Expression of the C-C Chemokine Receptor 7 Mediates Metastasis of Breast Cancer to the Lymph Nodes in Mice

Abstract

C-C chemokine receptor 7 (CCR7) controls lymphocyte migration to secondary lymphoid organs. Although CCR7 has been implicated in targeting the metastasis of cancers to lymph nodes, the role of CCR7 in the metastasis of breast cancer, along with the molecular mechanisms that are controlled by CCR7 that target breast cancer metastasis to the lymph nodes, has yet to be defined. To explore the cellular and molecular mechanisms of breast cancer cell migration to the lymph nodes, we used the mouse MMTV-PyVmT mammary tumor cells (PyVmT) transfected with CCR7 and the human CCR7-expressing MCF10A and MCF7 mammary cell lines. We found that the CCR7 ligands CCL19 and CCL21, controlled cell migration using the β(1)-integrin heterodimeric adhesion molecules. To define a physiological significance for CCR7 regulation of migration, we used the FVB syngeneic mouse model of metastatic breast cancer. When CCR7-negative PyVmT cells transfected with control vector were orthotopically transferred to the mammary fat pad of FVB mice, tumors metastasized to the lungs (10/10 mice) but not to the lymph nodes (0/10). In contrast, CCR7-expressing PyVmT (CCR7-PyVmT) cells metastasized to the lymph nodes (6/10 mice) and had a reduced rate of metastasis to the lungs (4/10 mice). CCR7-PyVmT tumors grew significantly faster than PyVmT tumors, which mirrored the growth in vitro, of CCR7-PyVmT, MCF7, and MCF10A mammospheres. This model provides tools for studying lymph node metastasis, CCR7 regulation of tumor cell growth, and targeting of breast cancer cells to the lymph nodes.

Immature myeloid Gr-1+ CD11b+ cells from lipopolysaccharide-immunosuppressed mice acquire inhibitory activity in the bone marrow and migrate to lymph nodes to exert their suppressive function

“…In this sense, CCR7 recruits naive T-cells and dendritic cells to LNs, where they engage with each other and initiate adaptive immune responses [43]. In addition, studies have shown a significant correlation between CCR7 expression and LN metastasis [44]. Although other receptors may be involved in trafficking of IS BM Gr-1 + CD11b + cells to LNs, the expression of CCR7 may be sufficient in itself because new expression of CCR7 has been described as enough to induce metastasis to LNs in several human and mouse breast tumour cell lines [44].…”

“…In addition, studies have shown a significant correlation between CCR7 expression and LN metastasis [44]. Although other receptors may be involved in trafficking of IS BM Gr-1 + CD11b + cells to LNs, the expression of CCR7 may be sufficient in itself because new expression of CCR7 has been described as enough to induce metastasis to LNs in several human and mouse breast tumour cell lines [44]. It remains for future studies to identify which chemokines are increased in LNEs from IS mice.…”

GPCR Signaling Mediates Tumor Metastasis via PI3Kβ

“…Numerous chemokines have been shown to promote cellular behaviors associated with breast tumor metastasis, including cell migration, increased expression and activity of matrix metalloproteinases (MMPs), increased heparanase activity, and invasion (4–12). Expression of chemokine receptors such as CXCR4 and CCR7 in tumor cells has also been linked to the dissemination of breast cancer cells to secondary organ sites that express high levels of their respective ligands (12,13). In addition to chemokine receptors, several other types of GPCRs, including protease-activated receptor-1 (PAR1), lysophosphatidic acid (LPA), and prostaglandin (EP) receptors, have been implicated in breast cancer metastasis (14–18).…”

The chemokine receptor CCR7 promotes mammary tumorigenesis through amplification of stem-like cells

“…In breast carcinogenesis it has been attributed a number of potential functions, including promotion of cell motility, migration and adhesion, regulation of matrix metalloproteinases leading to basement membrane degradation (12), and cell survival through inhibition of anoikis (13). Data obtained using cell lines has implicated CCR7 in breast cancer spread to the lymph nodes (14), and in human breast cancer its role was inferred from retrospective studies on archived tumor tissues (15). High CCR7 promotes breast cancer via stem-like cells 4 expression levels of CCR7 were also correlated with higher grade and occurrence of secondary tumors, and poor prognosis (16,17).…”