CXCR4 and VEGF expression in the primary site and the metastatic site of human osteosarcoma: analysis within a group of patients, all of whom developed lung metastasis

Abstract

The chemokine, CXCL12, and its receptor, CXCR4, have recently been shown to play an important role in metastasis of several kinds of carcinoma. It has also been demonstrated that VEGF regulates both the expression of CXCR4 and invasiveness in breast cancer cell lines. We compared the immunohistochemical expression of CXCR4 and VEGF between the primary site and a concordant pulmonary metastatic site in 30 osteosarcoma patients, all of which had undergone thoracotomy. Microvessel density (MVD) as shown by immunostaining of CD34 and proliferative activity with MIB-1 monoclonal antibody was also evaluated. CXCR4 expression (primary, 33.3% positive vs metastatic, 66.6% positive; P ¼ 0.0097) and MVD (primary, 29.8676 ; P ¼ 0.0015) in the metastatic site were both significantly increased compared with those in the primary site, whereas no difference between primary and metastatic sites was observed with regard to VEGF expression. There was a significant positive correlation between immunohistochemical CXCR4 and VEGF expression (P ¼ 0.0269). In total population, the MIB-1-labeling index (LI) was significantly higher in tumors, which showed immunoreactivity for VEGF (MIB-1-LI in VEGF-positive tumors, 24.2975.4 vs VEGF-negative tumors, 18.3374.16; P ¼ 0.034). Furthermore, those patients with VEGFpositive primary tumors had a significantly worse prognosis compared with the patients with VEGF-negative primary tumors (P ¼ 0.0053). Our results suggested that CXCR4 expression was associated with metastatic progression, and immunohistochemical VEGF expression in the primary site had predictive value for the osteosarcoma patients, who developed lung metastasis. It has been demonstrated that certain chemokines can serve as tissue-specific attractant molecules for tumor cells, promoting tumor cell migration to particular sites in vivo. Among chemokines and their receptors, the stromal cell-derived factor-1 (SDF-1/CXCL12)/CXCR4 system has been demonstrated to be involved in the lymph node metastasis or distant metastasis of several types of cancer. [1][2][3][4][5][6][7][8][9][10][11][12] Osteosarcoma is the most frequent primary bone tumor in young adults and adolescents. Despite recent advances in multimodality treatments consisting of adjuvant chemotherapy and surgical-wide resection, pulmonary metastasis occurs in approximately 40-50% of the patients. 13 In such cases, the overall 5-year survival rate is only 28%, despite the multidisciplinary therapy.14 Involvement of the CXCR4/SDF-1 pathway in the metastatic process in the lung has also been demonstrated in osteosarcoma cell lines. 15Immunohistochemical VEGF expression in the untreated primary site has been reported to be correlated with pulmonary metastasis and microvessel density (MVD) in osteosarcoma.16 Wang

Chemokine receptor CXCR4 expression is correlated with VEGF expression and poor survival in soft‐tissue sarcoma

“…In our previous study, we found a significant positive correlation between immunohistochemical VEGF and CXCR4 expression. 22 In the current study, we also found a significant relationship between CXCR4 mRNA expression and VEGF mRNA expression in MNRCT. Therefore, VEGF may also be a candidate for a molecular target in the treatment of MNRCT, because of its close correlation with CXCR4 expression and because of its adverse effect on patient's survival in this tumor group.…”

“…23 We also demonstrated increased immunohistochemical expression of CXCR4 at the metastatic site, compared with that at the primary site in osteosarcoma. 22 In the current study, no significant difference was detected between the expression level of CXCR4 mRNA at the primary site and that at the metastatic or recurrent site.…”

“…22 The number of CD31-positive vessels was counted in four selected hot spots in a 3400 field (0.26-mm 2 field area). The mean value of the two independent readings of the same specimen was calculated, and MVD was defined as the mean count of microvessels per 0.26-mm 2 field area.…”

“…Sections from breast carcinoma specimens that had resulted in lymph node metastasis were used as a positive control for CXCR4. 22 …”

Specific Tyrosine Kinase Inhibitors Regulate Human Osteosarcoma Cells In vitro

“…Because many of the receptors and downstream signaling molecules are tyrosine kinases [18,22], inhibitors of these kinases are a majority of the most promising anticancer drugs [4,10,21,27]. Although osteosarcoma has not been as well studied as other types of cancer, overexpression in osteosarcoma has been reported for both growth factors and their tyrosine kinase receptors, and overexpression of some of these molecules correlates with metastasis and poor survival in patients with osteosarcoma [5,8,9,15,17,20,23,28,33,36,47,49,60,65].…”