Sahadev A. Shankarappa

The tumor microenvironment (TME) is a complex ecosystem composed of cancer cells, stromal components, immune infiltrates, and neural elements. The presence and growth of nerves within or in close association with tumor tissue, a phenomenon known as tumor innervation, has long been observed. However, recent evidence supports a more active role for peripheral nerves in regulating cancer growth, metastasis, and therapeutic resistance. What remains underappreciated is the reciprocal influence of cancer cells on the nervous system. Accumulating data indicate that cancer cells remodel adjacent nerve terminals, triggering structural, neurochemical, bioelectrical, and transcriptional changes in a tumour‐type‐specific manner. These adaptations resemble pathways observed in nerve regeneration and suggest a tightly regulated, bidirectional signaling axis between cancer and nerves. In this review, we systematically consolidate emerging literature describing these nerve adaptations and categorize them across multiple levels, from morphological remodeling and neurotransmitter shifts to bioelectrical signaling and neuroimmune crosstalk. We highlight the central role of the tumor secretome in mediating nerve‐cancer communication and emphasize how neural elements actively shape tumor behavior. By consolidating and critically examining findings across diverse cancer models and experimental systems, this review provides a mechanistic framework for understanding neural remodeling in cancer and identifies key areas for future investigation, including the potential of targeting nerve–tumor interactions as a therapeutic strategy.

Introduction: The tumor microenvironment (TME) is a heterogeneous system composed of cancer cells, stromal cells, immune cells, and neural elements. Recent evidence highlights the crucial role of peripheral and autonomic nerve terminals in regulating tumor growth, metastasis, and therapy resistance. However, what remains relatively underexplored is the reciprocal influence of cancer on the nervous system itself. Emerging evidence suggests that cancer cells induce structural, functional, and molecular adaptations in adjacent nerve terminals, pointing to a bidirectional and adaptive communication within the TME. Understanding these nerve adaptations is essential to fully delineate the neurobiology of cancer and identify novel therapeutic targets.Objective: The objective of this scoping review is to systematically map existing literature on cancer-induced adaptations in the nervous system and to explore current understanding of chemical signaling and morphological changes in neural elements within the TME.Methods: We conducted a comprehensive literature search across databases including MEDLINE, Ovid Embase, and Web of Science Core Collection. Additionally, gray literature sources such as Google Scholar (screening up to 20 pages), Elicit, and Connected Papers were explored. We included studies involving animal models, primary and immortalized cell lines, and patient-derived observational studies that focused on cancer-neuron interactions and subsequent neural adaptations. Only articles published in English were considered, with no restrictions on publication date. Article selection and data extraction were performed independently by two reviewers, and findings were reported descriptively.Conclusion: By mapping the current landscape of research on cancer-induced nerve adaptations, this review aims to consolidate fragmented evidence and provide insights into the bidirectional crosstalk between nerves and tumors. Through this review, we aim to enhance current understanding of nerve adaptations in the TME and encourage further exploration in this emerging area of cancer research.

The barrier function of the epidermis poses a significant challenge to nanoparticle-mediated topical delivery. A key factor in this barrier function is the thickness of the stratum corneum (SC) layer within the epidermis, which varies across different anatomical sites. The epidermis from the palms and soles, for instance, have thicker SC compared to those from other areas. Previous studies have attempted to bypass the SC layer for nanoparticle penetration by using physical disruption; however, these studies have mostly focused on non-thick skin. In this study, we investigate the role of SC-disrupting mechano-physical strategies (tape-stripping and microneedle abrasion) on thick and thin skin, in allowing transdermal penetration of topically applied nanoparticles using an ex-vivo skin model from rat. Our findings show that tape-stripping reduced the overall thickness of SC in thick skin by 87%, from 67.4 ± 17.3 μm to 8.2 ± 8.5 μm, whereas it reduced thin skin SC by only 38%, from 9.9 ± 0.6 μm to 6.2 ± 3.2 μm. Compared to non-thick skin, SC disruption in thick skin resulted in higher nanoparticle diffusion. Tape-stripping effectively reduces SC thickness of thick skin and can be potentially utilized for enhanced penetration of topically applied nanoparticles in skin conditions that affect thick skin.

The natural barrier function of the epidermal skin layer poses a significant challenge to nanoparticle-mediated topical delivery. A key factor in this barrier function is the thickness of the stratum corneum (SC) layer within the epidermis, which varies across different anatomical sites. The epidermis from the palms and soles, for instance, have thicker SC compared to those from other areas. Previous studies have attempted to bypass the SC layer for nanoparticle penetration by using physical disruption; however, these studies have mostly focused on non-thick skin. In this study, we investigate the role of mechano-physical strategies on SC of thick skin for transdermal nanoparticle penetration. We characterize and compare two mechano-physical strategies, namely tape-stripping and microneedle abrasion, for epidermal disruption in both thick and thin skin. Furthermore, we examine the impact of SC disruption in thick and thin skin on the penetration of topically applied 100 nm sized polystyrene nanoparticles using an ex-vivo model. Our findings show that tape-stripping reduced the overall thickness of SC in thick skin by 87%, from 67.4 ± 17.3 µm to 8.2 ± 8.5 µm, whereas it reduced thin skin SC by only 38%, from 9.9 ± 0.6 µm to 6.2 ± 3.2 µm. Compared to non-thick skin, SC disruption in thick skin resulted in higher nanoparticle diffusion. Tape-stripping effectively reduces SC thickness of thick skin and can be potentially utilized for enhanced penetration of topically applied nanoparticles in skin conditions that affect thick skin.

