目前全球死亡率中癌症排名第二。腫瘤會改變微環境使癌細胞更容易生長，稱之為“腫瘤微環境”。近年發現神經也參與腫瘤微環境，癌細胞能藉由神經浸潤進行轉移。神經浸潤被認為是導致手術後腫瘤的復發率增加和與胰腺癌相關的疼痛發生的原因之一。過去研究發現的胰臟癌中高達90%病患發生神經浸潤，發生率遠高於其他類型癌症。
研究發現癌細胞能釋放神經滋養因子結合到神經元促進突觸新生、神經新生。然而神經向腫瘤生長過程其機制尚未明了。為了探討神經和癌細胞之間的串擾與潛在機制。我們培養初級背根神經節 (DRG) 作為體外模型，發現背根神經節的神經元能被癌細胞的條件培養基所增加突起生長。 在未來研究，我們打算在動物模型中探索神經周圍侵襲是否與軸突發生機制有關。

Cancer currently ranks second in the global death rate. Past studies have found that tumors improve the tissue environment and make it easier for cancer cells to grow, known as the "tumor microenvironment". Researchers recently discovered that neurons are involved in the tumor microenvironment. Cancer metastasis can spread through perineural invasion (PNI), which is defined as the presence of cancer cells in the perineurium of local peripheral nerves. PNI has been considered responsible for the high tumor recurrence rate after surgery and the pain generation associated with pancreatic cancer (PC). It has been reported that pancreatic cancer has a higher incidence of PNI compared to other types of cancer.
Previous studies have found that cancer cell release neurotrophic factors. When neurotrophic factors bind to neurotrophin receptors on nerves can promote axonogenesis and neurogenesis. However, the detailed mechanism of nerve infiltration into the tumor microenvironment has not yet been elucidated. To understand the nerve-cancer cells cross-talk and the underlying mechanism. We cultured primary dorsal root ganglia (DRG) as an in vitro model and found that condition medium from cancer cells promotes DRG neurite outgrowth. In the future study, we intend to explore whether the mechanism related to axonogenesis is involved in the perineural invasion in vitro and in the animal model.

1 Labani-Motlagh, A., Ashja-Mahdavi, M. & Loskog, A. The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses. Front Immunol 11, 940, doi:10.3389/fimmu.2020.00940 (2020).
2 Shibuya, M. Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies. Genes Cancer 2, 1097-1105, doi:10.1177/1947601911423031 (2011).
3 Mo, R. J. et al. Expression of PD-L1 in tumor-associated nerves correlates with reduced CD8(+) tumor-associated lymphocytes and poor prognosis in prostate cancer. Int J Cancer 144, 3099-3110, doi:10.1002/ijc.32061 (2019).
4 Silverman, D. A. et al. Cancer-Associated Neurogenesis and Nerve-Cancer Cross-talk. Cancer Res 81, 1431-1440, doi:10.1158/0008-5472.Can-20-2793 (2021).
5 Mauffrey, P. et al. Progenitors from the central nervous system drive neurogenesis in cancer. Nature 569, 672-678, doi:10.1038/s41586-019-1219-y (2019).
6 Lu, R. et al. Neurons generated from carcinoma stem cells support cancer progression. Signal Transduct Target Ther 2, 16036, doi:10.1038/sigtrans.2016.36 (2017).
7 Demir, I. E. et al. Neural invasion in pancreatic cancer: the past, present and future. Cancers (Basel) 2, 1513-1527, doi:10.3390/cancers2031513 (2010).
8 Deborde, S. et al. Schwann cells induce cancer cell dispersion and invasion. J Clin Invest 126, 1538-1554, doi:10.1172/jci82658 (2016).
9 Liebig, C., Ayala, G., Wilks, J. A., Berger, D. H. & Albo, D. Perineural invasion in cancer: a review of the literature. Cancer 115, 3379-3391, doi:10.1002/cncr.24396 (2009).
10 Schneider, M. B. et al. Expression of nerve growth factors in pancreatic neural tissue and pancreatic cancer. J Histochem Cytochem 49, 1205-1210, doi:10.1177/002215540104901002 (2001).
11 Liu, B. & Lu, K. Y. Neural invasion in pancreatic carcinoma. Hepatobiliary Pancreat Dis Int 1, 469-476 (2002).
12 Yi, S. Q. et al. Innervation of the pancreas from the perspective of perineural invasion of pancreatic cancer. Pancreas 27, 225-229, doi:10.1097/00006676-200310000-00005 (2003).
