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Neurotrophins play an important role in the perineural invasion and distant metastasis of malignant tumor
Bioscience Hypotheses (2009) 2, 75e77
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/bihy
Neurotrophins play an important role in the perineural invasion and distant metastasis of malignant tumor Li-xin Su, Xing-zhou Qu, Chen-ping Zhang* Department of Oral and Maxillofacial Surgery, School of Stomatology, Affiliated Ninth People’s Hospital, 639 Zhizaojiu Road, Shanghai Jiaotong University, Shanghai 200011, China Received 18 December 2008; accepted 31 December 2008
KEYWORDS Neurotrophins; Metastasis; Cancer
Abstract Neurotrophins (NTs) family was first discovered in nervous system and it regulates the proliferation and differentiation of many neural cell types in the peripheral and central nervous system. Due to their perineural invasive characters, certain part of malignant tumor cases was first diagnosed because of nerve paralysis or idiopathic neuralgia caused by perineural invasion. For this reason, the study on the association between NTs and perineural invasion of malignant tumor aroused the attention of many researchers. Increasing evidence indicates that NTs and their receptors, Trks, play important roles in malignant cells, especially the exhibiting perineural invasive phenotype. It was suggested that NTs produced by neural tissue can act as a chemotactic factor, and tumor cells in which the overexpression of Trks’ exists seem to be selected to invade the perineural space. Except for contributing to perineural invasion of malignant tumor, accumulated evidence proved NTs now also significantly associated with the metastasis of malignant tumor. Overexpression of NTs or Trks often correlated with the tumorigenesis, angiogenesis and anoikis resistance in these malignancies, contributing significantly to the metastasis and poor prognosis. In summary, besides its role in development and function of nervous system, NTs also play an important role in the perineural invasion and metastasis of malignant tumor. Considering the role that NTs played in malignant tumor, we believe that further studies between NTs and malignant tumor are necessary. Research on the role of NTs pathway might allow advancements in this field. ª 2009 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel./fax: þ86 21 63135412. E-mail address: [email protected] (C.-ping Zhang). 1756-2392/$ - see front matter ª 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bihy.2008.12.001
76
Introduction Neurotrophins (NTs) consist of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, NT-4 (also called NT-5), NT-6, NT-7, etc. NTs family was first discovered in nervous system and it regulates the proliferation and differentiation of many neural cell types in the peripheral and central nervous system, just as its name implies. However, recent reports showed that NTs might also have important function outside of the central neural system. Now NTs were also found to be present in lung, thyroid, breast, salivary gland, pancreas, etc. [1e4]. Though the investigations are limited and the underlying mechanism remains unclear, when NTs combined with its receptors TrkA, TrkB, TrkC, and p75NGFR, have been shown to play important roles in malignant cells, including stimulating chemotaxis, tumor invasiveness, clonal growth, and altering cell morphology in a variety of cancers, especially those malignant tumor exhibiting a perineural invasive phenotype such as neuroblastomas, lymphoma, pancreatic cancer and salivary gland adenoid cystic carcinoma [5e7]. It was suggested that Trk receptor tyrosine kinases were a bridge between cancer and neural development [8]. In spite of the expression and prognostic significance of NTs and their receptors in cancer development vary among different tissue types, yet it strongly indicates that NTs may be involved in the perineural invasion and metastasis in carcinomas. Han et al. supposed that TrkB could be used as a predictor of poor prognosis for carcinoma patients [9]. In the present article, we propose another hypothesis that NTs play an important role in the perineural invasion and distant metastasis of malignant tumor.
