- Open Access
Nerve growth factor: role in growth, differentiation and controlling cancer cell development
© The Author(s). 2016
- Received: 18 May 2016
- Accepted: 12 July 2016
- Published: 21 July 2016
Recent progress in the Nerve Growth Factor (NGF) research has shown that this factor acts not only outside its classical domain of the peripheral and central nervous system, but also on non-neuronal and cancer cells. This latter observation has led to divergent hypothesis about the role of NGF, its specific distribution pattern within the tissues and its implication in induction as well as progression of carcinogenesis. Moreover, other recent studies have shown that NGF has direct clinical relevance in certain human brain neuron degeneration and a number of human ocular disorders. These studies, by suggesting that NGF is involved in a plethora of physiological function in health and disease, warrant further investigation regarding the true role of NGF in carcinogenesis. Based on our long-lasting experience in the physiopathology of NGF, we aimed to review previous and recent in vivo and in vitro NGF studies on tumor cell induction, progression and arrest. Overall, these studies indicate that the only presence of NGF is unable to generate cell carcinogenesis, both in normal neuronal and non-neuronal cells/tissues. However, it cannot be excluded the possibility that the co-expression of NGF and pro-carcinogenic molecules might open to different consequence. Whether NGF plays a direct or an indirect role in cell proliferation during carcinogenesis remains to demonstrate.
- Naïve cell
- Tumor cells NGF
- Cell proliferation
- Cell differentiation
The Nerve Growth Factor (NGF) was discovered by R. Levi-Montalcini nearly 60 years ago after the transplantation of a malignant mouse sarcoma into the body wall of a 3-day-old chick embryo [1, 2]. Subsequent studies revealed that the purified murine NGF (adult submaxillary gland) stimulates morphological differentiation, regulates neuronal gene expression (through interaction with specific cellular receptors) and plays a critical role in mature neurons for acting directly on peripheral sensory and sympathetic neurons and for maintaining their function and phenotype [3, 4]. Structural, biochemical and molecular studies indicate that a trophic interaction failure between target cells and their innervations might result in nerve dysfunction and neuronal degeneration [5, 6]. These findings led to the hypothesis that purified NGF might be a useful tool to prevent and/or protect peripheral nerves from degeneration, as observed in Diabetes . The history of NGF in clinical trials of Diabetes is exemplary with respect to the potentiality of NGF in the care of peripheral neuropathies [8, 9]. Moreover, studies carried out in animal models and humans demonstrated that NGF can promote survival, differentiation and functional activity of peripheral sensory and sympathetic nerve cells . Diabetes is a metabolism disorder characterized by degeneration of peripheral neuron/fibers and altered local levels of NGF/NGF receptors and deregulation of NGF signal pathway . In experimental models of diabetic neuropathies, NGF administration reversed the neurodegenerative signs and normalized the activity of neurons belonging to the Peripheral Nervous System . The results of the above reported clinical trials were partially confirmed by succeeding clinical trials and thereafter the human studies were closed . The reason of dissimilar outcomes between first and second clinical trials is still not clear. A possible hypothesis might encompass a different biological preparation and/or composition of NGF formulation, the not-homogeneous study populations (in terms of age, onset and severity as well as clinical history of the neuropathy), the different selection of the placebo patient group and finally the occurrence of undesirable side effects . The most reasonable explanation for this clinical study failure and the interruption of NGF investigations in diabetic neuropathies could be associated with the necessity to use low NGF dosage (for side effects) in comparison with those of animal studies . The Authors concluded that a simply approach to investigate the role of NGF in human peripheral neuropathy could be the use of molecules with the ability to stimulate both synthesis and release of NGF at the proximity of damaged tissue . This aspect would imply the possibility to induce endogenous NGF upregulation, with no NGF-related side effects . Subsequently, studies revaled that NGF exerts a critical protective action on specific brain cells and particularly on the basal forebrain derived neurons undergoing degeneration in Alzheimer disease (AD)  and a variety of non-neuronal and neoplastic cells . Moreover, these studies revealed that the protective NGF role in human target cells might occur also outside the classical nervous system domain, as observed in the treatment of corneal ulcers , Glaucoma , Maculopathy , Retinitis Pigmentosa  and AD [15, 16]. These studies would suggest the use of NGF in the near future for the treatment of human pathologies with damaging of NGF-responsive cells.
