Cooperation of neurotrophin receptor TrkB and Her2 in breast cancer cells facilitates brain metastases.

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.

Inhibition of ß2-adrenergic receptor reduces triple-negative breast cancer brain metastases: The potential benefit of perioperative ß-blockade.

In response to recent studies, we investigated an association between perioperative ß-blockade and breast cancer metastases. First, a retrospective study examining perioperative ß-blocker use and cancer recurrence and metastases was conducted on 1,029 patients who underwent breast cancer surgery at the City of Hope Cancer Center between 2000 and 2010. We followed the clinical study and examined proliferation, migration, and invasion in vitro of primary and brain-metastatic breast cancer cells in response to ß2-activation and inhibition. We also investigated in vivo the metastatic potential of propranolol-treated metastatic cells. For stage II breast cancer patients, perioperative ß-blockade was associated with decreased cancer recurrence using Cox regression analysis (hazard's ratio =0.51; 95% CI: 0.23-0.97; p=0.041). Triple-negative (TN) brain-metastatic cells were found to have increased ß2-adrenergic receptor mRNA and protein expression relative to TN primary cells. In response to ß2-adrenergic receptor activation, TN brain-metastatic cells also exhibited increased cell proliferation and migration relative to the control. These effects were abrogated by propranolol. Propranolol decreased ß2-adrenergic receptor-activated invasion. In vivo, propranolol treatment of TN brain-metastatic cells decreased establishment of brain metastases. Our results suggest that stress and corresponding ß2-activation may promote the establishment of brain metastases of TN breast cancer cells. In addition, our data suggest a benefit to perioperative ß-blockade during surgery-induced stress with respect to breast cancer recurrence and metastases.

Sideline concussion testing in high school football on Guam.

BACKGROUND: The risks of repeat concussions and returning to play (RTP) prior to the resolution of concussive symptoms are medically established. However, RTP guidelines for high school sports are varied and often notably absent. The island of Guam, a US territory, has a robust athletics program but lacks structure to reduce concussions or establish RTP protocols. Consequently, there is an opportunity to limit the incidence of "second-hit syndrome" and other harmful effects through education and testing. METHODS: We evaluated the feasibility of Sideline Concussion Testing SCT) as a novel feature of Guam high school athletics. Thirteen high school football players were observed over three consecutive football games. They were first given a questionnaire about concussion history, symptoms, medical evaluation, and RTP. Researchers used the King-Devick Test, a SCT tool, and baseline scores were recorded. If players were then observed to have significant head trauma or to show concussive symptoms, they were sidelined and tested. RESULTS: Five of 13 students had a previous concussion and limited awareness of RTP guidelines. Of those five, four received no medical consultation or stand down period before RTP. There was also a lack of understanding of what constitutes a concussion; five out of eight individuals who denied previous concussion confirmed having bell ringers, seeing stars, and other classic concussive symptoms. Over the course of the study the SCT identified three concussions, with significant deviations from baseline time on a test that measured visual and speech disturbances. CONCLUSIONS: The feasibility of SCT use in Guam high school football was established and our pilot study identified areas for improvement. Established definitions of concussion and RTP guidelines were lacking. Therefore, an opportunity exists through public health efforts that involve the entire community to increase concussion awareness and reduce injuries in high school sports on Guam.

Strategic design for pediatric neurosurgery missions across the Western Hemisphere.

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.