Background NTs and perineural invasion of SACC Due to its perineural invasive character, certain part of malignant tumor cases was first diagnosed because of nerve paralysis or idiopathic neuralgia caused by perineural invasion. For this reason, the study on the association between NTs and perineural invasion of malignant tumor aroused the attention of many researchers. Available evidence indicates that most of the NT numbers were found in different malignant tumor samples and cell lines, especially those malignant tumor exhibiting a perineural invasive phenotype as described above. In spite of that the mechanism of perineural invasion is still not clear, several studies reported a significant association between expression level of NTs with perineural invasion of malignant tumor. It was reported that higher levels of expression of Trk receptors in cutaneous squamous cell carcinoma cells may predict perineural invasion and the increased p75NGFR expression found in cutaneous squamous cell carcinoma perineurally may allow p75NGFR immunohistochemical staining to be used for detecting perineural invasion [2]. Similar results were found in the research of pancreatic ductal adenocarcinoma and salivary adenoid cystic carcinoma, it was suggested that NGF and TrkA can be considered as biomarkers for perineural invasion, and the overexpression of NGF and TrkA constituted a reason for the affinity of cancer cells for nerves. It is possible that NGF
L.-xin Su et al. produced by neural tissue can act as a chemotactic factor, and tumor cells in which the overexpression of TrkA exists seem to be selected to invade the perineural space [10,11]. Similar dose-dependent effects of NGF have been also observed in melanoma cell lines [12]. A study carried by Paul et al. in 2002 reported that perineural invasion in salivary adenoid cystic carcinoma was caused and promoted by BDNF [3]. Increasing evidence indicates that NTs may play an important role in the perineural invasion of malignant tumor.
NTs and metastasis of malignant tumor Metastasis is very important for the prognosis of malignant tumor. Although overlooked in the past, a significant association between NTs and metastasis of malignant tumor has been suggested by recently studies. A new conception of Anoikis was introduced to explain the role of NTs played in the metastasis of malignant tumor. Anoikis (Greek for ‘‘homelessness’’) is a form of apoptosis triggered by lack of cell survival signals generated from the interactions between cells and extracellular matrix (ECM). Physiological anoikis is considered to be important for the maintenance of homeostasis and tissue architecture, and acts as a barrier to the metastasis of cancer cells. Acquisition of resistance to anoikis may allow survival of cancer cells during systemic circulation, thereby facilitate secondary tumor formation in distant organs. The transformed cells or cell lines derived from human cancers are generally anchorage-independent and can survive under loss of adhesion, which promote their migration and colonization at secondary sites [13]. So, obtain the anoikis resistance is essential for the metastasis of malignant tumor. Douma et al. had reported TrkB, receptor of BDNF, as a potent and specific suppressor of caspase-associated anoikis in non-malignant epithelial cells. In mice, cells highly expressing TrkB can form rapid-growing tumors, which infiltrate into lymphatic and blood vessels and colonize in distant organs. Suppression of anoikis and promotion of metastasis by TrkB demonstrate the potent oncogenic effects of TrkB, which providing a possible explanation for the aggressive nature of human tumors that overexpress TrkB [14]. A recent study focus on the effect of BDNF on biological behaviors of ovarian cancer cell in vitro proved that the migration and invasion capabilities of ovarian cancer cell were highly improved by increasing the concentration of BDNF in culture system in vitro [15]. A similar result was also observed in study of pancreatic ductal adenocarcinoma and malignant melanoma cell lines [12,16]. A series recent study has supported the hypothesis of the effect of NTs on metastasis of SACC. In summary, current evidence suggests that metastasis of SACC is significantly associated with NTs.
The hypothesis Given the association between NTs and malignant tumor behaviors, we hypothesize that the high expression of NTs in malignant tumor contributes to explaining the perineural invasion and distant metastasis of malignant tumor. To our knowledge, currently, no studies have explored this hypothesis. Therefore, we believe that studies assessing the
NTs in the perineural invasion and distant metastasis relationship between NTS and malignant tumor behaviors using methods both in vivo and in vitro should be encouraged. Moreover, it would be of interest to gain insight into the molecular mechanisms involved in the relationship between NTs and malignant tumor behaviors.
Implications Our hypothesis generates potentially relevant clinical and therapeutic implications for the management of malignant tumor. It is proposed currently that perineural space provides a suitable microenvironment for the growth of cancer cells. Perineural invasion is observed in many kinds of malignant tumors and is recognized as one of the most important prognostic factors. If the hypothesis that NTs contribute to the perineural invasion and metastasis of malignant tumor is true, it may suggest that expression level of NTs could be considered as biomarkers for prognosis evaluation in human malignant tumor. Furthermore, more closed follow-up is necessary for the cases with nerve paralysis or idiopathic neuralgia before first treatment, including general physical checkup regularly to detect metastasis for early treatment. With regard to the therapeutic implications, we suggest that the results may lead to development of a possible treatment for metastasis of in patients with malignant tumor by targeting of NTs pathway. For potential treatment options, inhibition of NTs signaling can be beneficial in some case. NTs signaling blocking reagents such as neutralizing monoclonal antibodies, receptor extracellular domain-Fc fusion proteins and low molecular weight chemical inhibitors are already available and might be part of the oncologist’s therapeutic repertoire in the future.