13 Bockman, D. E., Büchler, M. & Beger, H. G. Interaction of pancreatic ductal carcinoma with nerves leads to nerve damage. Gastroenterology 107, 219-230, doi:10.1016/0016-5085(94)90080-9 (1994).
14 Ceyhan, G. O. et al. Pancreatic neuropathy and neuropathic pain--a comprehensive pathomorphological study of 546 cases. Gastroenterology 136, 177-186.e171, doi:10.1053/j.gastro.2008.09.029 (2009).
15 Eide, F. F., Lowenstein, D. H. & Reichardt, L. F. Neurotrophins and their receptors--current concepts and implications for neurologic disease. Exp Neurol 121, 200-214, doi:10.1006/exnr.1993.1087 (1993).
16 Yoshii, A. & Constantine-Paton, M. Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev Neurobiol 70, 304-322, doi:10.1002/dneu.20765 (2010).
17 Peng, T. et al. Nerve Growth Factor (NGF) Encourages the Neuroinvasive Potential of Pancreatic Cancer Cells by Activating the Warburg Effect and Promoting Tumor Derived Exosomal miRNA-21 Expression. Oxid Med Cell Longev 2022, 8445093, doi:10.1155/2022/8445093 (2022).
18 Tagliabue, E. et al. Nerve growth factor cooperates with p185(HER2) in activating growth of human breast carcinoma cells. J Biol Chem 275, 5388-5394, doi:10.1074/jbc.275.8.5388 (2000).
19 Chiarenza, A. et al. Tamoxifen inhibits nerve growth factor-induced proliferation of the human breast cancerous cell line MCF-7. Cancer Res 61, 3002-3008 (2001).
20 Jin, W. Regulation of BDNF-TrkB Signaling and Potential Therapeutic Strategies for Parkinson's Disease. J Clin Med 9, doi:10.3390/jcm9010257 (2020).
21 Cattaneo, A., Cattane, N., Begni, V., Pariante, C. M. & Riva, M. A. The human BDNF gene: peripheral gene expression and protein levels as biomarkers for psychiatric disorders. Transl Psychiatry 6, e958, doi:10.1038/tp.2016.214 (2016).
22 Pruunsild, P., Kazantseva, A., Aid, T., Palm, K. & Timmusk, T. Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters. Genomics 90, 397-406, doi:10.1016/j.ygeno.2007.05.004 (2007).
23 Foltran, R. B. & Diaz, S. L. BDNF isoforms: a round trip ticket between neurogenesis and serotonin? J Neurochem 138, 204-221, doi:10.1111/jnc.13658 (2016).
24 Pradhan, J., Noakes, P. G. & Bellingham, M. C. The Role of Altered BDNF/TrkB Signaling in Amyotrophic Lateral Sclerosis. Front Cell Neurosci 13, 368, doi:10.3389/fncel.2019.00368 (2019).
25 Cunha, C., Brambilla, R. & Thomas, K. L. A simple role for BDNF in learning and memory? Front Mol Neurosci 3, 1, doi:10.3389/neuro.02.001.2010 (2010).
26 Wang, T. et al. Flux of signalling endosomes undergoing axonal retrograde transport is encoded by presynaptic activity and TrkB. Nature Communications 7, 12976, doi:10.1038/ncomms12976 (2016).
27 Balkowiec, A. & Katz, D. M. Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons. J Neurosci 22, 10399-10407, doi:10.1523/jneurosci.22-23-10399.2002 (2002).
28 Sasi, M., Vignoli, B., Canossa, M. & Blum, R. Erratum to: Neurobiology of local and intercellular BDNF signaling. Pflugers Arch 469, 611, doi:10.1007/s00424-017-1971-5 (2017).
29 Slaugenhaupt, S. A. et al. The human gene for neurotrophic tyrosine kinase receptor type 2 (NTRK2) is located on chromosome 9 but is not the familial dysautonomia gene. Genomics 25, 730-732, doi:10.1016/0888-7543(95)80019-i (1995).
30 Kaplan, D. R., Hempstead, B. L., Martin-Zanca, D., Chao, M. V. & Parada, L. F. The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science 252, 554-558, doi:10.1126/science.1850549 (1991).
