+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Enhancement of the CXCL12/CXCR4 axis due to acquisition of gemcitabine resistance in pancreatic cancer: effect of CXCR4 antagonists

Enhancement of the CXCL12/CXCR4 axis due to acquisition of gemcitabine resistance in pancreatic cancer: effect of CXCR4 antagonists

Bmc Cancer 16: 305

The CXCL12-CXCR4 signaling axis in malignant tumor biology has increased in importance, and these peptides are implicated in tumor growth, invasion and metastasis. The aim of our study was to examine the important role of the axis in pancreatic cancer (PaCa) cells' relationship with stromal cells in gemcitabine-resistant (GEM-R) tumors and to confirm the effectiveness of CXCR4 antagonists for the treatment of GEM-R PaCa cells. We established two GEM-R PaCa cell lines using MIA PaCa-2 and AsPC-1 cells. The expression of CXCR4 mRNA in PaCa cells and the expression of CXCL12 mRNA in fibroblasts were examined by reverse transcription polymerase chain reaction (RT-PCR). The expression of CXCR4 protein in PaCa cells was examined by immunosorbent assay (ELISA) and immunocytochemistry. Using Matrigel invasion assays and animal studies, we then examined the effects of two CXCR4 antagonists, AMD11070 and KRH3955, on the invasiveness and tumorigenicity of GEM-R PaCa cells stimulated by CXCL12. We found that the expression of CXCR4 in GEM-R PaCa cells was significantly enhanced by GEM but not in normal GEM-sensitive (GEM-S) PaCa cells. In RT-PCR and ELISA assays, the production and secretion of CXCL12 from fibroblasts was significantly enhanced by co-culturing with GEM-R PaCa cells treated with GEM. In Matrigel invasion assays, the invasiveness of GEM-R PaCa cells treated with GEM was significantly activated by fibroblast-derived CXCL12 and was significantly inhibited by CXCR4 antagonists, AMD11070 and KRH3955. In vivo, the tumorigenicity of GEM-R PaCa cells was activated by GEM, and it was significantly inhibited by the addition with CXCR4 antagonists. Our findings demonstrate that the CXCL12-CXCR4 signaling axis plays an important role in PaCa cells' resistance to GEM. CXCR4 expression was significantly enhanced by the exposure to GEM in GEM-R PaCa cells but not in GEM-S PaCa cells. Furthermore, CXCR4 antagonists can inhibit the growth and invasion of GEM-R PaCa cells. These agents may be useful as second-line chemotherapy for GEM-R PaCa in the future.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 057773467

Download citation: RISBibTeXText

PMID: 27175473

DOI: 10.1186/s12885-016-2340-z

Related references

Role of CXCL12-CXCR4 axis in ovarian cancer metastasis and CXCL12-CXCR4 blockade with AMD3100 suppresses tumor cell migration and invasion in vitro. Journal of Cellular Physiology 2018, 2018

The CXCL12 (SDF-1)/CXCR4 chemokine axis: Oncogenic properties, molecular targeting, and synthetic and natural product CXCR4 inhibitors for cancer therapy. Chinese Journal of Natural Medicines 16(11): 801-810, 2018

Role of CXCL12/CXCR4 signaling axis in pancreatic cancer. Chinese Medical Journal 126(17): 3371-3374, 2014

Expression of chemokine CXCL12 and its receptor CXCR4 in folliculostellate (FS) cells of the rat anterior pituitary gland: the CXCL12/CXCR4 axis induces interconnection of FS cells. Endocrinology 153(4): 1717-1724, 2012

Emerging roles of the CXCL12/CXCR4 axis in pancreatic cancer progression and therapy. Pharmacology and Therapeutics 179: 158-170, 2017

CXCR4, CXCL12 and the relative CXCL12-CXCR4 expression as prognostic factors in colon cancer. Tumour Biology 37(6): 7441-7452, 2017

Small molecule CXCR4 antagonists block the HIV-1 Nef/CXCR4 axis and selectively initiate the apoptotic program in breast cancer cells. Oncotarget 9(24): 16996-17013, 2018

Inhibition of the CXCL12/CXCR4 chemokine axis with AMD3100, a CXCR4 small molecule inhibitor, worsens murine hepatic injury. Hepatology Research 45(7): 794-803, 2014

Effect of CXCL12/CXCR4 on increasing the metastatic potential of non-small cell lung cancer in vitro is inhibited through the downregulation of CXCR4 chemokine receptor expression. Oncology Letters 7(4): 941-947, 2014

The CXCR4/CXCL12 axis in endometrial cancer. Clinical and Experimental Metastasis 26(3): 261-268, 2009

Effect of the LPA-mediated CXCL12-CXCR4 axis in the tumor proliferation, migration and invasion of ovarian cancer cell lines. Oncology Letters 7(5): 1581-1585, 2014

Research Progress on TKI Resistance of CML Cells Mediated by MSC through CXCL12/CXCR4 Axis. Zhongguo Shi Yan Xue Ye Xue Za Zhi 23(4): 1221-1224, 2015

CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression. Cancer Metastasis Reviews 29(4): 709-722, 2011

The Cxcl12/Cxcr4 Axis as a Therapeutic Target in Cancer and Hiv-1 Infection. Current Medicinal Chemistry 18(4): 497-512, 2011

The CXCL12/CXCR4 axis as a therapeutic target in cancer and HIV-1 infection. Current Medicinal Chemistry 18(4): 497-512, 2011