Neurogenic differentiation factor 1 (NeuroD1) is a basic helix–loop–helix transcription factor found in neurons that plays an important role in neuronal differentiation ^[1][64]. NeuroD1 has been shown to play an important role in the tumorigenesis of various peripheral tumors such as schwannomas and neuroblastomas.

In a study assessing the impact of NeuroD1 in neuroblastoma, researchers examined the expression profile of NeuroD1 in MYCN-overexpressing transgenic mice and the role of NeuroD1 in tumor formation ^[2][65]. They found that NeuroD1 was strongly expressed in the celiac sympathetic ganglion of MYCN mice and expressed in all subsequently generated advanced cancer tissue. Moreover, the authors noted that inhibition of NeuroD1 via short hairpin RNA (shRNA) resulted in decreased neuroblastoma cellular motility. They also noted that tumor proliferation was suppressed with NeuroD1 inhibition. The researchers concluded that NeuroD1 expression is associated with increased tumorigenesis of neuroblastoma and associated with a poor prognosis in mouse models ^[2][65].

Investigators in another study used a variety of transgenic mouse lines to determine how the expression of NeuroD1 affects schwannoma tumor progression, vestibular function, and schwannoma cell proliferation ^[3][66]. The authors found that gene transfer of NEUROD1 significantly reduced the proliferation of schwannoma cells ^[3][66]. The researchers then deleted the neurofibromatosis 2 suppressor gene (NF2) in schwannoma cells and, as expected, noted increased intraganglionic schwannoma cell proliferation ^[3][66]. Interestingly, in these intraganglionic schwannoma cells, addition of NeuroD1 induced variable effects, with no overt decrease in schwannoma cell proliferation ^[3][66]. The researchers next performed sciatic nerve axotomy to determine the effect of Neuro D1 on peripheral nerves ^[3][66]. Axotomy significantly increased schwannoma cell proliferation, as expected ^[3][66]. The authors concluded that NeuroD1 inhibits the proliferation of Schwann cells and functions as a tumor suppressor. However, they noted that the results were mixed and that further research is needed to explore NeuroD1′s potential role as a therapeutic agent ^[3][66].

The protein tubulin beta-3 chain (TUBB3) has many critical cellular functions, including roles in structural support, protein delivery, and cell division ^[4][67]. The expression of TUBB3 in cancers has also been postulated to play a role in resistance to taxane-based chemotherapy and thus is of great interest to researchers ^[4][67]. In one study, immunohistochemical expression of TUBB3 was assessed in 3911 tissue samples from 100 different tumor categories and 76 different normal tissue types ^[4][67]. The study found that all neuroblastoma samples strongly expressed TUBB3. Thus, the investigators suggested that clinicians should consider prescribing taxane-based therapy in patients with neuroblastoma.

In another study, researchers investigated the impact of TUBB3 expression in neurogenic cancers ^[5][60]. They noted differing patterns of expression of the TUBB3 protein in the various cancers. In both embryonic and adult neuronal tumors of the peripheral nervous systems, TUBB3 expression was associated with lower rates of neuronal proliferation caused by higher rates of neuronal differentiation. In contrast, in non-neurogenic tumors such as lung cancer, the presence of TUBB3 increased the histologic grade of tumors and promoted cellular proliferation. Thus, in neurogenic tumors, TUBB3 may act as a protective factor by promoting cellular differentiation and thereby attenuating tumorigenesis ^[6][68].

Stathmin 1 (STMN1) belongs to a family of proteins that are important regulators of microtubule dynamics ^[7][69]. Stathmin 1 depolymerizes and prevents the polymerization of several different microtubules. Recently, researchers have begun to take an interest in this protein and have noted its involvement in neurogenic cancers ^[7][69].

A study found that stathmin 1 suppression reduced neuroblastoma cell invasion into the extracellular matrix and that its role in tumor invasion is mediated by RHO-associated protein kinase (ROCK), a key regulator of cell migration ^[8][70]. In neuroblastoma cells, the suppression of ROCK inhibited cell migration. Moreover, reduced stathmin 1 expression in neuroblastoma cells significantly increased the activity of transforming protein RhoA, which is upstream of ROCK, and induced expression of the RhoA/ROCK pathway. Finally, stathmin 1 suppression in neuroblastoma tumor models decreased whole-body metastasis in the lung, kidney, and liver. Thus, the role of stathmin 1 in neuroblastoma tumorigenesis makes it a potential target for cancer therapeutics ^[8][70].

Microtubule-associated protein 2 (MAP2) belongs to the family of microtubule-associated proteins, which are thought to be involved in assembling microtubules and to play a crucial role in neurogenesis ^[9][71]. MAP2 proteins have also been shown to be expressed in neuronally differentiated neurons ^[10][72] A study seeking to establish the neural features of peripheral neuroblastic tumors analyzed samples of 12 neuroblastomas, 2 ganglioneuroblastomas, and 4 ganglioneuromas. All tumor samples expressed MAP2, suggesting that MAP2 may be a biomarker for identifying tumors with neural origins or those with significant neural involvement ^[11][73].

Another study assessed whether MAP2 expression could be used in the diagnosis of neuroblastoma ^[12][74]. Researchers used immunohistochemical analyses of tissue microarrays to evaluate the utility of a commercially available antibody against MAP2 in detecting primary and metastatic neuroblastomas. They found that MAP2 showed cytoplasmic reactivity in 95% of primary and 100% of metastatic neuroblastomas. In contrast, MAP2 was not found in other small round blue cell tumors. Additionally, in normal tissue, MAP2 was expressed only in organs of neural crest origin such as the adrenal medulla. Thus, the authors concluded that MAP2 is both a sensitive and specific marker to detect neuroblastoma and can differentiate neuroblastoma from other tumors with similar morphological features ^[12][74].

In a study evaluating the utility of synaptophysin for detecting childhood neuroblastoma, synaptophysin immunoreactivity was found in six of six neuroblastoma samples tested but not in other small round cell tumors with similar features ^[13][75]. In addition, rhabdomyosarcomas, lymphomas, and Ewing sarcomas were all negative for synaptophysin. This study indicated that synaptophysin could be an important diagnostic marker for evaluating neuroblastoma and should be included in marker panels ^[13][75].