31 Schneider, R. & Schweiger, M. A novel modular mosaic of cell adhesion motifs in the extracellular domains of the neurogenic trk and trkB tyrosine kinase receptors. Oncogene 6, 1807-1811 (1991).
32 Ultsch, M. H. et al. Crystal structures of the neurotrophin-binding domain of TrkA, TrkB and TrkC11Edited by I. A. Wilson. Journal of Molecular Biology 290, 149-159, doi:https://doi.org/10.1006/jmbi.1999.2816 (1999).
33 Shen, J. et al. Extracellular Juxtamembrane Motif Critical for TrkB Preformed Dimer and Activation. Cells 8, doi:10.3390/cells8080932 (2019).
34 Banfield, M. J. et al. Specificity in Trk receptor:neurotrophin interactions: the crystal structure of TrkB-d5 in complex with neurotrophin-4/5. Structure 9, 1191-1199, doi:10.1016/s0969-2126(01)00681-5 (2001).
35 Ghosh, A., Carnahan, J. & Greenberg, M. E. Requirement for BDNF in activity-dependent survival of cortical neurons. Science 263, 1618-1623, doi:10.1126/science.7907431 (1994).
36 Tang, S., Machaalani, R. & Waters, K. A. Immunolocalization of pro- and mature-brain derived neurotrophic factor (BDNF) and receptor TrkB in the human brainstem and hippocampus. Brain Res 1354, 1-14, doi:10.1016/j.brainres.2010.07.051 (2010).
37 Liao, G. Y., Kinney, C. E., An, J. J. & Xu, B. TrkB-expressing neurons in the dorsomedial hypothalamus are necessary and sufficient to suppress homeostatic feeding. Proc Natl Acad Sci U S A 116, 3256-3261, doi:10.1073/pnas.1815744116 (2019).
38 Klein, R. et al. The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell 66, 395-403, doi:10.1016/0092-8674(91)90628-c (1991).
39 Middlemas, D. S., Lindberg, R. A. & Hunter, T. trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Mol Cell Biol 11, 143-153, doi:10.1128/mcb.11.1.143-153.1991 (1991).
40 Baxter, G. T. et al. Signal transduction mediated by the truncated trkB receptor isoforms, trkB.T1 and trkB.T2. J Neurosci 17, 2683-2690, doi:10.1523/jneurosci.17-08-02683.1997 (1997).
41 Cao, T. et al. Function and Mechanisms of Truncated BDNF Receptor TrkB.T1 in Neuropathic Pain. Cells 9, doi:10.3390/cells9051194 (2020).
42 Fenner, B. M. Truncated TrkB: beyond a dominant negative receptor. Cytokine Growth Factor Rev 23, 15-24, doi:10.1016/j.cytogfr.2012.01.002 (2012).
43 Minichiello, L. TrkB signalling pathways in LTP and learning. Nature Reviews Neuroscience 10, 850-860, doi:10.1038/nrn2738 (2009).
44 Huang, E. J. & Reichardt, L. F. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24, 677-736, doi:10.1146/annurev.neuro.24.1.677 (2001).
45 Numakawa, T. et al. BDNF function and intracellular signaling in neurons. Histol Histopathol 25, 237-258, doi:10.14670/hh-25.237 (2010).
46 Klein, R., Conway, D., Parada, L. F. & Barbacid, M. The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain. Cell 61, 647-656, doi:10.1016/0092-8674(90)90476-u (1990).
47 Hartmann, M. et al. Truncated TrkB receptor-induced outgrowth of dendritic filopodia involves the p75 neurotrophin receptor. J Cell Sci 117, 5803-5814, doi:10.1242/jcs.01511 (2004).
48 Ohira, K. et al. A truncated tropomyosin-related kinase B receptor, T1, regulates glial cell morphology via Rho GDP dissociation inhibitor 1. J Neurosci 25, 1343-1353, doi:10.1523/jneurosci.4436-04.2005 (2005).
49 Patterson, S. L. et al. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16, 1137-1145, doi:10.1016/s0896-6273(00)80140-3 (1996).
50 Vilar, M. & Mira, H. Regulation of Neurogenesis by Neurotrophins during Adulthood: Expected and Unexpected Roles. Front Neurosci 10, 26, doi:10.3389/fnins.2016.00026 (2016).
