bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2023‒09‒24
eight papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute

  1. Front Genet. 2023 ;14 1181775
      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.
    Keywords:  bioinformatics; biomarker; cancer; head and neck squamous cell carcinoma; neurodevelopment; pancreatic ductal adenocarcinoma; perineural invasion; stomach adenocarcinoma
  2. Neuro Oncol. 2023 Sep 16. pii: noad175. [Epub ahead of print]
      BACKGROUND: Effective control of brain metastasis remains an urgent clinical need due a limited understanding of the mechanisms driving it. Although the gain of neuro-adaptive attributes in breast-to-brain metastases has been described, the mechanisms that govern this neural acclimation and the resulting brain metastasis competency are poorly understood. Herein, we define the role of neural-specific splicing factor Ser/Arg Repetitive Matrix Protein 4 (SRRM4) in regulating microenvironmental adaptation and brain metastasis colonization in breast cancer cells.METHODS: Utilizing pure neuronal cultures and brain-naïve and patient-derived BM tumor cells, along with in vivo tumor modeling, we surveyed the early induction of mediators of neural acclimation in tumor cells.
    RESULTS: When SRRM4 is overexpressed in systemic breast cancer cells, there is enhanced breast to brain metastasis leading to poorer overall survival in vivo. Concomitantly, SRRM4 knockdown expression does not provide any advantage in CNS metastasis. In addition, reducing SRRM4 expression in breast cancer cells slows down proliferation and increases resistance to chemotherapy. Conversely, when SRRM4/REST4 levels are elevated, tumor cell growth is maintained even in nutrient-deprived conditions. In neuronal co-culture, decreasing SRRM4 expression in breast cancer cells impairs their ability to adapt to the brain microenvironment, while increasing SRRM4/REST4 levels leads to greater expression of neurotransmitter and synaptic signaling mediators and a significant colonization advantage.
    CONCLUSIONS: Collectively, our findings identify SRRM4 as a regulator of brain metastasis colonization, and a potential therapeutic target in breast cancer.
    Keywords:  Breast-to-Brain Metastasis; Cancer neuroscience; REST; REST4; SRRM4
  3. Nature. 2023 Sep 20.
    Keywords:  Cancer; Immunology; Neuroscience
  4. BMC Gastroenterol. 2023 Sep 18. 23(1): 315
      BACKGROUND: Pancreatic cancer is a fatal tumor, and the status of perineural invasion (PNI) of pancreatic cancer was positively related to poor prognosis including overall survival and recurrence-free survival. This study aims to develop and validate a predictive model based on serum biomarkers to accurately predict the perineural invasion.MATERIALS AND METHODS: The patients from No.924 Hospital of PLA Joint Logistic Support Force were included. The predictive model was developed in the training cohort using logistic regression analysis, and then tested in the validation cohort. The area under curve (AUC), calibration curves and decision curve analysis were used to validate the predictive accuracy and clinical benefits of nomogram.
    RESULTS: A nomogram was developed using preoperative total bilirubin, preoperative blood glucose, preoperative CA19-9. It achieved good AUC values of 0.753 and 0.737 in predicting PNI in training and validation cohorts, respectively. Calibration curves showed nomogram had good uniformity of the practical probability of PNI. Decision curve analyses revealed that the nomogram provided higher diagnostic accuracy and superior net benefit compared to single indicators.
    CONCLUSION: The present study constructed and validate a novel nomogram predicted the PNI of resectable PHAC patients with high stability and accuracy. Besides, it could better screen high-risk probability of PNI in these patients, and optimize treatment decision-making.
    Keywords:  Nomogram; Pancreatic head adenocarcinoma; Perineural invasion; Serum indicator; Surgery
  5. BMC Cancer. 2023 Sep 18. 23(1): 797
      BACKGROUND: We aimed to analyze the benefit of adjuvant chemotherapy in high-risk stage II colon cancer patients and the impact of high-risk factors on the prognostic effect of adjuvant chemotherapy.METHODS: This study is a multi-center, retrospective study, A total of 931 patients with stage II colon cancer who underwent curative surgery in 8 tertiary hospitals in China between 2016 and 2017 were enrolled in the study. Cox proportional hazard model was used to assess the risk factors of disease-free survival (DFS) and overall survival (OS) and to test the multiplicative interaction of pathological factors and adjuvant chemotherapy (ACT). The additive interaction was presented using the relative excess risk due to interaction (RERI). The Subpopulation Treatment Effect Pattern Plot (STEPP) was utilized to assess the interaction of continuous variables on the ACT effect.
