Endothelial CXCR7 regulates breast cancer metastasis

Abstract

Atypical chemokine receptor CXCR7 (ACKR3) functions as a scavenger receptor for chemokine CXCL12, a molecule that promotes multiple steps in tumor growth and metastasis in breast cancer and multiple other malignancies. While normal vascular endothelium expresses low levels of CXCR7, marked upregulation of CXCR7 occurs in tumor vasculature in breast cancer and other tumors. To investigate effects of endothelial CXCR7 in breast cancer, we conditionally deleted this receptor from vascular endothelium of adult mice, generating CXCR7ΔEND/ΔEND animals. CXCR7ΔEND/ΔEND mice appeared phenotypically normal, although these animals exhibited a modest 35 ± 3% increase in plasma CXCL12 as compared with control. Using two different syngeneic, orthotopic tumor implant models of breast cancer, we discovered that CXCR7ΔEND/ΔEND mice had significantly greater local recurrence of cancer following resection, elevated numbers of circulating tumor cells, and more spontaneous metastases. CXCR7ΔEND/ΔEND mice also showed greater experimental metastases following intracardiac injection of cancer cells. These results establish that endothelial CXCR7 limits breast cancer metastasis at multiple steps in the metastatic cascade, advancing understanding of CXCL12 pathways in tumor environments and informing ongoing drug development targeting CXCR7 in cancer.

High Expression of CCR7 Predicts Lymph Node Metastasis and Good Prognosis in Triple Negative Breast Cancer

“…CCR7 positive cancer cells actively directed metastasis to lymph nodes but might also activate the immune system to trap escaped tumor cells [15]. In support of this notion, previous studies have reported that CCR7 actively targeted migration to the lymph nodes, but led to less efficient metastasis to the lung in PyVmT mice models [9]. The correlation between chemokine receptors and lymph node metastases could provide a new understanding of breast cancer metastasis, which is worthy for further studies to develop novel therapies.…”

“…Such roles have been extensively studied in adaptive immunity and secondary lymphoid organogenesis [13, 14]. The CCR7 -null mice mutant displayed a disrupted architecture of the thymus and lymph nodes, as well as reduced primary immune response [9]. Hence, we hypothesize that the expression of CCR7 could increase the migration of breast cancer cells to lymph nodes.…”

“…C-C chemokine receptor 7 (CCR7), a G protein-coupled trans-membrane protein, can promote immune cell viability and induce immune cells homing to secondary lymphoid organs following cognate ligand binding like cytokines CCL19 and CCL21 [9, 10]. Whereas the exact roles of CCR7 in disease progression and in tumor metastasis to lymphoid tissues remain controversial so far.…”

Tumor endothelial cells accelerate tumor metastasis

“…CXCR7 regulates CXCL12–CXCR4‐mediated tumor cell transendothelial migration . In contrast, another group demonstrated deletion of endothelial CXCR7 in conditional knockout mice, which resulted in an increased number of circulating tumor cells with elevated systemic CXCL12 levels . The authors suggested that CXCR7 partially functions as a scavenger receptor for CXCL12, and endothelial CXCR7 controls the amounts of systemic CXCL12 .…”

CXCL12 retargeting of an adenovirus vector to cancer cells using a bispecific adapter

“…Altered expression of the CXCR4 receptor drives the signaling process of cancer cell migration and invasion23 and is associated with metastasis 24. CXCR7 is an alternate receptor for CXCL12, which is overexpressed in endothelial cells associated with tumors 25. Similar to CXCR4, CXCR7 plays a role as a G-protein-coupled receptor in regulating immunity, angiogenesis, stem cell trafficking, and mediating organ-specific metastases of cancer 26.…”