Nerve Growth Factor and the Role of Inflammation in Tumor Development

**Background:** Inflammatory processes play a multifaceted role in tumor development and progression. While the immune system's inflammatory response is typically a defense mechanism against infections and tissue damage, chronic or persistent inflammation can contribute to the initiation, growth, and spread of certain types of tumors. In recent years, a growing body of evidence has emphasized the involvement of neurotrophins (NTs) in the complex landscape of both inflammation and cancer biology, showing their significant role in determining tumor cell growth and survival, particularly in certain types of cancers expressing NT receptors on their cell surfaces. One of the most well-studied NTs is the nerve growth factor (NGF), which binds to its specific receptor, tropomyosin-related kinase A (TrkA), expressed on various types of cancer cells, including those derived from the brain, prostate, breast, and pancreas. NGF contributes to inflammation by acting as a signaling molecule that stimulates immune cells to release cytokines and enhances the sensitivity of sensory nerves, contributing to the perception of pain and hypersensitivity in inflamed tissues. NTs promote tumor growth by stimulating cancer cell proliferation and suppressing apoptosis, which physiologically helps eliminate damaged or unwanted cells from the body. Furthermore, NTs can stimulate the production of pro-angiogenic factors, modulate the tumor microenvironment (TME), and induce the epithelial–mesenchymal transition (EMT), leading to increased cell mobility and invasiveness. This narrative report aims to provide a summary and subsequent review of literature evidence on the role of NGF and its role in regulating tumor cell growth and death as an inflammatory factor.

**Methods:** This is a narrative review that summarizes and synthesizes existing literature evidence on the role of NGF in inflammation and tumor development. The authors comprehensively explored the intricate molecular mechanisms through which inflammation and NGF impact tumor cell growth, survival, and death. They delved into the signaling pathways activated by inflammation and NGF, including the role in the microenvironment, interaction with the immune system, and the various molecules that play a role in tumorigenesis. The review covers a wide range of cancer types, including brain tumors, breast cancer, colorectal cancer, gastric cancer, head and neck cancer, leukemias, liver cancer, lung cancer, ovarian cancer, neuroblastoma, pancreatic cancer, pediatric tumors, prostate cancer, and skin tumors. The authors also discuss the role of NGF receptors (TrkA, p75NTR, sortilin, neuropilin-1) and their expression in cancer, as well as epigenetic modifications and therapeutic potential.

**Key Results:** The review highlights that NGF plays a significant role in various aspects of human health, including its involvement in tumors. Overall, evidence indicates that NGF is unable to generate cell carcinogenesis alone, both in normal neuronal and non-neuronal cells/tissues; however, it could be a major determinant in the case of co-expression with pro-carcinogenic molecules. Depending on the tumor's origin, pro-survival signaling can be facilitated through TrkA and/or p75NTR receptors. In breast cancer, NGF plays a crucial role in stimulating proliferative signaling via TrkA and pro-survival signaling through p75NTR. Furthermore, the activation of p75NTR in breast cancer promotes increased resistance to cell death induced by chemotherapeutic treatments. On the other hand, the role of p75NTR in prostate cells is distinct since p75NTR mediates cell death and acts as a tumor suppressor in the case of normal prostate cells. In prostate cancer, the expression of p75NTR is lost, contributing to tumor progression, death evasion, uncontrolled proliferation, and metastasis to distant sites. NGF plays a significant role in liver cancer progression and metastasis, exerting wide influences on liver cancer cell polarity and motility by regulating signaling pathways involved in cell movement, cytoskeletal organization, and cellular polarity. Heightened NGF disrupts cell polarity, boosts cell movement, triggers changes related to cell transition, rearranges the cell's structural framework, and protects cells from apoptosis and detachment-induced cell death. The review also discusses the role of NGF in the TME, where it can influence the interactions between cancer cells and surrounding stromal cells, immune cells, and other components, contributing to both tumor growth and suppression. NGF can promote endothelial cell proliferation and angiogenesis by stimulating pro-angiogenic factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), interleukin-8 (IL-8), and Matrix Metalloproteinases (MMPs). NGF can also influence the stabilization and activation of hypoxia-inducible factor 1-alpha (HIF-1α). In the context of the TME, increased levels of NGF may be released and engage with immune cells in autocrine or paracrine manners, potentially contributing to the establishment of an immunosuppressive TME, thereby fostering resistance to immunotherapy. NGF may promote the expansion of regulatory T cells (Tregs), which can suppress the activity of cytotoxic T cells and dampen the anti-tumor immune response. NGF can modulate the production of cytokines and chemokines in the TME, influencing the function of immune cells, creating an immunosuppressive milieu, and favoring tumor growth and immune escape. Furthermore, NGF may indirectly induce the expression of immune checkpoint molecules such as the programmed death-1 ligand (PD-L1) on tumor cells or immune cells within the TME, further inhibiting the activity of cytotoxic T cells. NGF can influence the polarization of tumor-associated macrophages (TAMs) within the TME. The review also discusses the role of NGF in Cancer Stem Cell (CSC) metabolism, where NGF can activate signaling pathways associated with stem cell characteristics, such as the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. NGF has been shown to regulate insulin signaling and combat insulin resistance by enhancing glucose uptake, particularly in degenerating neurons, while TrkA can transactivate the insulin receptor (IR) signaling pathway. The review also covers the role of NGF in EMT, where emerging evidence suggests that NGF plays a significant role in triggering the EMT in specific cancer cell types, further enhancing their invasive potential and metastatic capabilities. The review also discusses the role of NGF receptor expression in cancer, including TrkA, TrkB, TrkC, and p75NTR, and their cross-talk. The most common gene variation associated with NTRK in tumors is NTRK gene fusion, which is widely distributed in several cancer types, with the most evident cases being congenital fibrosarcoma and mammary analog secretory carcinoma, with 100% NTRK fusion discovered in these two cancers. The review also discusses the role of epigenetics, where NGF signaling can regulate the expression of DNA methyltransferases (DNMTs) and affect histone modifications, as well as regulate the expression of specific miRNAs. The therapeutic potential of targeting NGF and its receptors is also discussed, with studies on anti-NGF treatments in mouse models showing that NGF impacts tumor progression and metastasis in a temporally dependent manner. The review notes that blocking NGF and its receptors, or the involved pathways, alongside chemotherapy could sensitize cancer cells to chemotherapy, preventing the development of drug resistance.

**Clinical Implications:** The insights gained from unraveling the intricate interactions of NGF, inflammatory molecules, and the TME may pave the way for the development of precision therapies, enabling the exploitation of its dual nature for more effective and personalized cancer interventions. The review suggests that targeting NGF signaling pathways could offer novel therapeutic strategies for cancer treatment, though further research is needed to fully understand the complexities of NGF signaling in different cancer types and to develop effective and safe targeted therapies. The review also highlights the potential of NGF and its receptors as diagnostic and prognostic tools in various cancers, as well as potential therapeutic targets. The paradoxical effects of NGF in cancer, where it can both promote tumor growth and induce apoptosis, underscore the need for context-dependent therapeutic approaches. The review also discusses the potential of using NGF inhibitors to reduce symptomatology (mostly neuropathy) associated with chemotherapy. Overall, the review provides a comprehensive overview of the multifaceted role of NGF as a component of the inflammatory phenomena in tumor cell growth and death, offering new perspectives on its potential as a therapeutic target in cancer treatment.