The influence of tumor-host interactions in the stromal cell-derived factor-1/CXCR4 ligand/receptor axis in determining metastatic risk in breast cancer.
The chemokine stromal cell-derived factor-1 (SDF-1) may function to attract CXCR4-expressing cancer cells to metastatic organs. We have previously demonstrated that low plasma SDF-1, a host-derived marker, increases distant metastatic risk in breast cancer. We therefore hypothesized that tumors overexpressing the SDF-1 receptor CXCR4 have an enhanced ability to metastasize in patients with low plasma SDF-1 levels. In this study, we determined the prognostic significance of activated CXCR4, or phosphorylated CXCR4 (p-CXCR4), and CXCR7, another receptor for SDF-1. Immunohistochemistry was performed on a tissue microarray built using 237 samples from the same cohort of patients for which we measured plasma SDF-1 levels. We found that the prognostic value of p-CXCR4 expression (hazard ratio or HR, 3.95; P = 0.004) was superior to total CXCR4 expression (HR, 3.20; P = 0.03). The rate of breast cancer-specific mortality was much higher in patients with both high p-CXCR4 expression and low plasma SDF-1 levels (HR, 5.96; P < 0.001) than either low plasma SDF-1 (HR, 3.59; P = 0.01) or high p-CXCR4 expression (HR, 3.83; P = 0.005) alone. The added prognostic value of low plasma SDF-1 was only effective in patients with high p-CXCR4 expression, and as such, provides clinical validation for modulation of the metastatic potential of tumor cells by an inherent host-derived metastatic risk factor.
Hassan
Saima
S
Department of Oncology, Lady Davis Institute, Sir Mortimer B Davis Jewish General Hospital, McGill University, Montréal, Québec, Canada.
Ferrario
Cristiano
C
Saragovi
Uri
U
Quenneville
Louise
L
Gaboury
Louis
L
Baccarelli
Andrea
A
Salvucci
Ombretta
O
Basik
Mark
M
D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D054377:Chemokine CXCL12 / Q000097:blood*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D009361:Neoplasm Invasiveness / Q000235:genetics; D010766:Phosphorylation; D011379:Prognosis; D054387:Receptors, CXCR / Q000096:biosynthesis / Q000235:genetics; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics; D012307:Risk Factors; D046888:Tissue Array Analysis
C501896:ACKR3 protein, human; D014408:Biomarkers, Tumor; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D008024:Ligands; D054387:Receptors, CXCR; D019718:Receptors, CXCR4