Induction of CXCR2 ligands, stem cell-like phenotype, and metastasis in chemotherapy-resistant breast cancer cells

Abstract

CXCR2 and its ligands have been shown to play an important role in tumor angiogenesis, therapy resistance and progression. In this study, we investigated whether CXCR2 ligands are responsible for the survival advantage and metastasis of drug-resistant cells and examined the underlying mechanism(s) doxorubicin or paclitaxel resistant mammary tumor cells. Our results demonstrated that drug-resistant Cl66 cells upregulated CXCR2 ligands but down regulated expression of CXCR2. We observed delayed tumor growth but increased metastasis in mice using these drug-resistant cells. Furthermore, we observed differential upregulation of stem cell and mesenchymal markers in the doxorubicin and paclitaxel-resistant tumor cells. Abrogation of the CXCR2 signaling axis using CXCR2 ligand neutralization resulted in significant inhibition of drug-resistant cell growth. Together, our data suggest chemotherapy-specific differential regulation of CXCR2 ligands, stem cell-like and mesenchymal phenotypes, and enhanced metastasis in drug-resistant cells and targeting CXCR2 signaling may help circumvent therapy resistance in breast cancer.

CXCR2-Expressing Tumor Cells Drive Vascular Mimicry in Antiangiogenic Therapy–Resistant Glioblastoma

“…We originally reported in this study that CXCR2+ GBM cells acquire stem cell–like and endothelial phenotypes following AAT both in vitro and in vivo , strengthening our hypothesis that CXCR2+ GBM cells drive the AAT resistance via VM. Recently, utilization of IL-8-CXCR2 pathway disrupting agents showed an inhibition of cell growth and drug resistance [34] and an improvement in the antitumorigenic and anti-AAT responses [28] . In our current study, SB225002 was able to inhibit tube formation in both normoxic and hypoxic conditions.…”

Application prospective of nanoprobes with MRI and FI dual-modality imaging on breast cancer stem cells in tumor

“…These methods are able to rapidly isolate, purify BCSCs. They push forward the advancement of BCSCs research, and enrich understanding of BCSCs for scientists [ 16 , 17 ]. However, the former approaches are mainly well applied in cell line level; and they have difficulties to track BCSCs in solid tumors in vivo.…”

Bicyclo[2.2.1]heptane containing N,N′-diarylsquaramide CXCR2 selective antagonists as anti-cancer metastasis agents

“…[4][5][6][7][8][9] Here, the blockade of CXCR2 represents an attractive strategy for the treatment of cancer metastasis. 5,7,[10][11][12][13][14][15][16][17][18][19] As shown in Fig. 1…”