Table 1.

Detailed overview of the role of NGF and its receptors in various types of tumors. While NGF’s primary function is related to neural development and function, its relationship with tumors is complex and multifaceted. The involvement of NGF in tumors is not as straightforward as in normal nerve growth, and its effects on different types of tumors can vary. Acetylcholine, Ach; A disintegrin and metalloprotease 17, ADAM17; protein kinase B, Akt; extracellular signal-regulated kinase, ERK; F-box-only protein 22, FBOXO22; hypoxia-inducible factor 1 subunit alpha, HIF1α; nerve growth factor, NGF; non-small-cell lung cancer, NSCLC; neurotrophic tyrosine receptor kinase, NTRK; nuclear factor kB, NF-kB; p75 pan-neurotrophin receptor, p75NTR; programmed death-ligand 1, PD-L1; rearranged during transfection, RET; small nuclear ribonucleoprotein polypeptide A, SNRPA; tissue inhibitor of metalloproteinases, TIMP; tropomyosin receptor kinase, Trk; vascular endothelial growth factor, VEGF. (*) MYCN is amplified in 20% of neuroblastomas and correlates with aggressive phenotype and poor prognosis. (**) Perineural invasion driven by the TME has been identified as a key pattern of several malignancies including breast, pancreatic, and prostate cancers.

Kind of Tumor	Role of NGF	References
Brain tumors	Pro-NGF, NGF, and TrkA are expressed in numerous brain tumor cells (especially glioblastoma) and can promote cell survival and growth. p75NTR proteolysis is required for brain tumor proliferation. NGF concentrated in centrosome can phosphorylate TrkA, which may in return phosphorylate tubulin and promote mitotic spindle assembly, causing mitogenic effects in glioma cells. In ependymoblastoma tumors, NGF exerts a marked action on differentiation rather than proliferation in vitro. The potential of pro-NGF, NGF, and its receptors as clinical biomarkers and therapeutic targets has been highlighted.	[81,82,83,84,85,86,87,88,89]
Breast Cancer	NGF is both synthesized and released by breast cancer cells. NGF exerts mitogenic, antiapoptotic, and angiogenic influences on breast cancer cells by engaging distinct signaling pathways that encompass the participation of TrkA and NGFR/p75NTR receptors. Pro-NGF signaling has been linked to breast cancer invasion and metastasis. NGF and its receptors have been identified as diagnostic and prognostic tools. NGF and its receptors are promising therapeutic targets for breast cancer. Norepinephrine/β2-Adrenergic Receptor pathway promotes cell proliferation and NGF production in triple-negative breast cancer. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or β2-adrenoceptor in triple-negative breast cancer tumor cells enhances the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. Electroacupuncture promotes apoptosis and inhibits axonogenesis by activating the p75NTR receptor for triple-negative breast xenograft in mice. In rat models, it has been found that NGF from breast cancer may mediate spinal bone pain from metastasis via axonal growth and up-regulation of pain-associated neuropeptides.	[26,90,91,92,93,94,95,96,97,98,99]
Colorectal Cancer	NGF can stimulate the growth and survival of colon cancer cells and influence their invasive behavior. NGF has been identified as a potential therapeutic target for the treatment of colon cancer. NGF receptors may play a key role in androgen’s effect on hormone-sensitive tumor cells. NGF has been included in new immunogenomic prognostic risk scores for colorectal cancer.	[17,47,100,101,102,103]
Gastric Cancer	In gastric cancer, NGF and Trk receptor mRNA expression are down-regulated. NGF Trk receptors may elicit cell apoptosis by a Ras or Raf signal transduction pathway. SNRPA (small nuclear ribonucleoprotein polypeptide A) enhances tumor cell growth in gastric cancer through modulating NGF expression. ACh-NGF positive feedback loop may be the basis for the abnormal innervation observed in the TME and acts through the Trk receptors. p75NTR inhibits the invasive and metastatic abilities of gastric cancer cells by down-regulating uPA and matrix metalloproteinase 9 proteins and up-regulating TIMP1 protein via the NF-kB signal transduction pathway. p75NTR may be used as a new potential therapeutic target in metastatic gastric cancer. Individual and co-expression patterns of NGF and heme oxygenase-1 may predict shorter survival of gastric carcinoma patients.	[104,105,106,107,108]
