RESUMEN
BACKGROUND: Patients with primary breast cancer that is positive for human epidermal growth factor receptor 2 (Her2+) have a high risk of developing metastases in the brain. Despite gains with systemic control of Her2+ disease using molecular therapies, brain metastases remain recalcitrant to therapeutic discovery. The clinical predilection of Her2+ breast cancer cells to colonize the brain likely relies on paracrine mechanisms. The neural niche poses unique selection pressures, and neoplastic cells that utilize the brain microenvironment may have a survival advantage. METHODS: Tropomyosin-related kinase B (TrkB), Her2, and downstream targets were analyzed in primary breast cancer, breast-to-brain metastasis (BBM) tissues, and tumor-derived cell lines using quantitative real-time PCR, western blot, and immunohistochemical assessment. TrkB function on BBM was confirmed with intracranial, intracardiac, or mammary fat pad xenografts in non-obese diabetic/severe combined immunodeficiency mice. The function of brain-derived neurotrophic factor (BDNF) on cell proliferation and TrkB/Her2 signaling and interactions were confirmed using selective shRNA knockdown and selective inhibitors. The physical interaction of Her2-TrkB was analyzed using electron microscopy, co-immunoprecipitation, and in silico analysis. Dual targeting of Her2 and TrkB was analyzed using clinically utilized treatments. RESULTS: We observed that patient tissues and cell lines derived from Her2+ human BBM displayed increased activation of TrkB, a neurotrophin receptor. BDNF, an extracellular neurotrophin, with roles in neuronal maturation and homeostasis, specifically binds to TrkB. TrkB knockdown in breast cancer cells led to decreased frequency and growth of brain metastasis in animal models, suggesting that circulating breast cancer cells entering the brain may take advantage of paracrine BDNF-TrkB signaling for colonization. In addition, we investigated a possible interaction between TrkB and Her2 receptors on brain metastatic breast cancer cells, and found that BDNF phosphorylated both its cognate TrkB receptor and the Her2 receptor in brain metastatic breast cancer cells. CONCLUSION: Collectively, our findings suggest that heterodimerization of Her2 and TrkB receptors gives breast cancer cells a survival advantage in the brain and that dual inhibition of these receptors may hold therapeutic potential.
Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias de la Mama/genética , Glicoproteínas de Membrana/genética , Receptor ErbB-2/genética , Receptor trkB/genética , Animales , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/secundario , Factor Neurotrófico Derivado del Encéfalo/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/genética , Dimerización , Femenino , Humanos , Glicoproteínas de Membrana/química , Ratones , Receptor ErbB-2/química , Receptor trkB/química , Transducción de Señal/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: With growing interest in global health, surgeons have created outreach missions to improve health care disparities in less developed countries. These efforts are mainly episodic with visiting surgeons performing the operations and minimal investment in local surgeon education. To create real and durable advancement in surgical services in disciplines that require urgent patient care, such as pediatric neurosurgery, improving the surgical armamentarium of the local surgeons must be the priority. METHODS: We propose a strategic design for extending surgical education missions throughout the Western Hemisphere in order to transfer modern surgical skills to local neurosurgeons. A selection criteria and structure for targeted missions is a derivative of logistical and pedagogical lessons ascertained from previous missions by our teams in Peru and Ukraine. RESULTS: Outreach programs should be applied to hospitals in capital cities to serve as a central referral center for maximal impact with fiscal efficiency. The host country should fulfill several criteria, including demonstration of geopolitical stability in combination with lack of modern neurosurgical care and equipment. The mission strategy is outlined as three to four 1-week visits with an initial site evaluation to establish a relationship with the hospital administration and host surgeons. Each visit should be characterized by collaboration between visiting and host surgeons on increasingly complex cases, with progressive transfer of skills over time. CONCLUSION: A strategic approach for surgical outreach missions should be built on collaboration and camaraderie between visiting and local neurosurgeons, with the mutual objective of cost-effective targeted renovation of their surgical equipment and skill repertoire.