51 Galvão, R. P., Garcia-Verdugo, J. M. & Alvarez-Buylla, A. Brain-derived neurotrophic factor signaling does not stimulate subventricular zone neurogenesis in adult mice and rats. J Neurosci 28, 13368-13383, doi:10.1523/jneurosci.2918-08.2008 (2008).
52 Bergami, M. et al. TrkB signaling directs the incorporation of newly generated periglomerular cells in the adult olfactory bulb. J Neurosci 33, 11464-11478, doi:10.1523/jneurosci.4812-12.2013 (2013).
53 Kang, H. & Schuman, E. M. Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 267, 1658-1662, doi:10.1126/science.7886457 (1995).
54 McAllister, A. K., Lo, D. C. & Katz, L. C. Neurotrophins regulate dendritic growth in developing visual cortex. Neuron 15, 791-803, doi:10.1016/0896-6273(95)90171-x (1995).
55 Conner, J. M., Lauterborn, J. C., Yan, Q., Gall, C. M. & Varon, S. Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J Neurosci 17, 2295-2313, doi:10.1523/jneurosci.17-07-02295.1997 (1997).
56 Jovanovic, J. N., Czernik, A. J., Fienberg, A. A., Greengard, P. & Sihra, T. S. Synapsins as mediators of BDNF-enhanced neurotransmitter release. Nat Neurosci 3, 323-329, doi:10.1038/73888 (2000).
57 Scharfman, H. E. Hyperexcitability in combined entorhinal/hippocampal slices of adult rat after exposure to brain-derived neurotrophic factor. J Neurophysiol 78, 1082-1095, doi:10.1152/jn.1997.78.2.1082 (1997).
58 Gatto, R. G. Molecular and microstructural biomarkers of neuroplasticity in neurodegenerative disorders through preclinical and diffusion magnetic resonance imaging studies. JIN 19, 571-592, doi:10.31083/j.jin.2020.03.165 (2020).
59 Brierley, J. B. The penetration of particulate matter from the cerebrospinal fluid into the spinal ganglia, peripheral nerves, and perivascular spaces of the central nervous system. J Neurol Neurosurg Psychiatry 13, 203-215, doi:10.1136/jnnp.13.3.203 (1950).
60 Ahimsadasan, N., Reddy, V., Khan Suheb, M. Z. & Kumar, A. in StatPearls (StatPearls Publishing Copyright © 2023, StatPearls Publishing LLC., 2023).
61 Sandoval-Castellanos, A. M., Claeyssens, F. & Haycock, J. W. Biomimetic surface delivery of NGF and BDNF to enhance neurite outgrowth. Biotechnol Bioeng 117, 3124-3135, doi:10.1002/bit.27466 (2020).
62 Michael, G. J. et al. Nerve growth factor treatment increases brain-derived neurotrophic factor selectively in TrkA-expressing dorsal root ganglion cells and in their central terminations within the spinal cord. J Neurosci 17, 8476-8490, doi:10.1523/jneurosci.17-21-08476.1997 (1997).
63 Luo, X. G., Rush, R. A. & Zhou, X. F. Ultrastructural localization of brain-derived neurotrophic factor in rat primary sensory neurons. Neurosci Res 39, 377-384, doi:10.1016/s0168-0102(00)00238-8 (2001).
64 Salio, C., Lossi, L., Ferrini, F. & Merighi, A. Ultrastructural evidence for a pre- and postsynaptic localization of full-length trkB receptors in substantia gelatinosa (lamina II) of rat and mouse spinal cord. Eur J Neurosci 22, 1951-1966, doi:10.1111/j.1460-9568.2005.04392.x (2005).
65 Merighi, A. et al. BDNF as a pain modulator. Prog Neurobiol 85, 297-317, doi:10.1016/j.pneurobio.2008.04.004 (2008).
66 de León, A., Gibon, J. & Barker, P. A. NGF-Dependent and BDNF-Dependent DRG Sensory Neurons Deploy Distinct Degenerative Signaling Mechanisms. eNeuro 8, doi:10.1523/eneuro.0277-20.2020 (2021).
67 Kerr, B. J. et al. Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord. J Neurosci 19, 5138-5148, doi:10.1523/jneurosci.19-12-05138.1999 (1999).
