CXCR4 Regulates Growth of Both Primary and Metastatic Breast Cancer

Abstract

The chemokine receptor CXCR4 and its cognate ligand CXCL12 recently have been proposed to regulate the directional trafficking and invasion of breast cancer cells to sites of metastases. However, effects of CXCR4 on the growth of primary breast cancer tumors and established metastases and survival have not been determined. We used stable RNAi to reduce expression of CXCR4 in murine 4T1 cells, a highly metastatic mammary cancer cell line that is a model for stage IV human breast cancer. Using noninvasive bioluminescence and magnetic resonance imaging, we showed that knockdown of CXCR4 significantly limited the growth of orthotopically transplanted breast cancer cells. Mice in which parental 4T1 cells were implanted had progressively enlarging tumors that spontaneously metastasized, and these animals all died from metastatic disease. Remarkably, RNAi of CXCR4 prevented primary tumor formation in some mice, and all mice transplanted with CXCR RNAi cells survived without developing macroscopic metastases. To analyze effects of CXCR4 on metastases to the lung, an organ commonly affected by metastatic breast cancer, we injected tumor cells intravenously and monitored cell growth with bioluminescence imaging. Inhibiting CXCR4 with RNAi, or the specific antagonist AMD3100, substantially delayed the growth of 4T1 cells in the lung, although neither RNAi nor AMD3100 prolonged overall survival in mice with experimental lung metastases. These data indicate that CXCR4 is required to initiate proliferation and/or promote survival of breast cancer cells in vivo and suggest that CXCR4 inhibitors will improve treatment of patients with primary and metastatic breast cancer.

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

“…However, knocking down CXCR4 expression specifically on tumor cells in murine models has generated conflicting data regarding the role of SDF-1 signaling on tumor cells in regulating angiogenesis. SDF-1 has been shown to promote directly tumor vasculature development [59] or to support only the growth and metastasis of CXCR4 + tumors [63], underscoring distinct SDF-1 functions in different cancer types.…”

“…Chronic treatment of AMD3100 efficiently blocks SDF-1-mediated vasculogenesis [20,21]. In tumor models, inhibition of the SDF-1-CXCR4 pathway with chronic administration of AMD3100 leads to efficient reduction of tumor growth and angiogenesis by targeting (i) proliferation of CXCR4-expressing tumor cells, (ii) diminishing recruitment of CXCR4 + angiogenic cells and (iii) promoting CXCR4-dependent metastasis [27,58,63]. In addition, CXCR4 antagonists might prevent vascular neointima formation and atherosclerosis [10].…”

The pathogenesis of the bone disease of multiple myeloma

“…Its receptor is CXCR4 which expressed on hematopoeitic stem cells and lymphocytes, as well as malignant cells and osteoclast precursors (41)(42)(43). SDF-1 is expressed by bone marrow stromal cells and endothelial cells.…”

Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells

“…Studies suggest that CXCR4 expression on tumor cells correlates with increased metastasis and decreased clinical prognosis (Salvucci et al, 2006). Moreover, blocking CXCR4 inhibits breast cancer cells from metastasizing to organs expressing CXCL12 (Muller et al, 2001;Smith et al, 2004). Although the mechanisms modulating CXCR4 expression in carcinoma cells is incompletely understood, increased expression on metastatic cancer cells seems to play a critical role in cancer tumorigenesis.…”