By the way, the presence of NGF and NGF-receptors in cancer cells raised the question as whether NGF is involved in promoting cell proliferation and eventually cancer cell survival . To gain further information on this aspect, our aim was to summarize and review our and other literature available finding on NGF in cancer cell survival, proliferation and cell arrest, within and outside nervous system, both at baseline and following exposure to purified NGF.
NGF as pro-survival molecule
NGF and uncontrolled cell proliferation
The question about NGF role in tumor induction/progression has been investigated in different in vivo and in vitro experimental approaches. Evidences that some tumor tissues and their isolated tumor cells can express NGF-receptors and/or store NGF protein suggested the hypothesis that NGF might be involved in tumor cell induction and/or progression [24–27]. A consistent number of experimental studies have demonstrated the expression of NGF and NGF-receptors in neural crest-derived cells as well as in tumor cell lines from neuroblastoma, lymphoma, glioma, medulloblastoma adrenal tumors and melanoma, suggesting that NGF administration on trkANGFR-bearing cells could lead to cell differentiation and improved prognosis [28–30]. On the contrary, NGF by itself is unable to induce/generate cancer cell proliferation from normal tissues/cells or sustain cancer cell progression . Therefore, the hypothesis that NGF administration can promote uncontrolled cell proliferation (leading to cancer development) seems to have weak experimental evidence. It is noterworth to highlight that consistent NGF amounts are physiologically produced, stored and secreted by several cells/tissues as well as released into mammalian bloodstream (including humans) [2, 32, 33]. Several tissues produce and release NGF under physiological and neoplastic conditions (prostate included) and the locally-released NGF can exert both differentiatial and pro-survival activities on neuronal and non-neuronal tumor cells, depending on type of tumor and expression of trkANGFR and/or p75NTR receptors [34, 35]. Cell proliferation, survival and differentiation are under control of different signal transduction systems. The Mitogen-activated protein kinases (MAPKs) and the Ras (Ras/Raf/MEK/ERK) cascades represent key molecules for trk signaling and modulate all the hallmarks of cancer cells (survival, migration and invasion). Thereafter, specific inhibitors targeting these pathways represent crucial approaches to counteract tumor developing/progression, as observed for the inhibitor of MEK1 (Cobimetinib) allowing the differentiation and apoptosis in neuroblastoma cells and the kinase inhibitor D11 mediating apoptosis of cancer cells resistant to chemotherapy [36, 37]. On the other side, growth factors modulate several aspects of cell functions inside different microenvironments. The presence of a stem-like phenotype in tumors was confirmed by the identification of a small portion of cell population with the characteristics of stem cells inside tumor tissues . Because of the self-renewing capacity and the multi-directional differentiative potential, these cancer stem cells can represent source of tumor cells with different degree of differentiation inside the tissue. Contrasting data encompass the relationship between CD133/nestin (markers of neural stem cells and of cancer stem cells in neurogenic tumors) and prognosis of patients with glioma . Therefore, it is undoubted the great value of understanding the role of growth factors, and merely NGF and NGF-receptors, in tumor developing/progression, as well as the development of tumor growth factor targeted approaches.
Merely to NGF interaction in tumor cells, Zhu and coworkers highlighted that the NGF–trkANGFR interaction influences growth and spread of pancreatic cancer cells, Zhang and coworkers highlighted the prognostic value of NGF-receptors while Missale and coworkers showed the NGF-receptor overexpression associated with a good prognosis [39–41]. Farina and coworkers described a different trkANGFR isoform (trkA III, the result of an alternative splicing) able to induce an aberrant and aggressive proliferation in neuroblastoma cells . In a very recent study, Ruggeri and co-workers highlighted that NGF binding to trkANGFR and TRAIL (TNF-related apoptotis-inducing ligand) might suppress neuroproliferation in neuroblastoma by inducing apoptosis . These findings suggest that the high trkANGFR expression can provide a more favorable survival prognosis in breast cancer and neuroblastoma, although the underlined mechanisms and the direct relationships between trkANGFR and p75NTR remain poorly understood and/or explored. In addition, it was reported that the selective p75NTR expression by prostate tumor cells could induce cell cycle arrest and apoptosis, both crucial steps for potential anti-tumoral therapy [34, 35]. Studies reported by Ødegaard and coworkers showed a reduced expression/activation of trkANGFR in effusions as compared with solid ovarian carcinoma and that trkANGFR expression appeared to be independent of cell cycle progression, suggesting the phosphorylated trkANGFR form (known as p-trkANGFR) as a potential marker of prognostic value [30, 39].