Conclusion In conclusion, considering the role that NTS played in malignant tumor, we believe that further studies between NTs and malignant tumor are necessary. Research on the role of NTs pathway might allow advancements in this field, suggesting a more effective management and, ultimately, a better quality of life of patients with malignant tumor.
Conflict of interest The authors have no conflict of interest to declare.
Acknowledgements This study was supported by Shanghai Leading Academic Discipline Project, project number: Y0203.
77
References [1] Hoyle GW. Neurotrophins and lung disease. Cytokine Growth Factor Rev 2003;14:551e8. [2] Sakamoto Y, Kitajima Y, Edakuni G, Hamamoto T, Miyazaki K. Combined evaluation of NGF and p75NGFR expression is a biomarker for predicting prognosis in human invasive ductal breast carcinoma. Oncol Rep 2001;8:973e80. [3] Kowalski PJ, Paulino AF. Perineural invasion in adenoid cystic carcinoma: its causation/promotion by brain-derived neurotrophic factor. Hum Pathol 2002;33:933e6. [4] Bonini P, Pierucci D, Cicconi S, Porzio O, Lauro R, Marlier LN, et al. Neurotrophins and neurotrophin receptors mRNAs expression in pancreatic islets and insulinoma cell lines. JOP 2001;2:105e11. [5] Stephan H, Zakrzewski JL, Boloni R, Grasemann C, Lohmann DR, Eggert A. Neurotrophin receptor expression in human primary retinoblastomas and retinoblastoma cell lines. Pediatr Blood Cancer 2008;50(2):218e22. [6] Pica F, Volpi A, Serafino A, Fraschetti M, Franzese O, Garaci E. Autocrine nerve growth factor is essential for cell survival and viral maturation in HHV-8-infected primary effusion lymphoma cells. Blood 2000;95:2905e12. [7] Miknyoczki SJ, Klein-Szanto AJ, Ruggeri BA. NeurotrophineTrk receptor interactions in neoplasia: a possible role in interstitial and perineural invasion in ductal pancreatic cancer. Crit Rev Oncog 1996;7:89e100. [8] Nakagawara A. Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett 2001; 169:107e14. [9] Han L, Zhang Z, Qin W, Sun W. Neurotrophic receptor TrkB: is it a predictor of poor prognosis for carcinoma patients? Med Hypotheses 2007;68:407e9. [10] Wang L, Sun M, Jiang Y, Yang L, Lei D, Lu C, et al. Nerve growth factor and tyrosine kinase A in human salivary adenoid cystic carcinoma: expression patterns and effects on in vitro invasive behavior. J Oral Maxillofac Surg 2006;64:636e41. [11] Miknyoczki SJ, Lang D, Huang L, Klein-Szanto AJ, Dionne CA, Ruggeri BA. Neurotrophins and Trk receptors in human pancreatic ductal adenocarcinoma: expression patterns and effects on in vitro invasive behavior. Int J Cancer 1999;81: 417e27. [12] Herrmann JL, Menter DG, Hamada J, Marchetti D, Nakajima M, Nicolson GL. Mediation of NGF-stimulated extracellular matrix invasion by the human melanoma low-affinity p75 neurotrophin receptor: melanoma p75 functions independently of trkA. Mol Biol Cell 1993;4:1205e16. [13] Liotta LA, Kohn E. Anoikis: cancer and the homeless cell. Nature 2004;430:973e4. [14] Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E, Peeper DS. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 2004;430:1034e9. [15] Yu X, Liu L, Cai B, He Y, Wan X. Suppression of anoikis by the neurotrophic receptor TrkB in human ovarian cancer. Cancer Sci 2008;99:543e52. [16] Truzzi F, Marconi A, Lotti R, Dallaglio K, French LE, Hempstead BL, et al. Neurotrophins and their receptors stimulate melanoma cell proliferation and migration. J Invest Dermatol 2008;128:2031e40.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/bihy
Neurotrophins play an important role in the perineural invasion and distant metastasis of malignant tumor Li-xin Su, Xing-zhou Qu, Chen-ping Zhang* Department of Oral and Maxillofacial Surgery, School of Stomatology, Affiliated Ninth People’s Hospital, 639 Zhizaojiu Road, Shanghai Jiaotong University, Shanghai 200011, China Received 18 December 2008; accepted 31 December 2008
