All these receptors tightly control tissue

All these receptors tightly control tissue homeostasis, and any dysregulation of these ligand–receptor systems (mutations, overexpression, etc.) disturbs cell communication and leads to pathological situations. Bone formation and bone remodelling are then controlled by a large panel of cytokines and growth factors regulating the dialogue between osteoblasts, osteoclasts and their environment [8]. It has been recognised that cancer ML-291 (bone sarcomas and metastatic cells originating from carcinomas) dysregulate the balance between osteoblasts and osteoclasts, activate osteoclastogenesis and then stimulate bone resorption. Consequently, activated osteoclasts resorb the extracellular bone matrix and release numerous growth factors entrapped in the organic matrix, which stimulate in turn the proliferation of cancer cells. Based on these observations, numerous chemical drugs have been developed to specifically target the various receptor tyrosine kinases activated by mutations, or by the ligands present in the tumour microenvironment. The present review summarises the classification, structure and mechanism, and focuses on the targeting of action of the receptor tyrosine kinases. Their use in the treatment of bone cancers (bone sarcomas and bone metastases) is described and discussed.
The receptor tyrosine kinase (RTK) family
RTKs in oncology
Conclusion In the last 15 years, there have been high expectations in oncology of therapies with RTK inhibitors. Imatinib mesylate was the first to show spectacular clinical success in chronic myeloid leukaemia patients, and has become the first line of treatment. Gastro-intestinal stromal tumour (GIST) is the second success for the use of an RTK inhibitor, and imatinib mesylate is the standard of care in patients who are at high risk for GIST recurrence following resection [166]. Unfortunately, patients develop resistance and relapse due to protein point mutations and/or the introduction of molecular feedback loops. Many other RTK inhibitors have shown disappointing results in clinical applications after encouraging pre-clinical results. In all cases, the efficacy of RTK inhibitors is linked with their ability to disrupt the crosstalk between tumour cells and their environment. A better understanding of both intracellular signal modulating by these RTK inhibitors, and the feedback loops developed during the establishment of resistance, will increase the chances of success for these drugs. In addition, adapted investigational approaches will be needed to define the expression profile of the RTK genuinely activated/mutated/expressed in patients before their inclusion in clinical trials.
Conflict of interest statement
Acknowledgements This review was written as a part of a research project which received funding from the Seventh Framework Programme ([FP7/2007-2013]) under Grant Agreement no. 264817-BONE-NET. This study was supported by the Region des Pays de la Loire (CIMATH II research project) and by the Ligue Nationale Contre le Cancer (Equipe LIGUE 2012).
Introduction Bone metastases are a common complication in advanced cancer patients. The incidence of bone metastases at postmortem examination is 73% for patients with primary breast cancer and 68% for patients with primary prostate cancer [1]. In bone metastases, what typically is a tightly regulated process of bone resorption and formation, is disrupted by the interaction of tumor cells with osteoclasts and osteoblasts in the bone [2]. The disruption of normal bone processes by the disease usually results in increased resorption and formation rates, which can often be quantitatively measured by biomarkers in the urine and blood of patients. Despite the convenience of urinary markers, their capabilities should not be underestimated. Urinary markers are still in need of further validation to enter routine clinical practice; however they are becoming increasingly important in the management of bone metastases. Changes in bone are often too slow for detection by imaging; therefore urinary markers can provide an alternative method to evaluate changes in disease status, even before such changes become clinically evident. Thus, urinary markers could potentially serve as a convenient and important diagnostic tool [3].