Abstract
Oncogenic events combined with a favourable environment are the two main factors in the oncological process. The tumour microenvironment is composed of a complex, interconnected network of protagonists, including soluble factors such as cytokines, extracellular matrix components, interacting with fibroblasts, endothelial cells, immune cells and various specific cell types depending on the location of the cancer cells (e.g. pulmonary epithelium, osteoblasts). This diversity defines specific “niches” (e.g. vascular, immune, bone niches) involved in tumour growth and the metastatic process. These actors communicate together by direct intercellular communications and/or in an autocrine/paracrine/endocrine manner involving cytokines and growth factors. Among these glycoproteins, RANKL (receptor activator nuclear factor-κB ligand) and its receptor RANK (receptor activator nuclear factor), members of the TNF and TNFR superfamilies, have stimulated the interest of the scientific community. RANK is frequently expressed by cancer cells in contrast with RANKL which is frequently detected in the tumour microenvironment and together they participate in every step in cancer development. Their activities are markedly regulated by osteoprotegerin (OPG, a soluble decoy receptor) and its ligands, and by LGR4, a membrane receptor able to bind RANKL. The aim of the present review is to provide an overview of the functional implication of the RANK/RANKL system in cancer development, and to underline the most recent clinical studies.
Highlights
In a physiological context, a healthy tissue microenvironment provides an adapted 3D microarchitecture with essential intercellular signalling, ensuring appropriate function
This description reflects the “seed and soil” theory proposed by Stephan Paget in 1889 to explain preferential metastatic sites depending on tumour subtype [3]. This “soil” or tumour microenvironment is a very complex and dynamic organization, defined by three main “niches” depending on their functional implication: (i) an immune niche involved in local immune tolerance, (ii) a vascular niche associated with tumour cell extravasation/migration and (iii) a metastatic niche hosting the metastastic tumour cells [4,5]
89 % of all the carcinomas assessed exhibit receptor activator of nuclear factor-κB (RANK) positive immunostaining, and approximately 60 % of cases showed more than 50 % of positive cancer cells
Summary
A healthy tissue microenvironment provides an adapted 3D microarchitecture with essential intercellular signalling, ensuring appropriate function. This tissue homoeostasis acts as a barrier to tumour development by inhibiting excessive cell growth and/or migration. The conjunction between one or more oncogenic events and this fertile environment can lead to the development of a tumour mass, which is frequently linked to the tumour cells escaping from the immune system [2] This description reflects the “seed and soil” theory proposed by Stephan Paget in 1889 to explain preferential metastatic sites depending on tumour subtype [3]. Lu et al [10] described a model of bone metastasis dormancy in breast cancer where
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