68 McIlwrath, S. L., Hu, J., Anirudhan, G., Shin, J. B. & Lewin, G. R. The sensory mechanotransduction ion channel ASIC2 (acid sensitive ion channel 2) is regulated by neurotrophin availability. Neuroscience 131, 499-511, doi:10.1016/j.neuroscience.2004.11.030 (2005).
69 Zhou, X. F., Deng, Y. S., Xian, C. J. & Zhong, J. H. Neurotrophins from dorsal root ganglia trigger allodynia after spinal nerve injury in rats. Eur J Neurosci 12, 100-105, doi:10.1046/j.1460-9568.2000.00884.x (2000).
70 Sclabas, G. M. et al. Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells. Clin Cancer Res 11, 440-449 (2005).
71 Yu, X., Liu, L., Cai, B., He, Y. & Wan, X. Suppression of anoikis by the neurotrophic receptor TrkB in human ovarian cancer. Cancer Sci 99, 543-552, doi:10.1111/j.1349-7006.2007.00722.x (2008).
72 Au, C. W. et al. Tyrosine kinase B receptor and BDNF expression in ovarian cancers - Effect on cell migration, angiogenesis and clinical outcome. Cancer Lett 281, 151-161, doi:10.1016/j.canlet.2009.02.025 (2009).
73 Bronzetti, E. et al. A possible role of BDNF in prostate cancer detection. Oncol Rep 19, 969-974, doi:10.3892/or.19.4.969 (2008).
74 Patani, N., Jiang, W. G. & Mokbel, K. Brain-derived neurotrophic factor expression predicts adverse pathological & clinical outcomes in human breast cancer. Cancer Cell International 11, 23, doi:10.1186/1475-2867-11-23 (2011).
75 Moriwaki, K. et al. TRKB tyrosine kinase receptor is a potential therapeutic target for poorly differentiated oral squamous cell carcinoma. Oncotarget 9, 25225-25243, doi:10.18632/oncotarget.25396 (2018).
76 Li, Z., Tan, F. & Thiele, C. J. Inactivation of glycogen synthase kinase-3beta contributes to brain-derived neutrophic factor/TrkB-induced resistance to chemotherapy in neuroblastoma cells. Mol Cancer Ther 6, 3113-3121, doi:10.1158/1535-7163.Mct-07-0133 (2007).
77 Chen, B. et al. Autocrine activity of BDNF induced by the STAT3 signaling pathway causes prolonged TrkB activation and promotes human non-small-cell lung cancer proliferation. Scientific Reports 6, 30404, doi:10.1038/srep30404 (2016).
78 Vanhecke, E. et al. Brain-derived neurotrophic factor and neurotrophin-4/5 are expressed in breast cancer and can be targeted to inhibit tumor cell survival. Clin Cancer Res 17, 1741-1752, doi:10.1158/1078-0432.Ccr-10-1890 (2011).
79 Cervantes-Villagrana, R. D., Albores-García, D., Cervantes-Villagrana, A. R. & García-Acevez, S. J. Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies. Signal Transduction and Targeted Therapy 5, 99, doi:10.1038/s41392-020-0205-z (2020).
80 Xing, L. et al. Layer specific and general requirements for ERK/MAPK signaling in the developing neocortex. Elife 5, doi:10.7554/eLife.11123 (2016).
81 Riccio, A., Ahn, S., Davenport, C. M., Blendy, J. A. & Ginty, D. D. Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science 286, 2358-2361, doi:10.1126/science.286.5448.2358 (1999).
82 Bonni, A. et al. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286, 1358-1362, doi:10.1126/science.286.5443.1358 (1999).
83 Vetter, M. L., Martin-Zanca, D., Parada, L. F., Bishop, J. M. & Kaplan, D. R. Nerve growth factor rapidly stimulates tyrosine phosphorylation of phospholipase C-gamma 1 by a kinase activity associated with the product of the trk protooncogene. Proc Natl Acad Sci U S A 88, 5650-5654, doi:10.1073/pnas.88.13.5650 (1991).
84 Numakawa, T. et al. Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLC-gamma signaling for glutamate release via a glutamate transporter. Proc Natl Acad Sci U S A 106, 647-652, doi:10.1073/pnas.0800888106 (2009).
85 Zhang, J. et al. Molecular markers associated with perineural invasion in pancreatic ductal adenocarcinoma. Oncol Lett 20, 5, doi:10.3892/ol.2020.11866 (2020).
