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    • In bone microenvironment OPG RANK RANKL molecular triad

    2019-04-22

    In bone microenvironment, OPG/RANK/RANKL molecular triad is not solely expressed by bone cells. Whether OPG is considered as a ubiquitary receptor [20], membrane RANK is expressed by various tumour ARCA that originate from primary bone tumours or bone metastases, from mesenchymal and epithelial origin (Fig. 2A and B). A recent study showed that more than 80% of bone metastases from solid tumours are RANK positive as revealed by immunohistochemistry [42,43]. RANK is also expressed in more than 50% of human osteosarcoma specimens, with preferential expression in osteosarcomas that develop in pathological bone and are bad responders to chemotherapy [39]. These observations then identify tumour cells as potential RANKL targets. In addition to its expression by osteoblasts and bone marrow stromal cells, RANKL is produced similarly as RANK by numerous cancer cell types from various origins (Fig. 2C). RANKL expression is modulated by a lot of cytokines, hormones [20] and by hypoxia dysregulating bone remodelling, a common feature of malignant tumours [77]. Indeed, the invasion of bone tissue by a primary or metastatic tumour cell precociously affects the balance between bone resorption and bone formation. According to the tumour entities, tumour-derived factors (IGF, BMP, etc.) can stimulate osteoblast differentiation and activation and lead to tumour associated osteoblastic lesions (Fig. 3) or in contrast, RANKL released by tumour cells can activate osteoclastogenesis and the recruitment of mature osteoclasts resulting in osteolytic lesions. The co-existence of both phenomena leads to the formation of mixed osteoblastic/osteoclastic lesions. In turn, dysregulated bone cells-released extracellular matrix components and soluble mediators (TGFβ, etc.) are initially trapped in the bone matrix and stimulate proliferation of tumour cells and then the growth of tumour mass (Fig. 3). This mechanism is defined as the osteoclast-dependent role of RANK/RANKL axis in tumorigenesis. However, RANK/RANKL axis influences tumorigenesis through osteoclast-independent pathway (Fig. 3). RANKL produced by bone microenvironment constitutes a fertile soil for RANK-positive tumour cells. Initially proposed by Paget at the end of 1900 the concept of the seed and soil for primary and secondary bone tumours has been strengthened by the discovery of RANKL and RANKL partly explains why various tumours preferentially metastasise to bone. RANKL released by osteoblasts and bone marrow stromal cells creates a cytokine gradient between bone site and extraosseous sites and triggers the migration of RANK-positive tumours cells. Interestingly, numerous tumour cells expressed functional RANK as shown by the signal transduction (P-ERK1/2, P-P38, P-IkB, etc.) induced by RANKL [39,47,50]. The first evidence of this mechanism has been established by Jones et al. [45] and has been now described as prostate carcinoma [45,47,48], breast carcinoma [45], oral squamous carcinoma [50], lung cancer cells [52] and melanoma [45]. The implication of RANK/RANKL axis in tumour cell migration has been confirmed by exploration in human samples. Indeed, the levels of RANK expressed by primary tumour cells are directly related to the occurrence of bone metastases in solid tumours and more specifically in breast, prostate and melanoma [42–44]. Furthermore, RANK expression could be considered as an independent predictor of poor prognosis in breast cancer patients with bone metastasis in contrast with visceral metastasis for which no correlation has been shown [77]. Similarly, increased RANKL expression is related to the migration of renal carcinoma [53]. Whether the role of functional RANK expression has been clarified for carcinomas, its role in the pathogenesis of sarcomas is not fully understood. Indeed, it has been shown that osteosarcoma cells express the RANK protein [39]. RANK signalling, under the action of RANKL, results in the modulation of a panel of more than 70 specific genes demonstrating that osteosarcoma cells are therefore RANKL targets [40]. Wittrant et al. [38] showed that RANKL directly induces BMP-2 expression in RANK positive osteosarcoma cells and may contribute by this way to the osteoblastic lesions characteristic of osteosarcomas. More recently, Lee et al. observed that RANKL expression is correlated to clinical behaviour of patients suffering from high-grade osteosarcoma [57].