Neurotrophin-3 modulates breast cancer cells and the microenvironment to promote the growth of breast cancer brain metastasis

Abstract

Metastasis, which remains incompletely characterized at the molecular and biochemical levels, is a highly specific process. Despite the ability of disseminated cancer cells to intravasate into distant tissues, it has been long recognized that only a limited subset of target organs develop clinically overt metastases. Therefore, subsequent adaptation of disseminated cancer cells to foreign tissue microenvironment determines the metastatic latency and tissue tropism of these cells. As a result, studying interactions between the disseminated cancer cells and the adjacent stromal cells will provide a better understanding of what constitutes a favorable or unfavorable microenvironment for disseminated cancer cells in a tissue-specific manner. Previously, we reported a protein signature of brain metastasis showing increased ability of brain metastatic breast cancer cells to counteract oxidative stress. In this study, we showed that another protein from the brain metastatic protein signature, neurotrophin-3 (NT-3), has a dual function of regulating the metastatic growth of metastatic breast cancer cells and reducing the activation of immune response in the brain. More importantly, increased NT-3 secretion in metastatic breast cancer cells results in a reversion of mesenchymal-like (EMT) state to epithelial-like (MET) state and vice versa. Ectopic expression of NT-3 in EMT-like breast cancer cells reduces their migratory ability and increases the expression of HER2 (human epidermal growth factor receptor 2) and E-cadherin at the cell–cell junction. In addition, both endogenous and ectopic expression of NT-3 reduced the number of fully activated cytotoxic microglia. In summary, NT-3 appears to promote growth of metastatic breast cancer cells in the brain by facilitating the re-epithelialization of metastatic breast cancer cells and downmodulating the cytotoxic response of microglia. Most importantly, our results provide new insights into the latency and development of central nervous system macrometastases in patients with HER2-positive breast tumors and provide mechanistic rationale to target HER2 signaling for HER2-positive breast cancer brain metastasis.

Roles of the Cyclooxygenase 2 Matrix Metalloproteinase 1 Pathway in Brain Metastasis of Breast Cancer

“…The brain is protected from tumor cell invasion by BBB, and even after successful invasion, the metastatic cells must adapt themselves in the brain microenvironment, which is utterly different from that of the primary site (35,36). Therefore, the failure of the BBB is considered as the first critical step of brain metastasis.…”

Emerging Strategies for Treating Brain Metastases from Breast Cancer

“…Recent findings demonstrate that tumor cells can increase the density of growth-permissive astrocytes by promoting the differentiation of neural progenitor cells into astrocytes (Neman et al, 2013). Although the outcome of microglia infiltration is less known, microglia activation is inversely correlated with the growth of breast cancer cells in the brain (Louie et al, 2013). In summary, the brain microenvironment clearly offers a unique milieu in which metastatic cancer cells can survive and proliferate.…”

Silencing LRH-1 in colon cancer cell lines impairs proliferation and alters gene expression programs

“…NTF3 is a secreted factor important during embryogenesis in gastrointestinal smooth muscle development and central nervous system function. NTF3 was recently shown to be important in breast-cancer metastases to brain where it encourages epithelial transition of breast-cancer cells, facilitating their integration to the CNS microenvironment as well as serving to reduce immunogenicity (32). Interestingly, NTF3 has also been shown to increase resistance to anoikis (33).…”