86 Cazorla, M. et al. Identification of a low-molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice. J Clin Invest 121, 1846-1857, doi:10.1172/jci43992 (2011).
87 Qin, T. et al. HGF/c-Met pathway facilitates the perineural invasion of pancreatic cancer by activating the mTOR/NGF axis. Cell Death Dis 13, 387, doi:10.1038/s41419-022-04799-5 (2022).
88 Gil, Z. et al. Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves. J Natl Cancer Inst 102, 107-118, doi:10.1093/jnci/djp456 (2010).
89 Zhang, W. et al. Autophagic Schwann cells promote perineural invasion mediated by the NGF/ATG7 paracrine pathway in pancreatic cancer. J Exp Clin Cancer Res 41, 48, doi:10.1186/s13046-021-02198-w (2022).
90 Zhang, L. et al. High‑glucose microenvironment promotes perineural invasion of pancreatic cancer via activation of hypoxia inducible factor 1α. Oncol Rep 47, doi:10.3892/or.2022.8275 (2022).
91 Deborde, S. et al. An In Vivo Murine Sciatic Nerve Model of Perineural Invasion. J Vis Exp, doi:10.3791/56857 (2018).
92 Gil, Z. et al. Nerve-sparing therapy with oncolytic herpes virus for cancers with neural invasion. Clin Cancer Res 13, 6479-6485, doi:10.1158/1078-0432.Ccr-07-1639 (2007).
93 Mashour, G. A. et al. Therapeutic efficacy of G207 in a novel peripheral nerve sheath tumor model. Exp Neurol 169, 64-71, doi:10.1006/exnr.2001.7641 (2001).
94 Dwivedi, S. & Krishnan, A. Neural invasion: a scenic trail for the nervous tumor and hidden therapeutic opportunity. Am J Cancer Res 10, 2258-2270 (2020).
95 Zhu, J. W., Li, Y. F., Wang, Z. T., Jia, W. Q. & Xu, R. X. Toll-Like Receptor 4 Deficiency Impairs Motor Coordination. Front Neurosci 10, 33, doi:10.3389/fnins.2016.00033 (2016).
96 Salvo, E. et al. Peripheral nerve injury and sensitization underlie pain associated with oral cancer perineural invasion. Pain 161, 2592-2602, doi:10.1097/j.pain.0000000000001986 (2020).
97 Ceyhan, G. O. et al. Neural invasion in pancreatic cancer: a mutual tropism between neurons and cancer cells. Biochem Biophys Res Commun 374, 442-447, doi:10.1016/j.bbrc.2008.07.035 (2008).
98 Miknyoczki, S. J. et al. Neurotrophins and Trk receptors in human pancreatic ductal adenocarcinoma: expression patterns and effects on in vitro invasive behavior. Int J Cancer 81, 417-427, doi:10.1002/(sici)1097-0215(19990505)81:3<417::aid-ijc16>3.0.co;2-6 (1999).
99 Park, J. R., Eggert, A. & Caron, H. Neuroblastoma: biology, prognosis, and treatment. Pediatr Clin North Am 55, 97-120, x, doi:10.1016/j.pcl.2007.10.014 (2008).
100 Ricci, A. et al. Neurotrophin system expression in human pulmonary carcinoid tumors. Growth Factors 23, 303-312, doi:10.1080/08977190500233813 (2005).
101 Tanaka, K. et al. Brain-derived neurotrophic factor (BDNF)-induced tropomyosin-related kinase B (Trk B) signaling is a potential therapeutic target for peritoneal carcinomatosis arising from colorectal cancer. PLoS One 9, e96410, doi:10.1371/journal.pone.0096410 (2014).
102 Kermani, P. et al. Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors. J Clin Invest 115, 653-663, doi:10.1172/jci22655 (2005).
103 Kermani, P. & Hempstead, B. Brain-derived neurotrophic factor: a newly described mediator of angiogenesis. Trends Cardiovasc Med 17, 140-143, doi:10.1016/j.tcm.2007.03.002 (2007).
104 Chédotal, A., Kerjan, G. & Moreau-Fauvarque, C. The brain within the tumor: new roles for axon guidance molecules in cancers. Cell Death Differ 12, 1044-1056, doi:10.1038/sj.cdd.4401707 (2005).
