Absence of multiple atypical chemokine binders (ACBs) and the presence of VEGF and MMP-9 predict axillary lymph node metastasis in early breast carcinomas

Abstract

The aim of this study was to determine the frequency of axillary lymph node (ALN) metastasis of early breast cancers by evaluating the status of DARC, D6 and CCX-CKR and the levels of VEGF and MMP-9. The status of DARC, D6 and CCX-CKR and the levels VEGF and MMP-9 were evaluated in ALN- (n = 130) and ALN + (n = 88) patients with T1 breast cancer by immunohistochemical staining. For ALN, likelihood ratio χ (2)-tests were used for univariate analysis and logistic regression for multivariate analysis. Univariate analysis identified the nuclear grade, VEGF and MMP-9 expression and absence of DARC, D6 and CCX-CKR as predictors of ALN involvement. When combining the three receptors (DARC, D6 and CCX-CKR) together, tumors with multiple absence (multi-absence, any two or three loss) had a higher likelihood of being ALN positive than non-multi-absence (coexpression of any two or three) tumors (56.2 vs. 27.9 %, P < 0.001). The final multivariate logistic regression revealed nuclear grade, VEGF, MMP-9 and non-multi-absence versus multi-absence to be independent predictors of ALN involvement; the odds ratio (OR) and 95 % CI for non-multi-absence tumors versus multi-absence were 0.469 (0.233-0.943). Multi-absence was also associated with the involvement of four or more lymph nodes among ALN + tumors. Moreover, tumors with multi-absence had higher VEGF (78.1 vs. 50.0 %, P < 0.001) and MMP-9 (81.3 vs. 36.1 %, P < 0.001) expression than non-multi-absence tumors. Our data highlight that the absence of DARC, D6 and CCX-CKR in combination, which is associated with higher VEGF and MMP-9 expression, predicts the presence and extent of ALN metastasis in breast cancer.

ACKR2: An Atypical Chemokine Receptor Regulating Lymphatic Biology

“…ACKR2 was also found to be expressed in human breast cancer, and its expression predicts relapse-free survival (RFS) (54) while it is inversely correlated with axillary lymph node metastasis (55). Of note, a functional non-synonymous single nucleotide polymorphism of ACKR2 is associated with lymph node metastasis and RFS in breast cancer, indicating that the expression and function of ACKR2 in the host could also affect tumor progression (54, 56).…”

Traditional Chinese Medicine Extract from Huaier Increases the Expression of Duffy Antigen Receptor for Chemokines and Reduces the Expression of Its Ligands

“…The absence of multiple atypical chemokine binders such as DARC, D6, and CCX-CKR, which is associated with higher VEGF and MMP-9 expression, predicts the presence and extent of ALN metastasis in breast cancer [ 26 ]. Moreover, DARC isoforms in the tumor microenvironment could reduce the levels of promalignant chemokines in different degrees, have differential effects on tumor growth and vascularization, and contribute to differential potential of metastasis [ 4 ].…”

Atypical chemokine receptors in cancer: friends or foes?

“…A protective role of ACKR1 in cancer is also suggested by data obtained with different human tumors. In breast [29,34,35], thyroid [36], colorectal [37], and laryngeal squamous cell [38] tumors, ACKR1 expression was positively correlated with a better outcome, even if the cell types expressing ACKR1 in these samples were not characterized. In summary, these results indicate ACKR1 as a negative regulator of tumor growth.…”

“…Indeed ACKR2 overexpression in a human breast cell line decreases levels of inflammatory chemokines and tumor aggressiveness; in human breast cancer samples, ACKR2 expression is inversely correlated to lymph node metastasis, as well as to clinical stage, and positively correlated to disease-free survival rate [56]. Moreover, ACKR2 is down-regulated during breast cancer progression, and the down-regulation, together with the other 2 atypical chemokine receptors, ACKR1 and ACKR4, correlates with a malignant outcome in the pathology [34,35]. Interestingly, the host Figure 1.…”