CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway

Abstract

CXC chemokine receptor 4 (CXCR4) has been shown to play a critical role in chemotaxis and homing, which are key steps in cancer metastasis. There is also increasing evidence that links this receptor to angiogenesis; however, its molecular basis remains elusive. Vascular endothelial growth factor (VEGF), one of the major angiogenic factors, promotes the formation of leaky tumor vasculatures that are the hallmarks of tumor progression. Here, we investigated whether CXCR4 induces the expression of VEGF through the PI3K/Akt pathway. Our results showed that CXCR4/ CXCL12 induced Akt phosphorylation, which resulted in upregulation of VEGF at both the mRNA and protein levels. Conversely, blocking the activation of Akt signaling led to a decrease in VEGF protein levels; blocking CXCR4/CXCL12 interaction with a CXCR4 antagonist suppressed tumor angiogenesis and growth in vivo. Furthermore, VEGF mRNA levels correlated well with CXCR4 mRNA levels in patient tumor samples. In summary, our study demonstrates that the CXCR4/ CXCL12 signaling axis can induce angiogenesis and progression of tumors by increasing expression of VEGF through the activation of PI3K/Akt pathway. Our findings suggest that targeting CXCR4 could provide a potential new anti-angiogenic therapy to suppress the formation of both primary and metastatic tumors.

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

“…While, Kijowski et al 35 demonstrated the stimulation of VEGF secretion by SDF-1-CXCR4 axis, using human hematopoietic cell lines. Because then, a close correlation between CXCR4 and VEGF expression has been demonstrated in epithelial malignancies 12,13 and osteosarcoma, 36 both in vitro and in vivo. In our previous study, we found a significant positive correlation between immunohistochemical VEGF and CXCR4 expression.…”

“…[7][8][9] Some investigators have revealed that exogenous VEGF up-regulated CXCR4 expression in human endothelial cells. 10,11 A close correlation between CXCR4 and VEGF expression has been demonstrated in a breast cancer cell line through the PI3K/Akt pathway, 12 and in pancreatic cancer cell lines through ERK pathway. 13 Moreover, a strong relationship between CXCR4 and VEGF mRNA levels has been demonstrated in breast cancer tumor tissue.…”

“…13 Moreover, a strong relationship between CXCR4 and VEGF mRNA levels has been demonstrated in breast cancer tumor tissue. 12 The incidence of soft-tissue sarcomas is relatively rare and these types of tumors constitute less than 1% of all human malignancies. 14 Generally, round-cell sarcomas such as Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) and rhabdomyosarcoma show a good response to chemotherapy and effective regimens have been established.…”

PKB/Akt-dependent regulation of inflammation in cancer

“…Given the general crucial role of PKB in cell motility [23], it is not surprising to observe a key contribution of PKB in lymphocyte chemotactic migration. Indeed, activation of PKB is induced by S1P (ligand for S1P1) [34], CCL19/CCL21 (ligands for CCR7) [34], CXCL13 (ligand for CXCR5) [34] and CXCL12 (ligand for CXCR4) [35], most probably downstream of PI3 K [34]. Interestingly, PKB dependent phosphorylation of S1P1 is required for S1P1 mediated chemotaxis [36].…”

“…Moreover, PKB activation induced by PTEN loss promotes prostate tumor growth and metastasis by up-regulating CXCR4 expression [78]. CXCR4 activation can further boost PKB activity [35,79]. Functionally, PKB activation is required for CXCR4-induced cancer cell migration [80].…”