NGF and tumor cell inhibition
Over the last three decades, a consistent number of published studies have shown that NGF can promote cell differentiation and arrest tumor progression, as observed in primary and cell line tumor cells [31, 44–50]. Particularly, several in vitro experiments have shown that NGF is capable of retarding growth and inducing persistent differentiation of neurogenic tumor cell lines . As shown, PC-12 tumor cells proliferate under baseline conditions (Fig. 1c) and start to differentiate and produce neuritis after NGF exposure over few consecutive days (see arrows in Fig. 1d). Likewise, cultured beta-tumor pancreatic cells proliferate in the absence (Fig. 1e) and stop to proliferate after the addition of NGF to the culture medium (arrows in Fig. 1f). Studies on animal models demonstrated that NGF is able to (i) induce the persistent reduction of the number of Ethylnitrosourea (ENU) -induced neurinomas and (ii) increase the survival time of rats after intracerebral implantation of the F98 anaplastic glioma cells . Either in tranplacental or postnatal ENU-exposure, NGF treatment caused a reduction of the number of ENU-induced neuromas in rats [52, 53]. As observed after topical administration, exogenous NGF can arrest tumor cell proliferation in human ocular glioma, prompting to the hypothesis of an inhibitory rather than promoting NGF effect on cancer cell (stimulation and tumor progression) [46, 54, 55]. These observations seem to support the hypothesis that the predominant expression of trkANGFR might facilitate cell differentiation while the p75NTR expression in the absence of trkANGFR might facilitate cell proliferation . Regarding the hypothesis of a favorable link between expression of NGF/NGF-receptors and tumor cell proliferation, it should be taken into consideration that the presence and/or release of “well established” pro-oncogenic molecules might precede the presence of NGF. These studies indicated that (i.) the NGF treatment can trigger the development of a more differentiated cell phenotype and as result cause the reduction or complete cessation of tumor growth and more interesting (ii.) the effects of NGF can be persistent, all together supporting the hypothesis that NGF can reverse transformed properties of susceptible tumor cell progression.
NGF, microenvironment and immunocompetent cell
The interaction between immune and tumor cells is crucial for tumor growth and progression, as highlighted by several old and recent studies in both animal and human models [47–49]. Although tumors have their own “cell shelter mechanisms” (immune escape, resistance to apoptosis and cell survival), a host-mediated immune response against tumors can occur and consequently two different models have been proposed. The “immunosurveillance model” suggests that tumor cells (by expressing proper surface antigens) are regarded as “non-self” and thereafter eliminated by the immune system, although some unknown mechanisms counteract with this physiological protective route . According to the “danger model”, the professional sentinels of tissue damage (Antigen Presenting Cells, APCs; dendritic cells and activated macrophages), B and T cells are activated/stimulated by risk-signals but do not recognize cancer cells as dangerous, and thereafter the appropriate T cell response to tumors does not occur .
In both cases, the composition of tissue microenvironment might play a crucial role. An accurate analysis of the microenvironment in a variety of solid tumor sections has revealed the presence of a T cell–infiltrated phenotype, macrophages, neutrophils, recruited mast cells and infiltrating eosinophils . Such a microenvironment might play a crucial role in tumor launch/progression, including the local sustaining and development of tumor-associated angiogenesis . Microenvironment is strictly linked to the genetic background and the interplay between infiltrating/resident immune (APCs, NK cells, B-T lymphocytes as well as mast cells and eosinophils) and epithelial/stromal cells. The release of different pro/anti-inflammatory and pro/anti-angiogenic factors (cytokines, chemokines, growth/fibrotic/angiogenic factors and tissue remodeling enzymes) might significantly influence and/or modulate local immune response and angiogenesis [48, 50, 57–59].