105 Pundavela, J. et al. Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer. Mol Oncol 9, 1626-1635, doi:10.1016/j.molonc.2015.05.001 (2015).
106 Zhang, Y. et al. Overexpression of tyrosine kinase B protein as a predictor for distant metastases and prognosis in gastric carcinoma. Oncology 75, 17-26, doi:10.1159/000151615 (2008).
107 Okugawa, Y. et al. Brain-derived neurotrophic factor/tropomyosin-related kinase B pathway in gastric cancer. Br J Cancer 108, 121-130, doi:10.1038/bjc.2012.499 (2013).
108 Smit, M. A., Geiger, T. R., Song, J. Y., Gitelman, I. & Peeper, D. S. A Twist-Snail axis critical for TrkB-induced epithelial-mesenchymal transition-like transformation, anoikis resistance, and metastasis. Mol Cell Biol 29, 3722-3737, doi:10.1128/mcb.01164-08 (2009).
109 Blondy, S. et al. Neurotrophins and their involvement in digestive cancers. Cell Death Dis 10, 123, doi:10.1038/s41419-019-1385-8 (2019).
110 Sakamoto, Y. et al. Expression of Trk tyrosine kinase receptor is a biologic marker for cell proliferation and perineural invasion of human pancreatic ductal adenocarcinoma. Oncol Rep 8, 477-484, doi:10.3892/or.8.3.477 (2001).
111 Zhu, Z. W. et al. Nerve growth factor exerts differential effects on the growth of human pancreatic cancer cells. Clin Cancer Res 7, 105-112 (2001).
112 Zhu, Z. et al. Nerve growth factor and enhancement of proliferation, invasion, and tumorigenicity of pancreatic cancer cells. Mol Carcinog 35, 138-147, doi:10.1002/mc.10083 (2002).
113 Bapat, A. A., Munoz, R. M., Von Hoff, D. D. & Han, H. Blocking Nerve Growth Factor Signaling Reduces the Neural Invasion Potential of Pancreatic Cancer Cells. PLoS One 11, e0165586, doi:10.1371/journal.pone.0165586 (2016).
114 Oyama, Y. et al. TrkB/BDNF Signaling Could Be a New Therapeutic Target for Pancreatic Cancer. Anticancer Res 41, 4047-4052, doi:10.21873/anticanres.15205 (2021).
115 Gonzalez, G. A. & Montminy, M. R. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59, 675-680, doi:10.1016/0092-8674(89)90013-5 (1989).
116 Finkbeiner, S. et al. CREB: a major mediator of neuronal neurotrophin responses. Neuron 19, 1031-1047, doi:10.1016/s0896-6273(00)80395-5 (1997).
117 Amidfar, M., de Oliveira, J., Kucharska, E., Budni, J. & Kim, Y. K. The role of CREB and BDNF in neurobiology and treatment of Alzheimer's disease. Life Sci 257, 118020, doi:10.1016/j.lfs.2020.118020 (2020).
118 Xi, Y. D. et al. Genistein Inhibits Aβ25-35-Induced Synaptic Toxicity and Regulates CaMKII/CREB Pathway in SH-SY5Y Cells. Cell Mol Neurobiol 36, 1151-1159, doi:10.1007/s10571-015-0311-6 (2016).
119 Zeng, B. et al. Involvement of PI3K/Akt/FoxO3a and PKA/CREB Signaling Pathways in the Protective Effect of Fluoxetine Against Corticosterone-Induced Cytotoxicity in PC12 Cells. J Mol Neurosci 59, 567-578, doi:10.1007/s12031-016-0779-7 (2016).
120 Walton, M. R. & Dragunow, I. Is CREB a key to neuronal survival? Trends Neurosci 23, 48-53, doi:10.1016/s0166-2236(99)01500-3 (2000).
121 Esvald, E. E. et al. CREB Family Transcription Factors Are Major Mediators of BDNF Transcriptional Autoregulation in Cortical Neurons. J Neurosci 40, 1405-1426, doi:10.1523/jneurosci.0367-19.2019 (2020).
122 Wang, H., Xu, J., Lazarovici, P., Quirion, R. & Zheng, W. cAMP Response Element-Binding Protein (CREB): A Possible Signaling Molecule Link in the Pathophysiology of Schizophrenia. Front Mol Neurosci 11, 255, doi:10.3389/fnmol.2018.00255 (2018).