ABSTRACT
BACKGROUND: Osteosarcoma (OS) is the most frequent primary malignant bone tumour in children and adolescents with a high propensity for lung metastasis. Chemokines and chemokine receptors have been described to have an important role in many malignancies including OS. The aim of this study was to investigate the expression of CXCR7 receptor in OS tissues and its role in the progression of the disease in the lungs. METHODS: Immunohistochemistry was used to study CXCR7 expression in primary tumours and metastatic tissues from patients with OS. Its contribution to tumour expansion in the lungs has been also assessed using animal models and synthetic-specific CXCR7 ligands. RESULTS: CXCR7 was expressed on human primary bone tumours and on lung metastases. Its expression was predominantly located on tumour-associated blood vessels. Mice challenged with OS cells and systematically treated with synthetic CXCR7 ligands presented a significant reduction of lung nodules compared with untreated mice. CONCLUSION: This study shows that CXCR7 has a critical role in OS progression in the lungs, where are expressed CXCR7 ligands, especially CXCL12. Moreover, we highlight that synthetic CXCR7 ligands could represent a powerful therapeutic tool to impede lung OS progression.
Subject(s)
Bone Neoplasms/metabolism , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , Osteosarcoma/metabolism , Osteosarcoma/secondary , Receptors, CXCR/biosynthesis , Animals , Bone Neoplasms/pathology , Disease Progression , Humans , Immunohistochemistry , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Osteosarcoma/genetics , Osteosarcoma/pathology , Receptors, CXCR/geneticsABSTRACT
BACKGROUND: Liver and lung metastases are the predominant cause of colorectal cancer (CRC)-related mortality. Chemokine-receptor pairs have a critical role in determining the metastatic progression of tumours. Our hypothesis was that disruption of CXCR7/CXCR7 ligands axis could lead to a decrease in CRC metastases. METHODS: Primary tumours and metastatic tissues from patients with CRC were tested for the expression of CXCR7 and its ligands. Relevance of CXCR7/CXCR7 ligands for CRC metastasis was then investigated in mice using small pharmacological CXCR7 antagonists and CRC cell lines of human and murine origins, which - injected into mice - enable the development of lung and liver metastases. RESULTS: Following injection of CRC cells, mice treated daily with CXCR7 antagonists exhibited a significant reduction in lung metastases. However, CXCR7 antagonists failed to reduce the extent of liver metastasis. Moreover, there were subtle differences in the expression of CXCR7 and its ligands between lung and liver metastases. CONCLUSION: Our study suggests that the activation of CXCR7 on tumour blood vessels by its ligands may facilitate the progression of CRC within lung but not within liver. Moreover, we provide evidence that targeting the CXCR7 axis may be beneficial to limit metastasis from colon cancer within the lungs.
Subject(s)
Carcinoma/metabolism , Carcinoma/secondary , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , Receptors, CXCR/metabolism , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Chemokine CXCL12/metabolism , Disease Models, Animal , Disease Progression , Female , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Interleukin-8/metabolism , Liver Neoplasms/metabolism , Liver Neoplasms/secondary , Mice , Mice, Inbred BALB C , Mice, SCID , Real-Time Polymerase Chain Reaction , Receptors, CXCR/antagonists & inhibitors , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Neuropsychiatric manifestations are not rarely associated with systemic lupus erythematosus (SLE). Magnetic resonance angiography and positron emission tomography can provide excellent images of cerebral perfusion and metabolism whereas information is still lacking on a possible diagnostic role of ultrasound. In this study we aim to assess whether duplex sonography of neck and intracranial vessels may be useful in distinguishing patients with and without neuropsychiatric SLE (NPSLE). Neck and transcranial duplex sonography was performed by a single operator on 33 women affected by SLE (mean age +/- SD: 47.69+/-8.17 years) and on 15 healthy control subjects. Nineteen patients presented NPSLE. Pulsatility and resistivity indices (PI and RI) were automatically calculated by the ultrasound instrument in internal carotid (ICA) and middle cerebral artery (MCA), on both sides, according to standard methods. No significant haemodynamic differences were found in mean and median PI and RI values of ICA and MCA comparing SLE with NPSLE patients and with healthy control subjects. No correlation was found between MCA and ICA parameters in the same group of patients. Duplex sonography of cerebral vessels is unable to distinguish SLE and NPSLE patients. Heterogeneity of causes in the pathogenesis of NPSLE and the different vascular adaptation of cerebral macrocirculation as opposed to cerebral microcirculation may represent possible reasons that explain the inability of ultrasound to differentiate SLE patients from NPSLE patients.
