Abstract B113: Role of I-TAC-binding receptors CXCR3 and CXCR7 in biology of various tumor cell lines

Abstract

Abstract Introduction: Chemokines and its receptors stimulate tumor growth, migration and invasion. SDF-1-CXCR4 axis plays a major role in these processes. However, other chemokines and their receptors are also important for tumor biology. Recently, SDF-1 was shown to bind with high affinity to the orphan receptor RDC1, later renamed CXCR7. In human tissues, CXCR7 expression has been described on endothelial cells and on some tumor cell lines. Recent studies confirmed a critical role for CXCR7/RDC1 in tumor vascular formation, angiogenesis and promotion of growth of breast and lung cancer in vivo. Objectives: In this study we evaluated the expression and function of CXCR3 and CXCR7 receptors in cervical carcinoma, rhabdomyosarcoma and glioblastoma cell lines. The main goal of this study was to explore the role of CXCR7 in biology of rhabdomyosarcoma, cervical carcinoma and glioblastoma. Material and Methods: Several cell lines were used in the study: rhabdomyosarcoma (SMS-CTR, RD, RH18, RH28, CW9019, RH30), cervical carcinoma (HeLa, HTB-34, HTB-35) and glioblastoma (LN18, LN229, T98G). To study the expression and function of CXCR3 and CXCR7 receptor real-time PCR, flow cytometry, western blot and chemotaxis assays were used. Results: We tested 12 different cell lines and found that all of them expressed CXCR7 and CXCR3 at mRNA and protein level. We noticed higher expression of CXCR7 on more aggressive tumor cell lines (e.g. CXCR7 expression differed between rhabdomyosarcoma subtypes and it was highly expressed by alveolar rhabdomyosarcoma and expressed at the low level by embryonal rhabdomyosarcoma). Since I-TAC binds CXCR3 receptor as well, its expression was also examined by flow cytometry. We observed expression of CXCR3 receptor on all tested cell lines except HeLa and CW9019 and these cell lines were chosen to check functionality of the CXCR7 receptor. Upon I-TAC stimulation the phosphorylation of AKT and MAPK was observed. We did not observed the migration of tumor cells toward I-TAC gradient. However, at the low dose I-TAC sensitized tumor cells toward SDF-1 gradient and synergized with SDF-1 in activation of intracellular pathways. Conclusions: We found that CXCR7 is expressed on various cell lines and its expression might correlate with aggressiveness of tumor. I-TAC, the ligand for CXCR7, was able to activate signaling transduction pathways responsible for tumor growth and survival. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B113.