Bone matrix proteins; breast cancer; bone metastases; bone sialoprotein; protéines de la matrice osseuse; cancer du sein; métastases osseuses; sialoprotéine osseuse
Abstract :
[en] The skeleton is the privileged target of metastatic human breast cancer cells. Bone metastases are indeed found in virtually all advanced breast cancer patients and generate major morbidity. The high osteotropism of breast cancer cells suggests that they exhibit a selective affinity for mineralized tissues. The observation that mammary malignant cells are able to induce hydroxyapatite crystals deposition within the primary tumour suggests that they can generate a microenvironment that favors the crystallization of calcium and phosphate ions into the bone specific hydroxyapatite. Osteonectin (OSN), osteopontin (OPN) and bone sialoprotein (BSP), 3 bone matrix proteins involved in bone matrix mineralization, are expressed in human breast cancers. BSP, an RGD (Arg-Gly-Asp) containing phosphoprotein, initiates hydroxyapatite deposition and mediates attachment of osteoclast to the same crystals prior to their resorption. Detection of BSP at both the protein and the mRNA levels in human breast cancer and in human breast cancer cell lines (MCF-7, T47-D and MDA-MB 231) indicates that mammary malignant cells synthesize directly BSP rather than uptaking it from the serum. Interestingly, the level of BSP expression correlates with the development of bone metastases and with poor survival. These data suggest that the ectopic expression of bone matrix proteins could be involved in conferring osteotropic properties to circulating metastatic breast cancer cells. These observations open new alleys of investigation for the identification of the molecular mechanisms responsible for the genesis of bone metastases. [fr] Le squelette est la cible privilégiée des cellules métastatiques cancéreuses mammaires humaines. En effet, la majorité des patients présentant un cancer du sein à un stade avancé développent des métastases osseuses responsables d’une morbidité importante. L’ostéotropisme fréquent des cellules cancéreuses mammaires suggère qu’elles possèdent une affinité particulière pour le tissu minéralisé. L’observation que les cellules cancéreuses mammaires sont capables d’induire la formation de microcalcifications au niveau de la tumeur primaire suggère qu’elles peuvent créer un microenvironnement favorable au dépôt d’hydroxyapatite comparable à celui retrouvé au niveau du tissu osseux. L’ostéonectine (OSN), l’ostéopontine (OPN) et la sialoprotéine osseuse (BSP), 3 protéines de la matrice osseuse, sont exprimées dans les cancers mammaires humains. La BSP, une phosphoprotéine comprenant une séquence RGD (Arg-Gly-Asp), joue un rôle important lors de la formation des cristaux d’hydroxyapatite mais aussi au moment de leur résorption en médiant l’attachement des ostéoclastes à la matrice extracellulaire osseuse. La détection de BSP, au niveau protéine et ARNm, dans les tumeurs mammaires et dans 3 lignées cellulaires cancéreuses mammaires (MCF-7, T47-D et MDA- MB-231) indique que les cellules cancéreuses mammaires sont capables de synthétiser cette protéine de la matrice osseuse. Il est intéressant de noter que l’expression de BSP au niveau de la tumeur primaire est corrélée au développement de métastases osseuses et qu’elle est un facteur de mauvais pronostic pour la patiente. Ces résultats suggèrent que l’expression ectopique de protéines de la matrice osseuse pourrait être impliquée dans l’acquisition d’un phénotype ostéotropique par les cellules cancéreuses mammaires métastatiques. Ces observations ouvrent de nouvelles perspectives pour la compréhension des mécanismes moléculaires impliqués dans la formation de métastases osseuses.
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