The role of the nervous system in aiding cancer progression and metastasis is an important aspect of cancer pathogenesis. Interaction between cancer cells and neurons in an in vitro platform is a simple and robust method to further understand this phenomenon. In our study, we aimed to examine in vitro reciprocal effect between breast cancer cells and cancer‐sensitized peripheral primary sensory neurons. Secretome obtained from either cultured DRG neurons from tumor‐burdened rats, or MRMT1 breast cancer cells were used to study neuronal and cancer cell reciprocity. We utilized neurite analysis, modified cell migration assay and cell signaling pathway inhibitors to determine neurite growth patterns and cell migration in PC12/DRG neurons and MRMT1 cells, respectively. MRMT1 secretome was found to induce significant neurite outgrowth in PC12 and primary sensory neurons. Secretome‐induced neurite growth in PC12 cells was partly mediated by PI3K and ERK pathways, but not by adenylyl cyclase. Conversely, secretome from tumor‐sensitized sensory neuron cultures induced increased rate of migration in cultured MRMT1 cells. Results from our study provide additional support to the hypothesis that both breast cancer cells and nerve terminals secrete signaling messengers that have a reciprocal effect on each other.

Nerve axonal injury and associated cellular mechanisms leading to peripheral nerve damage are important topics of research necessary for reducing disability and enhancing quality of life. Model systems that mimic the biological changes that occur during human nerve injury are crucial for the identification of cellular responses, screening of novel therapeutic molecules, and design of neural regeneration strategies. In addition to in vivo and mathematical models, in vitro axonal injury models provide a simple, robust, and reductionist platform to partially understand nerve injury pathogenesis and regeneration. In recent years, there have been several advances related to in vitro techniques that focus on the utilization of custom-fabricated cell culture chambers, microfluidic chamber systems, and injury techniques such as laser ablation and axonal stretching. These developments seem to reflect a gradual and natural progression towards understanding molecular and signaling events at an individual axon and neuronal-soma level. In this review, we attempt to categorize and discuss various in vitro models of injury relevant to the peripheral nervous system and highlight their strengths, weaknesses, and opportunities. Such models will help to recreate the post-injury microenvironment and aid in the development of therapeutic strategies that can accelerate nerve repair.

Accessing the peripheral nervous system (PNS) by topically applied nanoparticles is a simple and novel approach with clinical applications in several PNS disorders. Skin is richly innervated by long peripheral axons that arise from cell bodies located distally within ganglia. In this study we attempt to target dorsal root ganglia (DRG) neurons, via their axons by topical application of lectin-functionalized gold nanoparticles (IB4-AuNP). In vitro, 140.2 ± 1.9 nm IB4-AuNP were found to bind both axons and cell bodies of DRG neurons, and AuNP applied at the axonal terminals were found to translocate to the cell bodies. Topical application of IB4-AuNP on rat hind-paw resulted in accumulation of three to fourfold higher AuNP in lumbar DRG than in contralateral control DRGs. Results from this study clearly suggest that topically applied nanoparticles with neurotropic targeting ligands can be utilized for delivering nanoparticles to neuronal cell bodies via axonal transport mechanisms.

Microparticle shape, as a tunable design parameter, holds much promise for controlling drug-release kinetics from polymeric microparticulate systems. In this study we hypothesized that the intensity and duration of a local nerve block can be controlled by administration of bupivacaine-loaded stretch-induced anisotropic poly(lactic-co-glycolic acid) microparticles (MPs). MPs of size 27.3 ± 8.5 μm were synthesized by single emulsion method and subjected to controlled stretching force. The aspect ratio of the anisotropic–bupivacaine MPs was quantified, and bupivacaine release was measured in vitro. The anisotropic MPs were administered as local nerve block injections in rats, and the intensity and duration of local anesthesia was measured. Bupivacaine-loaded anisotropic MPs used in this study were ellipsoid in shape and exhibited increased surface pores in comparison to spherical MPs. Anisotropic MPs exhibited a higher rate of bupivacaine release in vitro, and showed significantly (P < 0.05) stronger sensory nerve blocking as compared to spherical bupivacaine MPs, even though the duration of the nerve block remained similar. This study demonstrates the utility of stretch-induced anisotropic MPs in controlling drug release profiles from polymeric MPs, under both in vitro and in vivo conditions. We show that shape, as a tunable design parameter, could play an important role in engineering drug-delivery systems.