KEYWORDS Neurotrophins; Metastasis; Cancer
Abstract Neurotrophins (NTs) family was first discovered in nervous system and it regulates the proliferation and differentiation of many neural cell types in the peripheral and central nervous system. Due to their perineural invasive characters, certain part of malignant tumor cases was first diagnosed because of nerve paralysis or idiopathic neuralgia caused by perineural invasion. For this reason, the study on the association between NTs and perineural invasion of malignant tumor aroused the attention of many researchers. Increasing evidence indicates that NTs and their receptors, Trks, play important roles in malignant cells, especially the exhibiting perineural invasive phenotype. It was suggested that NTs produced by neural tissue can act as a chemotactic factor, and tumor cells in which the overexpression of Trks’ exists seem to be selected to invade the perineural space. Except for contributing to perineural invasion of malignant tumor, accumulated evidence proved NTs now also significantly associated with the metastasis of malignant tumor. Overexpression of NTs or Trks often correlated with the tumorigenesis, angiogenesis and anoikis resistance in these malignancies, contributing significantly to the metastasis and poor prognosis. In summary, besides its role in development and function of nervous system, NTs also play an important role in the perineural invasion and metastasis of malignant tumor. Considering the role that NTs played in malignant tumor, we believe that further studies between NTs and malignant tumor are necessary. Research on the role of NTs pathway might allow advancements in this field. ª 2009 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel./fax: þ86 21 63135412. E-mail address: [email protected] (C.-ping Zhang). 1756-2392/$ - see front matter ª 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bihy.2008.12.001
76
Introduction Neurotrophins (NTs) consist of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, NT-4 (also called NT-5), NT-6, NT-7, etc. NTs family was first discovered in nervous system and it regulates the proliferation and differentiation of many neural cell types in the peripheral and central nervous system, just as its name implies. However, recent reports showed that NTs might also have important function outside of the central neural system. Now NTs were also found to be present in lung, thyroid, breast, salivary gland, pancreas, etc. [1e4]. Though the investigations are limited and the underlying mechanism remains unclear, when NTs combined with its receptors TrkA, TrkB, TrkC, and p75NGFR, have been shown to play important roles in malignant cells, including stimulating chemotaxis, tumor invasiveness, clonal growth, and altering cell morphology in a variety of cancers, especially those malignant tumor exhibiting a perineural invasive phenotype such as neuroblastomas, lymphoma, pancreatic cancer and salivary gland adenoid cystic carcinoma [5e7]. It was suggested that Trk receptor tyrosine kinases were a bridge between cancer and neural development [8]. In spite of the expression and prognostic significance of NTs and their receptors in cancer development vary among different tissue types, yet it strongly indicates that NTs may be involved in the perineural invasion and metastasis in carcinomas. Han et al. supposed that TrkB could be used as a predictor of poor prognosis for carcinoma patients [9]. In the present article, we propose another hypothesis that NTs play an important role in the perineural invasion and distant metastasis of malignant tumor.
