July 9, 2014 | by Cecilia Choy
Cecilia Choy, Josh Neman, Matthew Duenas, Hubert Li, Nagarajan Vaidehi, Rahul Jandial
Metastases are responsible for 90% of all cancer deaths, and patients diagnosed with brain metastasis have a dismal 20% probability of one-year survival. Breast cancer metastasizes to the brain in approximately 40% of patients who have a Her2+ tumor. The “seed and soil” hypothesis framing the current investigation of metastasis is uniquely exemplified by the colonization of the brain by circulating breast cancer cells. Accordingly, therapy for brain metastases should not only employ cytotoxic approaches against the tumor cell, but also perturbation of the microenvironment that facilitates cancer cell growth and resilience.
Despite disseminating to distant organs as malignant scouts, most tumor cells fail to remain viable after their arrival. Previous research shows that the brain’s physiologic microenvironment must become tumor-favorable for successful metastatic colonization by breast cancer cells. The bidirectional interplays of metastatic breast cancer cells and native brain cells are poorly understood and rarely studied. Astrocytes, prominent glial cells in the central nervous system, are responsible for homeostasis of the brain microenvironment. Furthermore, astrocytes secrete neurotrophins, such as brain-derived neurotrophic factor (BDNF), which are multifunctional growth factors with a crucial role in synaptic plasticity, survival, and cognitive function. BDNF binds to the extracellular domain of the Tropomyosin-Related Kinase B (TrkB) receptor. Therefore, we hypothesize that Her2+ breast cancers express TrkB receptors to exploit BDNF from the brain microenvironment for metastatic colonization.Our results show high expression of TrkB receptor in patient specimens of fresh tissue and cells from neurosurgical resections of Her2+ breast-to-brain metastases (BBMs). Because BDNF expression is highest in the brain microenvironment, paracrine signaling may potentiate tumor cell growth and survival. Indeed, our results show both exogenous and astrocyte-derived BDNFconfers a TrkB-dependent cellular proliferation in Her2+ BBMs. In vivo xenograft studies show a delay in brain colonization and metastatic growth with BBM TrkB-knockdowns (BBM-KD).
Because Her2 is an orphan receptor that can heterodimerize with ligand-bound receptors, we looked at the possible interaction between TrkB and Her2 in BBM cells. Our results show colocalization of Her2 and phosphorylated TrkB receptor in BBM tissue and cells. Co-immunoprecipitation and 3-D structural modeling confirm direct binding of Her2 and TrkB receptors. Furthermore, BDNF treatment induces TrkB-Her2 heterodimerization, which is abrogated in BBM-KD. These results suggest that in order to establish a metastatic niche, tumor cells exploit BDNF from the brain microenvironment, resulting in subsequent heterodimerization of TrkB and Her2 receptors and promoting proliferation and colonization.