Opposing effects of pigment epithelium-derived factor on breast cancer cell versus neuronal survival: implication for brain metastasis and metastasis-induced brain damage.
Brain metastases are a significant cause of morbidity and mortality for patients with cancer, yet preventative and therapeutic options remain an unmet need. The cytokine pigment epithelium-derived factor (PEDF) is downregulated in resected human brain metastases of breast cancer compared with primary breast tumors, suggesting that restoring its expression might limit metastatic spread. Here, we show that outgrowth of large experimental brain metastases from human 231-BR or murine 4T1-BR breast cancer cells was suppressed by PEDF expression, as supported by in vitro analyses as well as direct intracranial implantation. Notably, the suppressive effects of PEDF were not only rapid but independent of the effects of this factor on angiogenesis. Paralleling its cytotoxic effects on breast cancer cells, PEDF also exerted a prosurvival effect on neurons that shielded the brain from tumor-induced damage, as indicated by a relative 3.5-fold reduction in the number of dying neurons adjacent to tumors expressing PEDF. Our findings establish PEDF as both a metastatic suppressor and a neuroprotectant in the brain, highlighting its role as a double agent in limiting brain metastasis and its local consequences.
Women's Cancer's Section, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institute of Mental Health, Bethesda, Maryland 20892, USA.
Daniel P
DP
Fitzgerald
Preeti
P
Subramanian
Monika
M
Deshpande
Christian
C
Graves
Ira
I
Gordon
Yongzhen
Y
Qian
Yeva
Y
Snitkovsky
David J
DJ
Liewehr
Seth M
SM
Steinberg
José D
JD
Paltán-Ortiz
Mary M
MM
Herman
Kevin
K
Camphausen
Diane
D
Palmieri
S Patricia
SP
Becerra
Patricia S
PS
Steeg
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005136:Eye Proteins / Q000502:physiology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009414:Nerve Growth Factors / Q000502:physiology*; D009474:Neurons / Q000473:pathology*; D015843:Serpins / Q000502:physiology*; D000099174:Pigment Epithelium-Derived Factor
D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor