of the most potent inducers of CCN2, promoting CCN2 expression in bone metastatic cancer cells [39]; and the induction occurs through a complex network of transcriptional interactions requiring Smads, protein kinase C, and ras/MEK/ERK, as well as an Ets-1/transcription enhancer factor binding element in the CCN2 promoter [55], [56] and [57].