BDNF/TrkB信号途径与抗肿瘤治疗

doi:10.3969/j.issn.1004-616x.2014.06.017

摘要/Abstract

摘要：

肿瘤是目前危害人类健康的主要疾病之一。治疗肿瘤的主要手段包括手术、放疗、化疗和生物治疗等，但耐药现象的产生，导致药物治疗效果不甚理想。研究表明脑源性神经营养因子(BDNF)及其酪氨酸激酶爱体B(TrkB)在肿瘤的发生发展中起着非常重要的作用，激活BDNF/TrkB信号途径除了刺激肿瘤细胞存活，血管发生及失巢凋亡以外，还与肿瘤细胞的耐药性密切相关。本文主要综述BDNF/TrkB信号途径对肿瘤耐药的影响及相应的抗肿瘤治疗应用，以期为克服肿瘤多药耐药性提供新的研究思路，从而进一步提高肿瘤患者生存率和改善预后。

关键词: BDNF, TrkB, 肿瘤, 耐药性, 抗肿瘤治疗

莫赛军，郑乃刚，曹文波，周琦，杨胜利. BDNF/TrkB信号途径与抗肿瘤治疗[J]. 癌变·畸变·突变, doi: 10.3969/j.issn.1004-616x.2014.06.017.

参考文献

[1] Boulle F，Kenis G，Cazorla M，et al. TrkB inhibition as a therapeutic target for CNS-related disorders[J]. Prog Neurobiol，2012，98(2)： 197-206.

[2] Scala S，Wosikowski K，Giannakakou P，et al. Brain-derived neurotrophic factor protects neuroblastoma cells from vinblastine toxicity[J]. Cancer Res，1996，56(16)：3737-3742.

[3] Middlemas DS，Kihl BK，Moody NM. Brain derived neurotrophic factor protects human neuroblastoma cells from DNA damaging agents[J]. J Neurooncol，1999，45(1)：27-36.

[4] Odate S，Nakamura K，Onishi H，et al. TrkB/BDNF signaling pathway is a potential therapeutic target for pulmonary large cell neuroendocrine carcinoma[J]. Lung Cancer，2013，79(3)：205-214.

[5] Sclabas GM，Fujioka S，Schmidt C，et al. Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells[J]. Clin Cancer Res，2005，11：440-449.

[6] Sakamoto Y，Kitajima Y，Edakunni G，et al. Expression of Trk tyrosine kinase receptor is a biologic marker for cell proliferation and perineural invasion of human pancreatic ductal adenocarcinoma[J]. Oncol Rep，2001，8(3)：477-484.

[7] Brunetto de Farias，C，Rosemberg DB，Heinen TE，et al. BDNF/ TrkB content and interaction with gastrin-releasing peptide receptor blockade in colorectal cancer[J]. Oncology，2010，79(5/6)： 430-439.

[8] Moon A，Won KY，Lee JY，et al. Expression of BDNF，TrkB，and p53 in early-stage squamous cell carcinoma of the uterine cervix[J]. Pathology，2011，43(5)：453-458.

[9] Liu M，Su YH，Chen Y. Expressions of neurotrophic factors and their receptors in prostate cancer[J]. Zhonghua Nan Ke Xue，2010，16(2)： 129-131.

[10] Au CW，Siu MK，Liao X，et al. Tyrosine kinase B receptor and BDNF expression in ovarian cancers-Effect on cell migration，angiogenesis and clinical outcome[J]. Cancer Lett，2009，281(2)：151-161.

[11] 于晓辉. TrkB介导的失巢凋亡抑制与卵巢癌的转移和耐药[D]. 上海：上海交通大学，2007.

[12] Ng YK，Wong EY，Lau CP，et al. K252a induces anoikis-sensitization with suppression of cellular migration in Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma cells[J]. Invest New Drugs， 2012，30(1)：48-58.

[13] Kupferman ME，Jiffar T，EI-Naggar A，et al. TrkB induces EMT and has a key role in invasion of head and neck squamous cell carcinoma[J]. Oncogene，2010，29(14)：2047-2059.

[14] Lee J，Jiffar T，Kupferman ME. A Novel Role for BDNF-TrkB in the regulation of chemotherapy resistance in head and neck squamous cell carcinoma[J]. PLoS ONE，2012，7(1)：e30246.

