Premetastatic soil and prevention of breast cancer brain metastasis.

Abstract

BACKGROUND:

As therapies for systemic cancer improve and patients survive longer, the risk for brain metastases increases. We evaluated whether immune mechanisms are involved in the development of brain metastasis.

METHODS:

We conducted our studies using BALB/c mice bearing syngeneic 4T1 mammary adenocarcinoma cells in the mammary gland.

RESULTS:

The brains of mice bearing 4T1 tumors at day 14 had no detectable metastatic tumor cells but presented with marked accumulation of bone marrow-derived CD11b(+)Gr1(+) myeloid cells, which express high levels of inflammatory chemokines S100A8 and S100A9. In vitro, S100A9 attracts 4T1 cells through Toll-like receptor 4 and CD11b(+)Gr1(+) myeloid cells through Toll-like receptor 4 and the receptor for advanced glycation end-products. Systemic treatment of 4T1-bearing mice with anti-Gr1 (RB6-8C5) monoclonal antibody reduces accumulation of CD11b(+)Gr1(+) myeloid cells in the day-14 premetastatic brain as well as subsequent brain metastasis of 4T1 cells detected on day 30. Furthermore, treatment of 4T1 tumor-bearing mice with the cyclooxygenase-2 inhibitor celecoxib or genetic disruption of cyclooxygenase-2 in 4T1 cells inhibits the inflammatory chemokines and infiltration of CD11b(+)Gr1(+) myeloid cells in the premetastatic brain and subsequent formation of brain metastasis.

CONCLUSIONS:

Our results suggest that the primary tumor induces accumulation of CD11b(+)Gr1(+) myeloid cells in the brain to form "premetastatic soil" and inflammation mediators, such as S100A9, that attract additional myeloid cells as well as metastatic tumor cells. Celecoxib and anti-Gr1 treatment may be useful for blockade of these processes, thereby preventing brain metastasis in patients with breast cancer.

• Authors: Yan Liu, Akemi Kosaka, Maki Ikeura, Gary Kohanbash, Wendy Fellows-Mayle, Linda A Snyder, Hideho Okada
• Journal: Neuro-oncology (Neuro Oncol) Vol. 15 Issue 7 Pg. 891-903 (Jul 2013) ISSN: 1523-5866 [Electronic] England
• PMID: 23595625 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CD11b Antigen
• Calgranulin B
• Cyclooxygenase 2 Inhibitors
• Gr-1 protein, mouse
• Inflammation Mediators
• Pyrazoles
• RNA, Messenger
• Receptors, Chemokine
• S100A9 protein, mouse
• Sulfonamides
• enhanced green fluorescent protein
• Green Fluorescent Proteins
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Celecoxib

Topics

• Adenocarcinoma (metabolism, pathology, prevention & control)
• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Brain Neoplasms (metabolism, prevention & control, secondary)
• CD11b Antigen (genetics, metabolism)
• Calgranulin B (genetics, metabolism)
• Celecoxib
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cyclooxygenase 2 (chemistry, genetics, metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Female
• Flow Cytometry
• Green Fluorescent Proteins (metabolism)
• Immunoenzyme Techniques
• Inflammation Mediators (metabolism)
• Leukocytes (cytology, drug effects, metabolism)
• Mammary Neoplasms, Experimental (metabolism, pathology, prevention & control)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mice, Transgenic
• Myeloid Cells (drug effects, metabolism, pathology)
• Pyrazoles (pharmacology)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Receptors, Chemokine (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Sulfonamides (pharmacology)
• Tumor Cells, Cultured