CXCL12 in Malignant Glial Tumors: A Possible Role in Angiogenesis and Cross-Talk between Endothelial and Tumoral Cells

Abstract

CXCL12 (stromal cell-derived factor-1/CXCL12) regulates leukocyte, endothelial and hematopoietic precursor migration, bone-marrow myelopoiesis and angiogenesis. CXCL12 and its receptor CXCR4 are over-expressed in malignant gliomas, which are highly vascularized tumors with a poor prognosis. We studied the expression of CXCL12 and CXCR4 in glioma cell lines, endothelial cells, tissue sections and endocavitary fluids from patients with gliomas. We then analyzed the proliferative and the apoptotic effect of CXCL12 in endothelial cells and glioma primary cultures. We observed the release of CXCL12 in supernatants of human brain microvascular endothelial cells and at variable levels, in post-surgical endocavitary fluids. CXCL12 was expressed in both glioma and endothelial cells as assessed by immunostaining of surgical brain sections. CXCR4 was found in cells lines and primary cultures from malignant gliomas as well as in endothelial cells and was increased by vascular endothelial growth factor and basic fibroblast growth factor (bFGF). CXCL12 inhibited bFGF-induced proliferation of endothelial cells and increased the survival of endothelial cells. The survival of primary cells obtained from glioma specimens was also enhanced in the presence of CXCL12. We point out the presence and the release of CXCL12 in tumor microenvironment and we observed a modulating effect of CXCL12 on proliferation and survival of both endothelial and tumoral cells. Our data support in vivo studies suggesting a role in angiogenesis played by CXCL12, which could represent a possible prognostic factor.

Mechanisms by which CXCR4/CXCL12 cause metastatic behavior in pancreatic cancer

“…There are currently few studies investigating CXCL12 and tumor lesion, and studies have identified that there was abnormal expression of CXCL12 in certain types of cancer, including ovarian and pancreatic cancer and glioma (22)(23)(24). Several studies have demonstrated that increased expression levels of CXCL12 in the bone marrow could inhibit tumor cell migration (23,25), and that the progression of high-grade glioma with high expression of CXCL12 would be more rapid than normal (24).…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…VEGF induces bone marrow-derived myeloid cell mobilization to the circulation and through VEGF-mediated upregulation of SDF1/CXCL12 in activated perivascular myofibroblasts, the myeloid cells are kept in close proximity to angiogenic vessels [223]. VEGF is upregulated in a wide variety of tumors [69,[224][225][226][227], as is CXCL12 [228]. CXCL12, that is also upregulated by hypoxia [229], augments CXCR4 expression on vascular endothelial cells [230] and attracts CXCR4 + cells, including neutrophils, to the tumor [223].…”

Tumor-secreted SDF-1 promotes glioma invasiveness and TAM tropism toward hypoxia in a murine astrocytoma model

“…[28][29][30] To further explore the roles of SDF-1, its production by ALTS1C1 cells was suppressed by transfection with lentivirus particles carrying SDF-1 specific siRNA. SDF-knockdown ALTS1C1 (SDF kd ) cells expressed relatively low levels of SDF-1 mRNA and protein as assessed by RT-PCR and western blot (Supplementary Figure S5a).…”