Blockade of the Stromal Cell–Derived Factor-1/CXCR4 Axis Attenuates In vivo Tumor Growth by Inhibiting Angiogenesis in a Vascular Endothelial Growth Factor–Independent Manner

Abstract

The interaction between the chemokine receptor CXCR4 and its specific ligand, stromal cell-derived factor-1 (SDF-1/ CXCL12), mediates several cellular functions. In cancer, SDF-1-positive or CXCR4-positive cells of various lineages are detected within tumor tissues. Recent intensive research has indicated the possibility that blocking CXCR4 could reduce the metastatic potential of cancer cells. Here, we show that the inhibition of the SDF-1/CXCR4 axis decreases the growth of s.c. gastrointestinal tumors through the suppression of tumor neoangiogenesis. The neutralization of CXCR4 suppressed the growth in vivo of tumors derived from mouse Colon38 and PancO2 cells, whereas it did not affect the growth of Colon38 and PancO2 cells in vitro. This attenuation of tumor growth was found to be independent of the expression of CXCR4 by the cancer cells themselves, because CXCR4 knocked-down Colon38 cells grew similarly to control cells. Furthermore, CD31-positive tumor capillaries were reduced to 45% (P < 0.001) and intratumor blood flows were decreased to 65% (P < 0.01) by blockade of CXCR4. The vascular endothelial growth factor (VEGF) concentration in the tumors was not affected by the neutralization of CXCR4. Taken together with the detection of CXCR4-positive endothelial cells in the tumor tissues, the findings suggest that the antiangiogenic effects of the blockade of CXCR4 are related to a reduction of the establishment of tumor endothelium independently of VEGF inhibition. Our data indicate that the SDF-1/CXCR4 pathway might be a general target for anticancer strategies and that blocking this system could be cooperatively effective in combination with other antiangiogenic therapies, such as blockade of VEGF. (Cancer Res 2005; 65(13): 5864-71)

Chemokines in tumor angiogenesis and metastasis

“…Several lines of evidence indicate that CXCL12 induces endothelial cell migration, proliferation, tube formation and increases in VEGF release by endothelial cells [99][100][101]. Blockade of CXCL12/CXCR4 results in decreased tumor growth in vivo due to inhibition of angiogenesis in a VEGF-independent manner [102]. The source of CXCL12 that drives angiogenesis is likely to be derived from specialized stromal cells and tumor cells [103].…”

Manipulating the chemokine‐chemokine receptor network to treat cancer

“…In experimental systems, selective inhibition of CXCR4 suppresses CXCL12-induced migration of cancer cells, invasion, neoangiogenesis and metastases 6,9,[70][71][72][73][74][75][76][77] (Table 3). In immunodeficient mice, studies showed that lung metastases from human breast cancer could be inhibited by a neutralizing antibody against CXCR4 72 or that their growth could be delayed by inhibiting CXCR4 with an siRNA 73 or specific CXCR4 antagonists.…”

Inhibition of CXCR4 activity with AMD3100 decreases invasion of human colorectal cancer cells in vitro

“…High or persistent expression of CXCR4 has been associated with poor prognosis in osteosarcoma [9] , epithelial ovarian cancer [10] , colon cancer [6,11,12] , esophageal carcinoma [13] , and melanoma [14] . Recently, intensive research has shown that binding of CXCL12 to CXCR4 plays a role in tumor angiogenesis by influencing the secretion of vascular endothelial growth factor (VEGF) [15] and increasing invasion associated with matrix metalloproteinase (MMP)-9 activation [16] . Therefore, interruption of the interaction between CXCR4 and SDF-1 has received considerable attention since it may provide a means of inhibiting the metastatic process.…”