Background NTs and perineural invasion of SACC Due to its perineural invasive character, certain part of malignant tumor cases was first diagnosed because of nerve paralysis or idiopathic neuralgia caused by perineural invasion. For this reason, the study on the association between NTs and perineural invasion of malignant tumor aroused the attention of many researchers. Available evidence indicates that most of the NT numbers were found in different malignant tumor samples and cell lines, especially those malignant tumor exhibiting a perineural invasive phenotype as described above. In spite of that the mechanism of perineural invasion is still not clear, several studies reported a significant association between expression level of NTs with perineural invasion of malignant tumor. It was reported that higher levels of expression of Trk receptors in cutaneous squamous cell carcinoma cells may predict perineural invasion and the increased p75NGFR expression found in cutaneous squamous cell carcinoma perineurally may allow p75NGFR immunohistochemical staining to be used for detecting perineural invasion [2]. Similar results were found in the research of pancreatic ductal adenocarcinoma and salivary adenoid cystic carcinoma, it was suggested that NGF and TrkA can be considered as biomarkers for perineural invasion, and the overexpression of NGF and TrkA constituted a reason for the affinity of cancer cells for nerves. It is possible that NGF
L.-xin Su et al. produced by neural tissue can act as a chemotactic factor, and tumor cells in which the overexpression of TrkA exists seem to be selected to invade the perineural space [10,11]. Similar dose-dependent effects of NGF have been also observed in melanoma cell lines [12]. A study carried by Paul et al. in 2002 reported that perineural invasion in salivary adenoid cystic carcinoma was caused and promoted by BDNF [3]. Increasing evidence indicates that NTs may play an important role in the perineural invasion of malignant tumor.
NTs and metastasis of malignant tumor Metastasis is very important for the prognosis of malignant tumor. Although overlooked in the past, a significant association between NTs and metastasis of malignant tumor has been suggested by recently studies. A new conception of Anoikis was introduced to explain the role of NTs played in the metastasis of malignant tumor. Anoikis (Greek for ‘‘homelessness’’) is a form of apoptosis triggered by lack of cell survival signals generated from the interactions between cells and extracellular matrix (ECM). Physiological anoikis is considered to be important for the maintenance of homeostasis and tissue architecture, and acts as a barrier to the metastasis of cancer cells. Acquisition of resistance to anoikis may allow survival of cancer cells during systemic circulation, thereby facilitate secondary tumor formation in distant organs. The transformed cells or cell lines derived from human cancers are generally anchorage-independent and can survive under loss of adhesion, which promote their migration and colonization at secondary sites [13]. So, obtain the anoikis resistance is essential for the metastasis of malignant tumor. Douma et al. had reported TrkB, receptor of BDNF, as a potent and specific suppressor of caspase-associated anoikis in non-malignant epithelial cells. In mice, cells highly expressing TrkB can form rapid-growing tumors, which infiltrate into lymphatic and blood vessels and colonize in distant organs. Suppression of anoikis and promotion of metastasis by TrkB demonstrate the potent oncogenic effects of TrkB, which providing a possible explanation for the aggressive nature of human tumors that overexpress TrkB [14]. A recent study focus on the effect of BDNF on biological behaviors of ovarian cancer cell in vitro proved that the migration and invasion capabilities of ovarian cancer cell were highly improved by increasing the concentration of BDNF in culture system in vitro [15]. A similar result was also observed in study of pancreatic ductal adenocarcinoma and malignant melanoma cell lines [12,16]. A series recent study has supported the hypothesis of the effect of NTs on metastasis of SACC. In summary, current evidence suggests that metastasis of SACC is significantly associated with NTs.
The hypothesis Given the association between NTs and malignant tumor behaviors, we hypothesize that the high expression of NTs in malignant tumor contributes to explaining the perineural invasion and distant metastasis of malignant tumor. To our knowledge, currently, no studies have explored this hypothesis. Therefore, we believe that studies assessing the
NTs in the perineural invasion and distant metastasis relationship between NTS and malignant tumor behaviors using methods both in vivo and in vitro should be encouraged. Moreover, it would be of interest to gain insight into the molecular mechanisms involved in the relationship between NTs and malignant tumor behaviors.
Implications Our hypothesis generates potentially relevant clinical and therapeutic implications for the management of malignant tumor. It is proposed currently that perineural space provides a suitable microenvironment for the growth of cancer cells. Perineural invasion is observed in many kinds of malignant tumors and is recognized as one of the most important prognostic factors. If the hypothesis that NTs contribute to the perineural invasion and metastasis of malignant tumor is true, it may suggest that expression level of NTs could be considered as biomarkers for prognosis evaluation in human malignant tumor. Furthermore, more closed follow-up is necessary for the cases with nerve paralysis or idiopathic neuralgia before first treatment, including general physical checkup regularly to detect metastasis for early treatment. With regard to the therapeutic implications, we suggest that the results may lead to development of a possible treatment for metastasis of in patients with malignant tumor by targeting of NTs pathway. For potential treatment options, inhibition of NTs signaling can be beneficial in some case. NTs signaling blocking reagents such as neutralizing monoclonal antibodies, receptor extracellular domain-Fc fusion proteins and low molecular weight chemical inhibitors are already available and might be part of the oncologist’s therapeutic repertoire in the future.