Studies published during the early ’90s revealed that NGF plays a critical role in the mechanisms of neuro-immune-endocrine homeostasis . The first study prospecting this aspect reported that NGF stimulates the survival of Mast Cells (MCs) and modulates the specific function of MCs and lymphocytes, providing substantial evidences that NGF could actively contribute to both innate and adaptive immune responses [61, 62]. Further studies into this field led to the discovery that macrophages, granulocytes, T and B subtypes, NK cells and eosinophils are not only NGF-target cells (survival and function) but also synthesize, store and release consistent amounts of NGF [63–68]. The presence of physiological amounts sustains the crucial NGF role in both innate and adaptive immune cells. The tumor microenvironment might release high amount of NGF and respond to extracellular NGF in autocrine/paracrine fashion. NGF immunoreactivity has been observed in several tumor tissues and cells [69, 70]. The observation that NGF is a soluble mediator, either released into or produced by the tumor microenvironment, and the fact that NGF is able to act on certain immune-cell activities, would suggest a possible control of cell proliferation towards resistance to cancer survival [71, 72]. It is noteworthy to highlight that some soluble mediators can exert a dual-faced action, implying that immune cells can have both active and/or bystander effects [71, 72].
This hypothesis is consistent with a number of previous and recent studies showing that NGF promote differentiation of cultured tumor cells and that single/repeated in vivo subcutaneously [17, 22, 72, 73], intracerebrally [5, 74], intranasally , topically [11–13, 76–79] and orally  NGF administered or even endogenously-induced/released NGF  do not cause uncontrolled cell proliferation nor lead to cancer cell generation. Although the available observations are consistent with such hypothesis, further studies might be necessary to determine whether a given population of tumor cells is entirely NGF-responsive or contains a proportion of unresponsive cells.
Finally, in line with the observation that repeated NGF administration in human pathologies do not promote cell neoplasy [17, 46, 54, 55], our working hypothesis and future investigation are to pursue studies on biochemical and molecular signals and factors, as well as to develop novel in vitro and in vivo strategies to confirm or debate the anti-tumoral properties of NGF.
AD, Alzheimer disease; APCs, antigen presenting cells; ENU, EthylNitrosoUrea; MCs, mast cells; NGF, nerve growth factor; NK, natural killer cells; p75NTR, neurotrophin receptor (low affinity NGF receptor); PC-12, PheoChromocytoma cell line derived from rat adrenal medulla; trkANGFR, Tyrosine Kinases Receptor of NGF
The Authors’ work summarized in this review was partially supported by the National Research Council (CNR) and the Association NGF-ONLUS to Luigi Aloe and by the Italian Ministry of Health and Fondazione Roma to Bijorn Omar Balzamino and Alessandra Micera.
LA and AM conceived the paper and contributed to the drafting of the article and literature search or revising it for important intellectual content, BOB and MLR contributed to the literature search, analysis and drafting/editing of the manuscript. All authors have critically reviewed the intellectual content of the paper and approved the final submitted version.
The authors declare that they have no competing interests.