[15] Lin CY，Chen HJ，Li TM，et al. beta5 integrin up-regulation in brain-derived neurotrophic factor promotes cell motility in human chondrosarcoma[J]. PLoS One，2013，8(7)：e67990.

[16] Zhang S，Guo D，Luo W，et al. TrkB is highly expressed in NSCLC and mediates BDNF-induced the activation of Pyk2 signaling and the invasion of A549 cells[J]. BMC Cancer，2010，10：43.

[17] Liu JY，Li KX，LI AM，et al. Effects of TrkB-BDNF signaling pathway on chemoresistance and metastasis of neuroblastoma cells[J]. Chin J Pediatr Surg，2013，334(8)：607-612。

[18] Li Z，Oh DY，Nakamura K，et al. Perifosine-induced inhibition of Akt attenuates brain-derived neurotrophic factor/TrkB-induced chemoresistance in neuroblastoma in vivo[J]. Cancer，2011，117(23)： 5412-5422

[19] Geiger TR，Song JY，Rosado A，et al. Functional characterization of human cancer-derived TRKB mutations[J]. PLoS One，2011，6(2)： e16871.

[20] Imam JS，Plyler JR，Bansal H，et al. Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Rac1 signaling and actin reorganization[J]. PLoS One，2012，7(12)：e52397.

[21] Cittelly DM，Dimitrova I，Howe EN，et al. Restoration of miR-200c to ovarian cancer reduces tumor burden and increases sensitivity to paclitaxel[J]. Mol Cancer Ther，2012，11(12)：2556-2565.

[22] Li LX，Li SD，Yang YX，et al. Change of miRNA-200c expression in ovarian cancer and its clinical significance[J]. Acad J Sec Mil Med Univ，2011，32(6)：612-617.

[23] Kopp F，Oak PS，Wagner E，et al. miR-200c sensitizes breast cancer cells to doxorubicin treatment by decreasing TrkB and Bmi1 expression [J]. PLoS One，2012，7(11)：e50469.

[24] Rhein M，Schwarzer A，Yang M，et al. Leukemias induced by altered TRK-signaling are sensitive to mTOR inhibitors in preclinical models[J]. Ann Hematol，2011，90(3)：283-292.

[25] Cimmino F，Schulte JH，Zollo M，et al. Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness[J]. Oncogene，2009， 28(19)：2015-2023.

[26] Ryan J，Tivnan A，Fay J，et al. MicroRNA-204 increases sensitivity of neuroblastoma cells to cisplatin and is associated with a favourable clinical outcome[J]. Br J Cancer，2012，107(6)：967-976.

[27] Sun YX，Yang J，Wang PY，et al. Cisplatin regulates SH-SY5Y cell growth through downregulation of BDNF via miR-16[J]. Oncol Rep， 2013，30(5)：2343-2349.

[28] de Farias CB，Heinen TE，Dos Santos RP，et al. BDNF/TrkB signaling protects HT-29 human colon cancer cells from EGFR inhibition[J]. Biochem Biophys Res Commun，2012，425(2)：328-332.

[29] Akil H，Perraud A，Mélin C，et al. Fine-tuning roles of endogenous brain-derived neurotrophic factor，TrkB and sortilin in colorectal cancer cell survival[J]. PLoS One，2011，6(9)：e25097.

[30] Brierley GV，Priebe IK，Purins L，et al. Serum concentrations of brain-derived neurotrophic factor (BDNF) are decreased in colorectal cancer patients[J]. Cancer Biomark，2013，13(2)：67-73.。

[31] Kim JM，Kim SW，Stewart R，et al. Serotonergic and BDNF genes associated with depression 1 week and 1 year after mastectomy for breast cancer[J]. Psychosom Med，2012，74(1)：8-15.

[32] Kowalski PJ，Paulino AF. Perineural invasion in adenoid cystic carcinoma：Its causation/promotion by brain-derived neurotrophic factor[J]. Hum Pathol，2002，33(9)：933-936.

[33] Deindl E. Mechanistic insights into the functional role of VEGF and its signaling partner BDNF in angiogenic tube formation[J]. Acta Physiol： Oxf，2014，doi：10.1111/apha.12299.

[34] Hallden S，Sj?gren M，Hedblad B，et al. Smoking and obesity associated BDNF gene variance predicts total and cardiovascular mortality in smokers[J]. Heart，2013，99(13)：949-953.