Head and Neck Cancer	NGF can stimulate morphological differentiation, adhesion, proliferation, and migration in head and neck cancer. NGF controls cancer cell migration through Akt phosphorylation, suggesting a possible therapeutic role of Akt inhibitors. NGF and TrkA are highly expressed in cases of head and neck carcinomas with and without perineural invasion and are associated with improved tumor cell survival. (**) p75NTR and TrkC receptors demonstrate a different immunoreactivity profile in comparison to TrkA and TrkB receptors in the normal human pituitary gland and adenomas. p75NTR and pattern of invasion predict poor prognosis in oral squamous cell carcinoma. Pro-NGF may be a potential diagnostic biomarker for thyroid cancer. In thyroid cancer, increased expression of the TrkA receptor has been correlated with tumor progression and lymph node invasion.	[10,44,109,110,111,112,113,114,115,116,117]
Leukemias	NGF induces the ERK signaling pathway through TrkA receptors stimulating the production and survival of immune cells, but the actual impact on hematological diseases is still to be determined.	[118,119,120,121]
Liver Cancer	NGF and TrkA are highly expressed in hepatocarcinoma tissue (especially in males). p75NTR may provide a mechanism for selective apoptosis of hepatic stellate cells. NGF and its receptors may play a role in cellular interactions involving hepatocarcinoma cells, hepatic stellate cells, arterial cells, and nerve cells in cancer tissues. NGF regulates liver cancer cell polarity and motility associated with the invasion and metastasis process. Various therapies for liver cancer have been found to act on NGF pathways or influence the pro-NGF/NGF balance. NGF level evaluation may be useful to predict hepatic dysfunction after irradiation and has been studied as a possible biomarker for liver cancer.	[80,122,123,124,125,126,127,128,129,130,131,132,133]
Lung Cancer	NGF has been linked to lung cancer progression, promoting the growth and survival of lung cancer cells and contributing to the development of chemoresistance. TrkA is increased in squamous cell carcinoma, NGF and pro-NGF are increased in both squamous cell carcinoma and in adenocarcinoma, and p75NTR is increased across all lung cancer histological subtypes compared to normal lung. NGF might play a role in the interaction between lung cancer cells and nerve fibers, leading to increased tumor growth. NGF and chemokines secreted by apoptotic astrocytes cause the formation of an inflammatory and immunosuppressive microenvironment, enabling the formation of a pre-metastatic niche in lung cancer brain metastases. Evidence of Trk fusion in NSCLC suggests the potential of NGF receptors as targets for further therapeutical applications.	[83,134,135,136,137,138,139]
Ovarian Cancer	Ovarian cancer is marked by elevated levels of NGF and TrkA. NGF is involved in perineural invasion. (**) Through its interaction with the TrkA receptor, NGF decreases transcription of miR-145 levels, causing an increase in oncogenic proteins involved in promoting angiogenesis and cell proliferation and migration, as well as inhibiting apoptosis and influencing various molecules such as cyclooxygenase-2, ADAM17, and calreticulin, all essential for ovarian cancer progression. MicroRNAs may be associated with NGF/TrkA activation and alter key protein levels. The onset condition of ovarian cancer can be diagnosed through the detection of high or low expression of NGF and its receptors. TrkA may be considered a new potential tumor marker. NGF is also associated with increased resistance to chemotherapy in ovarian cancer cells. Blocking neurotrophin action could be a therapeutic target in treating ovarian cancer. Metformin treatment decreases the expression of c-MYC, β-catenin, and VEGF induced by NGF/TrkA while increasing oncosuppressor miRs, such as miR-145 and miR-23b.	[140,141,142,143,144,145,146,147,148,149]
Neuroblastoma	NGF promotes the survival and growth of neuroblastoma cells by binding to TrkA on the surface of cancer cells. TrkA and TrkC are overexpressed in biologically favorable neuroblastomas: their expression was associated with an absence of N-myc amplification, lower disease stage, lower patient age, differentiated tumors, and a greater likelihood of spontaneous regression or responding well to therapy. TrkB is mainly expressed in unfavorable, aggressive neuroblastomas. p75 plays an important role in enhancing both the sensitivity of Trk receptors to low levels of ligand, as well as enhancing ligand-induced differentiation in TrkA/p75 but not TrkB/p75 cells. Targeting Trk receptors is a potential therapeutic strategy for neuroblastoma treatment. MYCN (*) targets estrogen receptor alpha (Erα) and thereby NGF signaling to maintain an undifferentiated and aggressive phenotype. RET and TrkA physically interact and can induce reciprocal activation in response to ligand activation.	[24,150,151,152,153,154,155,156]