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- Levi-Montalcini R, Hamburger V. Selective growth stimulating effects of mouse sarcoma on the sensory and sympathetic nervous system of the chick embryo. J Exp Zool. 1951;116:321–61.View ArticlePubMedGoogle Scholar
- Levi-Montalcini R. The nerve growth factor 35 years later. Science. 1987;237:1154–62.View ArticlePubMedGoogle Scholar
- Meakin SO, Shooter EM. The nerve growth factor family of receptors. Trends Neurosci. 1992;15:323–31.View ArticlePubMedGoogle Scholar
- Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci. 2001;24:1217–12.View ArticlePubMedGoogle Scholar
- Fischer W, Wictorin K, Bjorklund A, et al. Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature. 1987;329:65–8.View ArticlePubMedGoogle Scholar
- Connor B, Dragunow M. The role of neuronal growth factors in neurodegenerative disorders of human brain. Brain Res Rev. 1998;27:1–39.View ArticlePubMedGoogle Scholar
- Apfel SC. Nerve growth factor for the treatment of diabetic neuropathy: what went wrong, what went right, and what does the future hold? Int Rev Neurobiol. 2002;50:393–413.View ArticlePubMedGoogle Scholar
- Apfel SC, Arezzo JC, Brownlee M, et al. Nerve growth factor administration protects against experimental diabetic sensory neuropathy. Brain Res. 1994;634:7–12.View ArticlePubMedGoogle Scholar
- Apfel SC, Kessler JA, Adornato BT, et al. Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF study group. Neurology. 1998;51:695–702.View ArticlePubMedGoogle Scholar
- Ferrari MP, Mantelli F, Sacchetti M, et al. Safety and pharmacokinetics of escalating doses of human recombinant nerve growth factor eye drops in a double-masked, randomized clinical trial. BioDrugs. 2014;28:275–83.View ArticlePubMedGoogle Scholar
- Lambiase A, Rama P, Bonini S, et al. Topical treatment with nerve growth factor for corneal neurotrophic ulcers. N Engl J Med. 1998;338:1174–80.View ArticlePubMedGoogle Scholar
- Lambiase A, Aloe L, Centofanti M, et al. Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma. Proc Natl Acad Sci U S A. 2009;106:13469–74.View ArticlePubMedPubMed CentralGoogle Scholar
- Lambiase A, Coassin M, Tirassa P, et al. Nerve growth factor eye drops improve visual acuity and electro functional activity in age-related macular degeneration: a case report. Ann Ist Super Sanita. 2009;45:439–42.PubMedGoogle Scholar
- Rocco ML, Balzamino BO, Petrocchi Passeri P, et al. Effect of purified murine NGF on isolated photoreceptors of a rodent developing retinitis pigmentosa. PLoS One. 2015;10, e0124810.View ArticlePubMedPubMed CentralGoogle Scholar
- Tuszynski MH, Sang H, Yoshida K, Gage FH. Recombinant human nerve growth factor infusions prevent cholinergic neuronal degeneration in the adult primate brain. Ann Neurol. 1991;30:625–36.View ArticlePubMedGoogle Scholar
- Ferreira D, Westman E, Eyjolfsdottir H, et al. Brain changes in Alzheimer's disease patients with implanted encapsulated cells releasing nerve growth factor. J Alzheimers Dis. 2015;43:1059–72.PubMedGoogle Scholar
- Fabricant RN, De Larco JE, Todaro GJ. Nerve growth factor receptors on human melanoma cells in culture. Proc Natl Acad Sci U S A. 1977;74:565–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Aloe L, Levi-Montalcini R. Nerve growth factor-induced transformation of immature chromaffin cells in vivo into sympathetic neurons: effect of antiserum to nerve growth factor. Proc Natl Acad Sci U S A. 1979;76:1246–50.View ArticlePubMedPubMed CentralGoogle Scholar
- Unsicker K, Skaper SD, Varon S. Phenotypical changes of embryonic chick adrenal medullary cells in vitro induced by nerve growth factor and ciliary neuronotrophic factor. Neurosci Lett. 1985;60:127–32.View ArticlePubMedGoogle Scholar
