Convective forces increase CXCR4-dependent glioblastoma cell invasion in GL261 murine model

Abstract

Glioblastoma is the most common and malignant form of brain cancer. Its invasive nature limits treatment efficacy and promotes inevitable recurrence. Previous in vitro studies have shown that interstitial fluid flow, a factor characteristically increased in cancer, increases glioma cell invasion via CXCR4-CXCL12. It is currently unknown if these effects translate in vivo. Using the therapeutic technique of convection enhanced delivery (CED), we tested if convective flow alters glioma invasion in vivo using the syngeneic GL261 mouse model of glioblastoma. We first confirmed that GL261 invasion in vitro increased under flow in a CXCR4-CXCL12 dependent manner. Additionally, approximately 65.4% and 6.59% of GL261 express CXCR4 and CXCL12 in vivo, respectively, with 3.38% expressing both. Inducing convective flow within implanted tumors indeed increased glioma cell invasion over untreated controls, and administering CXCR4 antagonist AMD3100 (5 mg/kg) effectively eliminated this response. Therefore, glioma invasion is in fact stimulated by convective flow in vivo through CXCR4. We also analyzed patient samples to show that expression of CXCR4 and CXCL12 increase in patients following therapy. These results suggesting that targeting flow-stimulated invasion may prove beneficial as a second line of therapy, particularly in patients chosen to receive convection enhanced drug delivery.