Pancreatic Cancer	NGF exerts both stimulatory and inhibitory effects on pancreatic cancers with the effect based on the expression levels and the ratio of TrkA and p75NTR. NGF from pancreatic stellate cells induces pancreatic cancer proliferation and invasion by the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase (GSK) signal pathway. TrkA expression in pancreatic cancer is a marker of tumor aggressiveness. Elevated p75NGFR expression is associated with a favorable prognosis. NGF overexpression combined with TrkA may contribute to perineural invasion by activating the Warburg effect, promoting tumor-derived exosomal miRNA-21 expression, prompting the hyperplasia of nerves, and inhibiting tumor cell apoptosis. (**) In pancreatic cancer, the high-glucose microenvironment promotes the invasion ability and raises the expression of NGF by upregulating HIF1α. NGF has been successfully used for diagnostic, therapeutic, and prognostic purposes in pancreatic cancer. Atorvastatin may exert an anti-tumor effect in pancreatic cells via the inhibition of NGF and other neurotrophin signaling pathways. In a mouse model, anti-NGF treatment beginning at 4 weeks may increase inflammation and negatively impact disease, while treatment starting at 8 weeks (after disease onset) reduces neural inflammation, neural invasion, and metastasis.	[13,15,16,157,158,159,160,161,162,163,164,165,166,167]
Pediatric tumors	NGF Trk receptors play a key role in pediatric tumors, especially in brain cancers. Trk receptors play a key role in transducing the mitogenic effects of NGF and Trk inhibitors have been proven to be an important therapeutic tool for the treatment of NTRK fusion cancers. NGF administration may be an effective and safe adjunct therapy in children with optic atrophy due to optic gliomas.	[28,36,82,168,169,170]
Prostate Cancer	NGF and its receptors are found in prostate cancer cells. NGF is released by both epithelial pancreatic cells and cancer-associated fibroblasts. NGF may be able to suppress tumor growth via an indirect effect, probably innervation or maturation of the tumor neo-vasculature. Aberrations and/or derangement of NGF signaling contribute to tumor growth and progression, enhancing the invasive potential of prostate cancer cells and promoting the development of cancer cells’ neuroendocrine features. Expression of p75NTR reduces NGF-induced cell growth by activation of programmed cell death. Cross-talk between androgen receptors and NGF receptors in prostate cancer cells may have implications for a new therapeutic approach. Pro-NGF correlates with the Gleason score and is a potential driver of nerve infiltration in prostate cancer. Cancer-associated fibroblasts can activate Yes-associated protein (YAP1)/TEA domain (TEAD1) signaling and increase the secretion of NGF, therefore promoting perineural invasion. (**) FBXO22 mediates the NGF/TrkA signaling pathway and stimulates macrophage M2 polarization in prostate cancer bone metastases, promoting cell activity and osteogenic lesions.	[77,171,172,173,174,175,176]
Skin tumors	NGF and its receptor seem to play a role in most skin tumors including malignant melanoma. In basal cell carcinoma and cutaneous squamous cell carcinoma, increased levels of NGF and TrkA, B, and C may reflect unique survival pathways. P75NTR may play a mechanistic role in invasive melanomas demonstrating perineural invasion. (**) Higher levels of Trk receptors in cutaneous squamous cell carcinoma cells may predict perineural invasion. Increased p75NTR expression in cutaneous squamous cell carcinoma perineurally may allow p75NTR immunohistochemical staining to be used for detecting sites of perineural invasion. NGF and TrkA are overexpressed in cervical squamous cell carcinoma. PD-L1 and NGF are co-expressed on spindle cells in the microenvironment of Merkel carcinoma, and TrkA receptors seem to play a major role. P75NTR has been identified as a useful marker to distinguish spindle cell melanoma from other spindle cell neoplasms of sun-damaged skin.	[54,177,178,179,180,181,182,183,184,185,186]