Messenger RNA Expression Levels of CXCR4 Correlate with Metastatic Behavior and Outcome in Patients with Osteosarcoma

Abstract

Purpose: To determine if osteosarcoma cells express chemokine receptors and if their presence or absence relates to clinical features. Experimental Design: Using fluorescent quantitative real-time PCR, the pattern of 17 chemokine receptors in 3 osteosarcoma cell lines and 68 osteosarcoma patient samples was analyzed.Results: The expression of the chemokine receptors was generally low among the cell lines. In the high-grade osteosarcoma patient samples (n = 47), CXCR4 was the most commonly expressed (63%) and its expression level was inversely correlated to overall survival (P < 0.0001), event-free survival (P < 0.001), and metastasis-free survival (MFS; P = 0.002). There was also a correlation between the expression level of CXCR4 and the presence of metastasis at diagnosis (P = 0.002). CCR7 was expressed in 43% of the samples and its expression level was inversely correlated with overall survival (P = 0.03) and MFS (P = 0.007). CCR10 mRNA expressionlevel was inversely correlated with MFS (P = 0.009). There was no association between the expression of CXCR4, CCR7, and CCR10. Of the 26 samples studied for stromal cell^derived factor-1 expression, 77% expressed it, but there was no correlation with the clinical variables or CXCR4 expression. Multivariate analysis revealed that mRNA expression level of CXCR4 was the only significant variable for overall survival (P = 0.0006), event-free survival (P = 0.004), and MFS (P = 0.025). Conclusions: These data suggest that CXCR4 could be useful as a prognostic factor and as a predictor of potential metastatic development in osteosarcoma. If further studies confirm that it is relevant to metastases in this disease, it could represent a new therapeutic target.Chemokines are small molecules that regulate leukocyte trafficking and homing. Their receptors are seven-transmembrane, G-coupled proteins (1 -3). Recent data suggest that the interactions between chemokines and their receptors are also critical components in the regulation of tumor progression and metastasis in breast cancer and other tumors (4, 5). The chemokine receptor CXCR4 and its ligand stromal cellderived factor-1 (SDF-1) have been shown to mediate organspecific metastasis by creating a chemotactic gradient between the primary tumor site and the metastatic site (4 -6). Prostate and breast cancer cells might use the CXCR4/SDF-1 pathway to localize to bones and develop metastasis (7 -9). Many studies also suggest that the CXCR4/SDF-1 pathway is involved in the metastatic process of rhabdomyosarcoma, neuroblastoma, melanoma, glioblastoma, and colon, lung, pancreatic, ovarian, and thyroid carcinomas (10 -17). In acute lymphoblastic leukemia, high expression of CXCR4 predicts extramedullary organ infiltration and, in acute myeloid leukemia, is a poor prognosis factor (18, 19). Mü ller et al. also found that two other chemokine receptors, CCR10 and CCR7, are highly expressed by melanoma and breast cancer cells, respectively (4). CCR7 and its ligand, CCL21, could have a role in lymph node metastasis in breast ...

Development and external validation of nomograms predicting distant metastases and overall survival after neoadjuvant chemotherapy and surgery for patients with nonmetastatic osteosarcoma: A multi‐institutional study

“…Therefore, considering the nature of this multi‐institutional study, we felt it necessary to omit the data for ALP and LDH. However, it is likely that the inclusion of these serological markers or known molecular markers such as P‐glycoprotein,31 CXCR4,32 and ezrin33 would improve the predictive ability of future nomograms. Fifth, the trunk cases had better outcomes than expected (better than proximal humerus cases) with respect to MFS.…”

Osteosarcoma

“…Similar to the integrin family of proteins, expression of chemokines and the chemokine receptors have been linked to osteosarcoma progression and metastasis in a number of preclinical and correlative studies. (47,48) Interactions between chemokines and integrin family members further contribute to the ability of metastatic cells to interact with their microenvironment and promote metastatic cell survival. (49) The insulin-like growth factor 1 (IGF-1) pathway.…”

Chemokines in tumor angiogenesis and metastasis

“…Patients with high CXCR4 expression in NSCLC, colorectal or prostate cancer were more prone to metastasis [149][150][151]. The expression of CXCR4 in nasopharyngeal carcinoma and osteosarcoma is also associated with metastasis [152,153]. In colorectal cancer, CXCR4 expression in primary tumors demonstrated significant association with recurrence, survival, and liver metastasis [154].…”