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CXCR4

CXCR4 pathway expressed on a tumor cell diagram

Chemokine (C-X-C motif) receptor 4 (CXCR4), a chemokine receptor expressed by immune and tumor cells, guides tumor-cell migration and is important for processes such as tumor metastasis. Inhibition of CXCR4 may impair these protumor effects.

  • CXCR4 is a G-protein–coupled receptor in the CXC chemokine receptor family found on the surface of immune cells, such as T cells1-3
    • The ligand for CXCR4 is (chemokine (C-X-C motif) ligand 12) CXCL12 or stromal cell-derived factor 1 (SDF-1), which is expressed by cells such as osteoblasts and endothelial cells5
    • Binding of CXCR4 to its ligand CXCL12 directs the migration and recruitment of immune cells,5,6 and is implicated in several biological processes such as immune response and cardiovascular development5
  • Preclinical data suggest that inhibition of the CXCR4 pathway may have a dual effect, as it impairs tumor-cell migration and blocks tumor growth.10 It also increases mobilization of leukocytes and leukemic blasts into the peripheral circulation, resulting in significant antileukemic activity11
    • CXCR4 may also promote the accumulation of cytotoxic
      T cells
      10

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REFERENCES–CXCR4

1. Xu C, Zhao H, Chen H, Yao Q. CXCR4 in breast cancer: oncogenic role and therapeutic targeting. Drug Des Devel Ther. 2015;9:4953-4964. 2. Lee B, Sharron M, Montaner LJ, et al. Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. Proc Natl Acad Sci U S A. 1999;96(9):5215-5220. 3. Loetscher M, Geiser T, O’Reilly T, et al. Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes. J Biol Chem. 1994;269(1):232-237. 4. Helbig G, Christopherson KW II, Bhat-Nakshatri P, et al. NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem. 2003;278(24):21631-21638. 5. Cheng M, Qin G. Progenitor cell mobilization and recruitment: SDF-1, CXCR4, α4-integrin, and c-kit. Prog Mol Biol Transl Sci. 2012;111:243-264. 6. Oberlin E, Amara A, Bachelerie F, et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature. 1996;382(6594):833-835. 7. Sun X, Cheng G, Hao M, et al. CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev. 2010;29(4):709-722. 8. Sehgal A, Keener C, Boynton AL, et al. CXCR-4, a chemokine receptor, is overexpressed in and required for proliferation of glioblastoma tumor cells. J Surg Oncol. 1998;69(2):99-104. 9. Chen Y, Stamatoyannopoulos G, Song C-Z. Down-regulation of CXCR4 by inducible small interfering RNA inhibits breast cancer cell invasion in vitro. Cancer Res. 2003;63(16):4801-4804. 10. Righi E, Kashiwagi S, Yuan J, et al. CXCL12/CXCR4 blockade induces multimodal antitumor effects that prolong survival in an immunocompetent mouse model of ovarian cancer. Cancer Res. 2011;71(16):5522-5534. 11. Kuhne MR, Mulvey T, Belanger B, et al. BMS-936564/MDX-1338: a fully human anti-CXCR4 antibody induces apoptosis in vitro and shows antitumor activity in vivo in hematologic malignancies. Clin Cancer Res. 2013;19(2):357-366.