- Angelucci F, Mathé AA, Aloe L. Neurotrophic factors and CNS disorders: findings in rodent models of depression and schizophrenia. Prog Brain Res. 2004;146:151–65.View ArticlePubMedGoogle Scholar
- Levi-Montalcini R, Skaper SD, Dal Toso R, et al. Nerve growth factor: from neurotrophin to neurokine. Trends Neurosci. 1996;19:514–20.View ArticlePubMedGoogle Scholar
- Levi-Montalcini R, Angeletti PU. Nerve growth factor. Physiol Rev. 1968;48:534–69.PubMedGoogle Scholar
- Dubanet L, Bentayeb H, Petit B, et al. Anti-apoptotic role and clinical relevance of neurotrophins in diffuse large B-cell lymphomas. Br J Cancer. 2015;113:934–44.View ArticlePubMedGoogle Scholar
- Yaeger MJ, Koestner A, Marushige K, Marushige Y. The use of nerve growth factor as a reverse transforming agent for the treatment of neurogenic tumors: in vivo results. Acta Neuropathol. 1992;83:624–9.View ArticlePubMedGoogle Scholar
- Keles GE, Berger MS, Schofield D, Bothwell M. Nerve growth factor receptor expression in medulloblastomas and the potential role of the nerve growth factor as a differentiating agent in medulloblastomas cell lines. Neurosurgery. 1993;32:274–80.View ArticlePubMedGoogle Scholar
- Wadhwa S, Nag TC, Jindal A, et al. Expression of the neurotrophin receptors Trk A and Trk B in adult human astrocytoma and glioblastoma. J Biosci. 2003;28:181–8.View ArticlePubMedGoogle Scholar
- Hamel W, Westphal M, Shepard HM. Loss in expression of the retinoblastoma gene product in human gliomas is associated with advanced disease. J Neurooncol. 1993;16:159–65.View ArticlePubMedGoogle Scholar
- Vinores SA, Koestner A. The effect of nerve growth factor on undifferentiated glioma cells. Cancer Lett. 1980;10:309–18.View ArticlePubMedGoogle Scholar
- Waris T, Rechardt L, Waris P. Differentiation of neuroblastoma cells induced by nerve growth factor in vitro. Experientia. 1973;29:1128–9.View ArticlePubMedGoogle Scholar
- Nakagawara A, Nakagawara AM, Scavarda NJ, et al. Association between high levels of expression of the trk gene and favourable outcome. N Engl J Med. 1993;328:847–54.View ArticlePubMedGoogle Scholar
- Antonelli A, Lenzi L, Nakagawara A, et al. Tumor suppressor proteins are differentially affected in human ependymoblastoma and medulloblastoma cells exposed to nerve growth factor. Cancer Invest. 2007;25:94–101.View ArticlePubMedGoogle Scholar
- Aloe L, Alleva E, Böhm A, Levi-Montalcini R. Aggressive behavior induces release of nerve growth factor from mouse salivary gland into the bloodstream. Proc Natl Acad Sci U S A. 1986;83:6184–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Alleva E, Calamandrei G. On the functional role of polypeptide growth factors in rodent neurobehavioral development. Acta Neurobiol Exp. 1990;50:341–52.Google Scholar
- Arrighi N, Bodei S, Zani D, et al. Nerve growth factor signaling in prostate health and disease. Growth Factors. 2010;28:191–201.View ArticlePubMedGoogle Scholar
- Goda M, Atagi S, Amitani K, et al. Nerve growth factor suppresses prostate tumor growth. J Pharmacol Sci. 2010;112:463–6.View ArticlePubMedGoogle Scholar
- Singh A, Ruan Y, Tippett T, et al. Targeted inhibition of MEK1 by cobimetinib leads to differentiation and apoptosis in neuroblastoma cells. J Exp Clin Cancer Res. 2015;34:104.View ArticlePubMedPubMed CentralGoogle Scholar
- Guerra B, Fischer M, Schaefer S, et al. The kinase inhibitor D11 induces caspase-mediated cell death in cancer cells resistant to chemotherapeutic treatment. J Exp Clin Cancer Res. 2015;34:125.View ArticlePubMedPubMed CentralGoogle Scholar
- Wu B, Sun C, Feng F, et al. Do relevant markers of cancer stem cells CD133 and Nestin indicate a poor prognosis in glioma patients? A systematic review and meta-analysis. J Exp Clin Cancer Res. 2015;34:44.View ArticlePubMedPubMed CentralGoogle Scholar
- Zhu ZW, Friess H, Wang L, et al. Nerve growth factor exerts differential effects on the growth of human pancreatic cancer cells. Clin Cancer Res. 2001;7:105–12.PubMedGoogle Scholar
