The neurotrophic tyrosine kinase receptor TrkA and its ligand NGF are increased in squamous cell carcinomas of the lung

Gao, Fangfang; Griffin, Nathan; Faulkner, Sam; Rowe, Christopher W; Williams, Lily M.; Roselli, Séverine; Thorne, Rick F.; Ferdoushi, Aysha; Jobling, Phillip; Walker, Marjorie M.; Hondermarck, Hubert

doi:10.1038/s41598-018-26408-2

Cited by 30 publications

(29 citation statements)

References 37 publications

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“…In the adult, TrkA also acts as a pain receptor in sensory neurons and contributes to the transmission of pain signals to the central nervous system [8]. Outside of neuronal growth and pain signaling, there is an increasing number of studies demonstrating that TrkA tumour-promoting signaling is present in several human cancers, including those of the breast [10], oral cavity [11], thyroid [13], cervix [43] and lung [14,15]. In our study, TrkA protein expression was found preferentially in IDC as compared to DCIS and ILC.…”

Section: Discussionmentioning

confidence: 99%

“…In the adult, where neurogenesis is largely reduced, TrkA acts as a pain receptor in sensory neurons and contributes to the transmission of pain signals to the central nervous system [8]. Interestingly, TrkA is also oncogenic and there is accumulating evidence for its overexpression and involvement in cancer progression [9][10][11][12][13][14], including in the form of TrkA fusion proteins as described in lung cancer [15]. Furthermore, TrkA is a therapeutic target in oncology and Trk inhibitors are being tested in several clinical trials [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer

et al. 2020

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The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), 158 invasive lobular carcinomas (ILC) and 50 ductal carcinomas in situ (DCIS). TrkA was expressed in cancer epithelial and myoepithelial cells, with higher levels of TrkA positively associated with IDC (39% of cases) (p < 0.0001). Interestingly, TrkA was significantly increased in tumours expressing the human epidermal growth factor receptor-2 (HER2), with expression in 49% of HER2-positive compared to 25% of HER2-negative tumours (p = 0.0027). A panel of breast cancer cells were used to confirm TrkA protein expression, demonstrating higher levels of TrkA (total and phosphorylated) in HER2-positive cell lines. Functional investigations using four different HER2-positive breast cancer cell lines indicated that the Trk tyrosine kinase inhibitor GNF-5837 reduced cell viability, through decreased phospho-TrkA (Tyr490) and downstream AKT (Ser473) activation, but did not display synergy with Herceptin. Overall, these data highlight a relationship between the tyrosine kinase receptors TrkA and HER2 and suggest the potential of TrkA as a novel or adjunct target for HER2-positive breast tumours.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer

et al. 2020

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“…Immunohistochemistry (IHC) was performed as described previously (23). Following deparaffinization and rehydration of the TMA slides using standard procedures, heat-induced epitope retrieval was carried out in a low-pH, citrate-based antigen unmasking solution (catalog number H-3300, Vector Laboratories, California, CA, United States) by a decloaking chamber (Biocare, West Midlands, United Kingdom) at 95 • C for…”

Section: Pancreatic Tissue Samples and Immunohistochemistrymentioning

confidence: 99%

Schwann Cell Stimulation of Pancreatic Cancer Cells: A Proteomic Analysis

Ferdoushi

Griffin

et al. 2020

Front. Oncol.

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Schwann cells (SCs), the glial component of peripheral nerves, have been identified as promoters of pancreatic cancer (PC) progression, but the molecular mechanisms are unclear. In the present study, we aimed to identify proteins released by SCs that could stimulate PC growth and invasion. Proteomic analysis of human primary SC secretome was performed using liquid chromatography-tandem mass spectrometry, and a total of 13,796 unique peptides corresponding to 1,470 individual proteins were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment were conducted using the Database for Annotation, Visualization, and Integrated Discovery. Metabolic and cell-cell adhesion pathways showed the highest levels of enrichment, a finding in line with the supportive role of SCs in peripheral nerves. We identified seven SC-secreted proteins that were validated by western blot. The involvement of these SC-secreted proteins was further demonstrated by using blocking antibodies. PC cell proliferation and invasion induced by SC-conditioned media were decreased using blocking antibodies against the matrix metalloproteinase-2, cathepsin D, plasminogen activator inhibitor-1, and galectin-1. Blocking antibodies against the proteoglycan biglycan, galectin-3 binding protein, and tissue inhibitor of metalloproteinases-2 decreased only the proliferation but not the invasion of PC cells. Together, this study delineates the secretome of human SCs and identifies proteins that can stimulate PC cell growth and invasion and therefore constitute potential therapeutic targets.

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“…Treatment of cancers presenting TrkA fusion proteins with selective Trk inhibitors resulted in a better prognosis [51,52]. Further, over-expression of the NGF specific receptor TrkA is considered a reliable index of tumorigenicity, invasiveness, and chemotherapy resistance in several types of squamous cancers [53].…”

Section: Neurotrophins In Cscs-driven Tumor Growthmentioning

confidence: 99%

Cancer stem cells-driven tumor growth and immune escape: the Janus face of neurotrophins

Triaca

Carito

Fico

et al. 2019

Aging

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Cancer Stem Cells (CSCs) are self-renewing cancer cells responsible for expansion of the malignant mass in a dynamic process shaping the tumor microenvironment. CSCs may hijack the host immune surveillance resulting in typically aggressive tumors with poor prognosis.In this review, we focus on neurotrophic control of cellular substrates and molecular mechanisms involved in CSC-driven tumor growth as well as in host immune surveillance. Neurotrophins have been demonstrated to be key tumor promoting signaling platforms. Particularly, Nerve Growth Factor (NGF) and its specific receptor Tropomyosin related kinase A (TrkA) have been implicated in initiation and progression of many aggressive cancers. On the other hand, an active NGF pathway has been recently proven to be critical to oncogenic inflammation control and in promoting immune response against cancer, pinpointing possible pro-tumoral effects of NGF/TrkA-inhibitory therapy.A better understanding of the molecular mechanisms involved in the control of tumor growth/immunoediting is essential to identify new predictive and prognostic intervention and to design more effective therapies. Fine and timely modulation of CSCs-driven tumor growth and of peripheral lymph nodes activation by the immune system will possibly open the way to precision medicine in neurotrophic therapy and improve patient’s prognosis in both TrkA- dependent and independent cancers.

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The neurotrophic tyrosine kinase receptor TrkA and its ligand NGF are increased in squamous cell carcinomas of the lung

Cited by 30 publications

References 37 publications

The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer

The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer

Schwann Cell Stimulation of Pancreatic Cancer Cells: A Proteomic Analysis

Cancer stem cells-driven tumor growth and immune escape: the Janus face of neurotrophins

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