背景：在体内包括胰腺、头颈、胃、前列腺、乳腺和结直肠癌在内的多种实体肿瘤中，肿瘤和神经的高密度以及通过神经传播（神经周界侵犯-PNI）的情况已得到广泛报道。肿瘤神经切除术可改善疾病预后，说明阻断神经-肿瘤交流可能是一种新的治疗策略。然而，目前仍对其分子机制了解甚少。因此，本研究旨在确定神经-肿瘤相互作用的分子途径，并确定与PNI相关癌症之间的共同分子特征。 结果：通过分析头颈鳞状细胞癌（HNSCC）、胰腺癌和胃癌（STAD）的基因表达综合数据库，筛选出差异表达基因（DEGs）。结果显示，细胞外基质成分高度失调。为了丰富与PNI相关的途径，分析了之前与STAD以及2个HNSCC研究中与PNI状态相关联的基因。结果发现，神经发育相关基因富集在PNI中。在未按PNI分离肿瘤样本的数据集中，神经发育途径占差异表达基因的12%-16%。进一步的研究发现，轴突导向基因在所有研究的癌症中存在普遍失调。通过检查同源基因，发现在所有研究的所有癌症中，至少有一种家族成员受到几个轴突导向途径的影响。总共有17个不同的轴突导向基因家族受到干扰，包括ephrin-Eph、semaforin-neuropilin/plexin和slit-robo途径。通过使用The Cancer Genome Atlas验证了这些发现，并与其他高发PNI的癌症如结肠癌、胆管癌、前列腺癌和乳腺癌进行了交叉参考。生存分析表明，神经发育基因家族的表达水平影响疾病生存。 结论：这些数据突出了肿瘤作为神经趋向和神经可塑性信号源的重要性，这是癌症的一个共同特征。分析支持了神经发育程序失调是与PNI相关的共同特征的假设。此外，数据表明不同的癌症可能已演化出采用不同的遗传策略来干扰相同途径。总的来说，这些发现为癌症管理的新型治疗提供了潜在的可靶向药物，并提供了多癌种分子生物标志物。 版权所有 © 2023 González-Castrillón、Wurmser、Öhlund和Wilson。

Background: High nerve density in tumors and metastasis via nerves (perineural invasion-PNI) have been reported extensively in solid tumors throughout the body including pancreatic, head and neck, gastric, prostate, breast, and colorectal cancers. Ablation of tumor nerves results in improved disease outcomes, suggesting that blocking nerve-tumor communication could be a novel treatment strategy. However, the molecular mechanisms underlying this remain poorly understood. Thus, the aim here was to identify molecular pathways underlying nerve-tumor crosstalk and to determine common molecular features between PNI-associated cancers. Results: Analysis of head and neck (HNSCC), pancreatic, and gastric (STAD) cancer Gene Expression Omnibus datasets was used to identify differentially expressed genes (DEGs). This revealed extracellular matrix components as highly dysregulated. To enrich for pathways associated with PNI, genes previously correlated with PNI in STAD and in 2 HNSCC studies where tumor samples were segregated by PNI status were analyzed. Neurodevelopmental genes were found to be enriched with PNI. In datasets where tumor samples were not segregated by PNI, neurodevelopmental pathways accounted for 12%-16% of the DEGs. Further dysregulation of axon guidance genes was common to all cancers analyzed. By examining paralog genes, a clear pattern emerged where at least one family member from several axon guidance pathways was affected in all cancers examined. Overall 17 different axon guidance gene families were disrupted, including the ephrin-Eph, semaphorin-neuropilin/plexin, and slit-robo pathways. These findings were validated using The Cancer Genome Atlas and cross-referenced to other cancers with a high incidence of PNI including colon, cholangiocarcinoma, prostate, and breast cancers. Survival analysis revealed that the expression levels of neurodevelopmental gene families impacted disease survival. Conclusion: These data highlight the importance of the tumor as a source of signals for neural tropism and neural plasticity as a common feature of cancer. The analysis supports the hypothesis that dysregulation of neurodevelopmental programs is a common feature associated with PNI. Furthermore, the data suggested that different cancers may have evolved to employ alternative genetic strategies to disrupt the same pathways. Overall, these findings provide potential druggable targets for novel therapies of cancer management and provide multi-cancer molecular biomarkers.Copyright © 2023 González-Castrillón, Wurmser, Öhlund and Wilson.