- Zhang Y, Dang C, Ma Q, Shimahara Y. Expression of nerve growth factor receptors and their prognostic value in human pancreatic cancer. Oncol Rep. 2005;14:161–71.PubMedGoogle Scholar
- Missale C, Boroni F, Losa M, et al. Nerve growth factor suppresses the transforming phenotype of human prolactinomas. Proc Natl Acad Sci U S A. 1993;90:7961–5.View ArticlePubMedPubMed CentralGoogle Scholar
- Farina AR, Di Ianni N, Cappabianca L, et al. TrkAIII promotes microtubule nucleation and assembly at the centrosome in SH-SY5Y neuroblastoma cells, contributing to an undifferentiated anaplastic phenotype. Biomed Res Int. 2013;2013:740187.PubMedPubMed CentralGoogle Scholar
- Ruggeri P, Cappabianca L, Farina AR, et al. NGF FLIPs TrkA onto the death TRAIL in neuroblastoma cells. Cell Death Dis. 2016;7(3), e2139.View ArticlePubMedPubMed CentralGoogle Scholar
- Ødegaard E, Staff AC, Abeler VM, et al. The activated nerve growth factor receptor p-TrkA is selectively expressed in advanced-stage ovarian carcinoma. Hum Pathol. 2007;38:140–6.View ArticlePubMedGoogle Scholar
- Greene LA, Tischler AS. Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A. 1976;73:2424–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Chiaretti A, Falsini B, Servidei S, et al. Nerve growth factor eye drop administration improves visual function in a patient with optic glioma. Neurorehabil Neural Repair. 2011;25:386–90.View ArticlePubMedGoogle Scholar
- Rosenberg SA. Progress in human tumour immunology and immunotherapy. Nature. 2001;411:380–4.View ArticlePubMedGoogle Scholar
- Igney FH, Krammer PH. Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer. 2002;2:277–88.View ArticlePubMedGoogle Scholar
- Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14:1014–22.View ArticlePubMedPubMed CentralGoogle Scholar
- Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996;87:159–70.View ArticlePubMedGoogle Scholar
- Mamidipudi V, Li X, Wooten MW. Identification of interleukin 1 receptor-associated kinase as a conserved component in the p75-neurotrophin receptor activation of nuclear factor-kappa B. J Biol Chem. 2002;277:28010–8.View ArticlePubMedGoogle Scholar
- Swenberg JA, Koestner A, Wechsler W, Denlinger RH. Quantitative aspects of transplacental tumor induction with ethylnitrosourea in rats. Cancer Res. 1972;32:2656–60.PubMedGoogle Scholar
- Raju NR, Koestner A, Marushige K, et al. Effect of nerve growth factor on the transplacental induction of neurinomas by ethylnitrosourea in Sprague–Dawley rats. Cancer Res. 1989;49:7120–3.PubMedGoogle Scholar
- Falsini B, Chiaretti A, Barone G, et al. Topical nerve growth factor as a visual rescue strategy in pediatric optic gliomas: a pilot study including electrophysiology. Neurorehabil Neural Repair. 2011;25:512–20.View ArticlePubMedGoogle Scholar
- Kanaka-Gantenbein C, Dicou E, Czernichow P, Scharfmann R. Growth control of C6 glioma in vivo by nerve growth factor. J Neurooncol. 2002;59:199–205.View ArticleGoogle Scholar
- Micera A, Lambiase A, Stampachiacchiere B, et al. Nerve growth factor and tissue repair remodeling: trkA(NGFR) and p75(NTR), two receptors one fate. Cytokine Growth Factor Rev. 2007;18:245–56.View ArticlePubMedGoogle Scholar
- Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315:1650–9.View ArticlePubMedGoogle Scholar
- Mischel PS, Umbach JA, Eskandari S, et al. Nerve growth factor signals via preexisting TrkA receptor oligomers. Biophys J. 2002;83:968–76.View ArticlePubMedPubMed CentralGoogle Scholar
- Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004;432:324–31.View ArticlePubMedGoogle Scholar
- Aloe L, Skaper SD, Leon A, Levi-Montalcini R. Nerve growth factor and autoimmune diseases. Autoimmunity. 1994;19:141–50.View ArticlePubMedGoogle Scholar