Conclusion In conclusion, considering the role that NTS played in malignant tumor, we believe that further studies between NTs and malignant tumor are necessary. Research on the role of NTs pathway might allow advancements in this field, suggesting a more effective management and, ultimately, a better quality of life of patients with malignant tumor.
Conflict of interest The authors have no conflict of interest to declare.
Acknowledgements This study was supported by Shanghai Leading Academic Discipline Project, project number: Y0203.
77
References [1] Hoyle GW. Neurotrophins and lung disease. Cytokine Growth Factor Rev 2003;14:551e8. [2] Sakamoto Y, Kitajima Y, Edakuni G, Hamamoto T, Miyazaki K. Combined evaluation of NGF and p75NGFR expression is a biomarker for predicting prognosis in human invasive ductal breast carcinoma. Oncol Rep 2001;8:973e80. [3] Kowalski PJ, Paulino AF. Perineural invasion in adenoid cystic carcinoma: its causation/promotion by brain-derived neurotrophic factor. Hum Pathol 2002;33:933e6. [4] Bonini P, Pierucci D, Cicconi S, Porzio O, Lauro R, Marlier LN, et al. Neurotrophins and neurotrophin receptors mRNAs expression in pancreatic islets and insulinoma cell lines. JOP 2001;2:105e11. [5] Stephan H, Zakrzewski JL, Boloni R, Grasemann C, Lohmann DR, Eggert A. Neurotrophin receptor expression in human primary retinoblastomas and retinoblastoma cell lines. Pediatr Blood Cancer 2008;50(2):218e22. [6] Pica F, Volpi A, Serafino A, Fraschetti M, Franzese O, Garaci E. Autocrine nerve growth factor is essential for cell survival and viral maturation in HHV-8-infected primary effusion lymphoma cells. Blood 2000;95:2905e12. [7] Miknyoczki SJ, Klein-Szanto AJ, Ruggeri BA. NeurotrophineTrk receptor interactions in neoplasia: a possible role in interstitial and perineural invasion in ductal pancreatic cancer. Crit Rev Oncog 1996;7:89e100. [8] Nakagawara A. Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett 2001; 169:107e14. [9] Han L, Zhang Z, Qin W, Sun W. Neurotrophic receptor TrkB: is it a predictor of poor prognosis for carcinoma patients? Med Hypotheses 2007;68:407e9. [10] Wang L, Sun M, Jiang Y, Yang L, Lei D, Lu C, et al. Nerve growth factor and tyrosine kinase A in human salivary adenoid cystic carcinoma: expression patterns and effects on in vitro invasive behavior. J Oral Maxillofac Surg 2006;64:636e41. [11] Miknyoczki SJ, Lang D, Huang L, Klein-Szanto AJ, Dionne CA, Ruggeri BA. Neurotrophins and Trk receptors in human pancreatic ductal adenocarcinoma: expression patterns and effects on in vitro invasive behavior. Int J Cancer 1999;81: 417e27. [12] Herrmann JL, Menter DG, Hamada J, Marchetti D, Nakajima M, Nicolson GL. Mediation of NGF-stimulated extracellular matrix invasion by the human melanoma low-affinity p75 neurotrophin receptor: melanoma p75 functions independently of trkA. Mol Biol Cell 1993;4:1205e16. [13] Liotta LA, Kohn E. Anoikis: cancer and the homeless cell. Nature 2004;430:973e4. [14] Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E, Peeper DS. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 2004;430:1034e9. [15] Yu X, Liu L, Cai B, He Y, Wan X. Suppression of anoikis by the neurotrophic receptor TrkB in human ovarian cancer. Cancer Sci 2008;99:543e52. [16] Truzzi F, Marconi A, Lotti R, Dallaglio K, French LE, Hempstead BL, et al. Neurotrophins and their receptors stimulate melanoma cell proliferation and migration. J Invest Dermatol 2008;128:2031e40.