    RESULTS: A total of 931 stage II colon cancer patients were enrolled in this study, the median age was 63 years old (interquartile range: 54-72 years) and 565 (60.7%) patients were male. Younger patients (median age, 58 years vs 65 years; P < 0.001) and patients with the following high-risk features, such as T4 tumors (30.8% vs 7.8%; P < 0.001), grade 3 lesions (36.0% vs 22.7%; P < 0.001), lymphovascular invasion (22.1% vs 6.8%; P < 0.001) and perineural invasion (19.4% vs 13.6%; P = 0.031) were more likely to receive ACT. Patients with perineural invasion showed a worse OS and marginally worse DFS (hazardous ratio [HR] 2.166, 95% confidence interval [CI] 1.282-3.660, P = 0.004; HR 1.583, 95% CI 0.985-2.545, P = 0.058, respectively). Computing the interaction on a multiplicative and additive scale revealed that there was a significant interaction between PNI and ACT in terms of DFS (HR for multiplicative interaction 0.196, p = 0.038; RERI, -1.996; 95%CI, -3.600 to -0.392) and OS (HR for multiplicative interaction 0.112, p = 0.042; RERI, -2.842; 95%CI, -4.959 to -0.725).
    CONCLUSIONS: Perineural invasion had prognostic value, and it could also influence the effect of ACT after curative surgery. However, other high-risk features showed no implication of efficacy for ACT in our study.
    TRIAL REGISTRATION: This study is registered on, NCT03794193 (04/01/2019).
    Keywords:  Adjuvant chemotherapy; Colon cancer; High-risk pathological features
  6. Int J Surg Case Rep. 2023 Sep 13. pii: S2210-2612(23)00946-X. [Epub ahead of print]111 108817
      INTRODUCTION AND IMPORTANCE: Solitary lymphomas of the peripheral nervous system are very rare and lymphomas of the sciatic nerve are uncommon, especially those arising from the proximal part of the nerve. This case report describes a rare presentation of solitary B cell Non-Hodgkin's Lymphoma arising from the proximal sciatic nerve that was managed via surgical excision.CASE PRESENTATION: A 28-year-old man experienced severe pain, motor and sensory issues in his right lower limb for a year. Magnetic Resonance Imaging identified a malignant peripheral nerve sheath tumour in the sciatic nerve involving S1 and S2 roots. No metastasis was found in CECT scans. Surgical resection via combined inguinal and gluteal approaches was followed by adjuvant chemoradiotherapy. Biopsy revealed diffuse large B-cell Lymphoma, non-Germinal Centre B-cell like subtype. Pain was reduced, and muscle power improved.
    CLINICAL DISCUSSION: Neurolymphomatosis (NL) is a rare condition where lymphoma cells invade nerves. It mostly involves peripheral nerves, particularly the sciatic nerve. Cases often present with painful neuropathy. Treatment varies, with surgery followed by chemotherapy and radiotherapy used in this unique case involving the pelvic sciatic nerve. Individual patient factors guide management due to limited case data.
    CONCLUSION: We present a unique case of neurolymphomatosis involving the proximal sciatic nerve, a rare occurrence. Surgical excision utilized a complex intra-abdominal and perineal approach, unprecedented in this context. This atypical presentation underscores the need to consider such cases in diagnosing unusual sensory motor neuropathies.
    Keywords:  Case report; Diffuse large B-cell Lymphoma; Non-Hodgkin's Lymphoma; Sciatic nerve
  7. J Invest Surg. 2023 Dec;36(1): 2257785
      BACKGROUND: The prognostic significance of neural invasion (NI) in gastric cancer (GC) has not been established. This study is to investigate the characteristic and prognostic value of NI in GC.METHODS: 592 patients who had undergone gastrectomy for GC were retrospectively analyzed. NI was defined when cancer cells infiltrated into the perineurium or neural fascicles by hematoxylin and eosin staining of surgical specimens. NI and the other clinical factors were analyzed.
    RESULTS: NI was detected in 270 of the 592 patients. NI was associated with tumor size, site, depth of invasion, lymph node metastasis, TNM stage, D dissection, tumor differentiation, Lauren classification, and blood vessel invasion. NI was associated with the overall survival. Multivariate analysis indicated that NI was not an independent prognostic factor for total patients, while NI independently predicted prognosis for age < 60 and lymph node metastasis negative patients by subgroup analysis. Concomitant existence of NI with tumor size ≥3cm, TNM stage III, or diffused Lauren classification independently predicted prognosis.
    CONCLUSIONS: The frequency of NI is high in GC patients and increases with disease progression. NI is related to poor survival in GC patients who underwent curative gastrectomy and provides independent prognostic value for young and lymph node metastasis negative patients.
    Keywords:  Gastric cancer; gastrectomy; lymph node negative; neural invasion; prognostic value
  8. Rev Esp Enferm Dig. 2023 Sep 21.
      A 45-year-old male visited our hospital for a medical examination without any clinical complaints. The patient had an gastroscopy, which revealed a 30mm*30mm hemispherical submucosal tumor arising from the lesser curvature of the gastric body , suggesting a gastrointestinal stromal tumor (GIST) as a preoperative diagnosis;Endoscopic resection was determined to be the best choice and the patient underwent a endoscopic full-thickness resection and endoscopic purse-string suture. Except for a slight low fever, the patient was well recovered and was discharged on his 7th post-operation. Pathological analysis and immunohistochemical staining showed fascicular growth of neoplastic Schwann cells and confirmed the diagnosis of gastric schwannoma through high positivity for S-100 protein.