- Aloe L. The effect of nerve growth factor and its antibody on mast cells in vivo. J Neuroimmunol. 1988;18:1–12.View ArticlePubMedGoogle Scholar
- Bracci-Laudiero L, Aloe L, Buanne P, et al. NGF modulates CGRP synthesis in human B-lymphocytes: a possible anti-inflammatory action of NGF? J Neuroimmunol. 2002;123:58–65.View ArticlePubMedGoogle Scholar
- Otten U, Ehrhard P, Peck R. Nerve growth factor induces growth and differentiation of human B lymphocytes. Proc Natl Acad Sci U S A. 1989;86:10059–63.View ArticlePubMedPubMed CentralGoogle Scholar
- Brodie C, Gelfand EW. Functional nerve growth factor receptors on human B lymphocytes. Interaction with IL-2. J Immunol. 1992;148:3492–7.PubMedGoogle Scholar
- Torcia M, Bracci-Laudiero L, Lucibello M, et al. Nerve growth factor is an autocrine survival factor for memory B lymphocytes. Cell. 1996;85:345–56.View ArticlePubMedGoogle Scholar
- Solomon A, Aloe L, Pe'er J, et al. Nerve growth factor is preformed in and activates human peripheral blood eosinophils. J Allergy Clin Immunol. 1998;102:454–60.View ArticlePubMedGoogle Scholar
- Lambiase A, Bracci-Laudiero L, Bonini S, et al. Human CD4+ T cell clones produce and release nerve growth factor and express high-affinity nerve growth factor receptors. Allergy Clin Immunol. 1997;100:408–14.View ArticleGoogle Scholar
- Lambiase A, Micera A, Sgrulletta R, et al. Nerve growth factor and the immune system: old and new concepts in the cross-talk between immune and resident cells during pathophysiological conditions. Curr Opin Allergy Clin Immunol. 2004;4:425–30.View ArticlePubMedGoogle Scholar
- Romon R, Adriaenssens E, Lagadec C, et al. Nerve growth factor promotes breast cancer angiogenesis by activating multiple pathways. Mol Cancer. 2010;9:157.View ArticlePubMedPubMed CentralGoogle Scholar
- Molloy TJ, Devriese LA, Helgason HH, et al. A multimarker QPCR-based platform for the detection of circulating tumour cells in patients with early-stage breast cancer. Br J Cancer. 2011;104:1913–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Witsch E, Sela M, Yarden Y. Roles for growth factors in cancer progression. Physiology (Bethesda). 2010;25:85–101.View ArticleGoogle Scholar
- Hanahan D. A flanking attack on cancer. Nat Med. 1998;4:13–4.View ArticlePubMedGoogle Scholar
- Aloe L, Alleva E, Fiore M. Stress and nerve growth factor: findings in animal models and humans. Pharmacol Biochem Behav. 2002;73:159–66.View ArticlePubMedGoogle Scholar
- Maysinger D, Jalsenjak I, Cuello AC. Microencapsulated nerve growth factor: effects on the forebrain neurons following devascularizing cortical lesions. Neurosci Lett. 1992;140:71–4.View ArticlePubMedGoogle Scholar
- Chen XQ, Fawcett JR, Rahman YE, et al. Delivery of Nerve Growth Factor to the Brain via the Olfactory Pathway. J Alzheimers Dis. 1998;1:35–44.PubMedGoogle Scholar
- Bernabei R, Landi F, Bonini S, et al. Effect of topical application of nerve-growth factor on pressure ulcers. Lancet. 1999;354:307.View ArticlePubMedGoogle Scholar
- Tuveri M, Generini S, Matucci-Cerinic M, Aloe L. NGF, a useful tool in the treatment of chronic vasculitic ulcers in rheumatoid arthritis. Lancet. 2000;356:1739–40.View ArticlePubMedGoogle Scholar
- Generini S, Tuveri MA, Matucci Cerinic M, et al. Topical application of nerve growth factor in human diabetic foot ulcers. A study of three cases. Exp Clin Endocrinol Diabetes. 2004;112:542–4.View ArticlePubMedGoogle Scholar
- Landi F, Aloe L, Russo A, et al. Topical treatment of pressure ulcers with nerve growth factor: a randomized clinical trial. Ann Intern Med. 2003;139:635–41.View ArticlePubMedGoogle Scholar
- Aloe L, Calissano P, Levi-Montalcini R. Effects of oral administration of nerve growth factor and of its antiserum on sympathetic ganglia of neonatal mice. Brain Res. 1982;256:31–4.View ArticlePubMedGoogle Scholar