Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis

Abstract

Lung cancer is notorious for its ability to metastasize, but the pathways regulating lung cancer metastasis are largely unknown. An in vitro system designed to discover factors critical for lung cancer cell migration identified brain-derived neurotrophic factor, which stimulates cell migration through activation of tropomyosinrelated kinase B (TrkB; also called NTRK2). Knockdown of TrkB in human lung cancer cell lines significantly decreased their migratory and metastatic ability in vitro and in vivo. In an autochthonous lung adenocarcinoma model driven by activated oncogenic Kras and p53 loss, TrkB deficiency significantly reduced metastasis. Hypoxiainducible factor-1 directly regulated TrkB expression, and, in turn, TrkB activated Akt signaling in metastatic lung cancer cells. Finally, TrkB expression was correlated with metastasis in patient samples, and TrkB was detected more often in tumors that did not have Kras or epidermal growth factor receptor mutations. These studies demonstrate that TrkB is an important therapeutic target in metastatic lung adenocarcinoma.TrkB/NTRK2 | NSCLC L ung cancer remains the major cause of death from cancer worldwide. The two types of lung cancer are non-small-cell lung cancers (NSCLCs; 80% of all lung cancers), which include adenocarcinomas, squamous cell carcinomas, and large cell carcinomas, and small-cell lung cancers (20%, exhibiting neuroendocrine features). The average 5-y survival rate for NSCLC is only 16% (1). Most NSCLC patients have advanced disease at diagnosis; 22% have regional lymph node metastases, and 56% have distant metastases in the brain, bone, liver, or adrenal glands (1). Surgery or therapies that treat primary lung tumors rarely prevent metastases (1). Understanding the mechanisms of NSCLC metastasis is crucial for the development of new therapies to improve survival for lung cancer patients.Tropomyosin-related kinase B (TrkB; also called NTRK2), a neurotrophin receptor, is important for neural development and is an independent prognostic marker in many tumor types (2). TrkB-expressing neural precursors migrate from their proliferative zone toward a gradient of the TrkB ligand, brainderived neurotrophic factor (BDNF), which is made near the site of residence of the mature neurons (3). High levels of TrkB are correlated with poor patient prognosis in neuroblastomas and ovarian, pancreatic, colon, prostate, and gastric cancers (2). TrkB was overexpressed in ovarian adenocarcinoma metastases compared with primary lesions (4). TrkB is also a supressor of anoikis in cell lines (5). Finally, overexpression of TrkB and BDNF in nonmalignant rat intestinal epithelial cells promoted metastasis from s.c. injection sites to the lungs (6).Despite these clues that TrkB regulates parts of the metastatic cascade in other tumor types, the role of TrkB in NSCLC metastasis remains unclear. TrkB immunoreactivity was correlated with advanced stage disease in lung squamous cell carcinomas, yet was also correlated with better survival (7). In contrast, TrkB expression was as...

BDNF: An Oncogene or Tumor Suppressor?

“…BDNF/TrkB overexpression (Table i) confers a migratory phenotype to tumor cells and primes cancer cells to resist substantial genotoxic stressors, most of which are front-line chemotherapies (4-6). BDNF-mediated activation of TrkB also results in RAs activation (7), in turn accelerating cell-cycle progression and presumably contributing to poor prognosis of patients with cancers dependent on the BDNF signaling pathway (8,9). BDNF and Trkb overexpression has also been shown to contribute to oncogenesis of aggressive neuroblastoma cells (10) and to post-chemotherapeutic recurrence of highly aggressive breast cancer stem cells (11), demonstrating that this signaling pathway seems to be ubiquitous in the progression of multiple cancers and dynamically regulates several aspects of tumor cell physiology.…”

“…What is of considerable interest is that the BDNF/TrkB pathway has been shown to mediate the resistance to anoikis of multiple cancers (9,18,(25)(26)(27)(28)(29). it was shown that in multiple cancers, metastatic tumor cells have up-regulated TrkB and BDNF compared to tumor cells that did not metastasize (18,26,29).…”

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

“…TrkB overexpression participates in tumorigenesis through ERK and Akt pathway activation. This enhances the maintenance of brain tumor-initiating cells (BTICs) and promotes lung adenocarcinoma metastasis formation [30, 31]. Similarly, p75NR promotes survival and proliferation of BTICs and this effect requires proper p75NR cleavage by α- and γ-secretases [32].…”

Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma

“…In lung adenocarcinoma, EGFR is overexpressed in more than 39% and has emerged as a leading target for the treatment of patients with adenocarcinoma (10)(11)(12). Some TKIs, like gefitinib, significantly improved survival and prognosis of patients with lung adenocarcinoma, while some patients acquired resistance after initial response to TKIs or even had intrinsic resistance without EGFR mutations (13).…”