Opposing Effects of Pigment Epithelium–Derived Factor on Breast Cancer Cell versus Neuronal Survival: Implication for Brain Metastasis and Metastasis-Induced Brain Damage

Abstract

Brain metastases are a significant cause of cancer patient morbidity and mortality, yet preventative and therapeutic options remain an unmet need. The cytokine PEDF is downregulated in resected human brain metastases of breast cancer compared to 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 pro-survival 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 that PEDF as both a metastatic suppressor and a neuroprotectant in the the brain, highlighting its role as a double agent in limiting brain metastasis and its local consequences.

Emerging Strategies for Treating Brain Metastases from Breast Cancer

“…Once infiltrated into the brain tissue, breast cancer cells encounter a number of host cell types, including pericytes, reactive glia, neural progenitor cells, neurons, and oligodendrocytes. Although the survival of neurons is reduced by growing BM (Fitzgerald et al, 2012), there are no studies implicating neurons, oligodendrocytes or pericytes in BM formation. Pericytes are present in BM (Lorger and Felding-Habermann, 2010), and play a significant role in the vasculature of primary brain tumors (Armulik et al, 2011; Cheng et al, 2013).…”

Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis

“…For instance, they have been used to demonstrate that Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain (7), that the anti-HER2 drug lapatinib can inhibit the growth of brain metastatic cells (8), and that the blood-tumor barrier permeability determines drug efficacy in experimental brain metastases (9). They have also been used to analyze brain metastasis in magnetic resonance imaging (10) and to investigate brain damage induced by brain metastases (11).…”

Cranial irradiation increases tumor growth in experimental breast cancer brain metastasis

“…Mouse models have been developed that permit the in‐depth evaluation of breast cancer metastasis to the brain and allow the investigation of research questions that cannot be easily addressed in the patient population . One of these such models, the 4T1‐BR5 model, is a relatively new syngeneic mouse model of TNBC brain metastasis . Unlike human–mouse xenogeneic models of metastasis, the main advantage of the 4T1‐BR5 model is that it permits the evaluation of tumor growth in an immune‐competent host environment.…”

“…Murine brain tropic breast cancer cells (4T1‐BR5) were a kind gift from Dr Patricia Steeg's laboratory at the National Cancer Institute (Bethesda, MA, USA) . Cells were grown in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 100 IU/mL penicillin and 100 μg/mL streptomycin.…”