bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2022‒03‒06
twelve papers selected by
Maksym V. Kopanitsa
The Francis Crick Institute

  1. Front Cell Dev Biol. 2022 ;10 766653
      Cancerous invasion of nerves has been reported in a list of malignant tumors as a high-risk pathological feature and marker of poor disease outcome especially in neurotrophic cancers (such as in pancreas and prostate), indicating that although once neglected, nerves could have played a pivotal role in tumorigenesis and cancer progression. In colorectal cancer, perineural invasion, a specific form of tumor-nerve interaction referring to the identification of tumor cells in proximity to the nerve, has been recognized as a strong and independent prognosis predictor; denervation of autonomic nerves and enteric nerves have shown that the existence of these nerves in the gut are accompanied by promoted cancer proliferation, further supporting that nerve is a potential accomplice to shield and nurture tumor cells. However, the precise role of nerve in CRC and the pattern of interaction between CRC cells and nerve has not been unveiled yet. Here we aim to review some basic knowledge of the importance of nerves in CRC and attempt to depict a mechanistic view of tumor-nerve interaction during CRC development.
    Keywords:  colorectal cancer; mechanism; perineural invasion; tumor microenvironment; tumor-nerve interaction
  2. Adv Mater. 2022 Mar 04. e2108653
      The tumor microenvironment is a complex milieu where neurons constitute an important non-neoplastic cell type. From "Cancer Neuroscience", the crosstalk between tumors and neurons favors the rapid growth of both, making the cancer-nerve interaction a reciprocally beneficial process. Thus, the cancer-nerve crosstalk may provide new targets for therapeutic intervention against cancer and cancer-related symptoms. We proposed a nerve-cancer crosstalk blocking strategy for metastatic bone cancer pain treatment, achieved by Mg/Al-layered double hydroxide nanoshells (Mg/Al-LDH) with AZ-23 loaded inside and alendronate (ALD) decorated outside. The pain-causing H+ was rapidly eliminated by LDH, with neurogenesis inhibited by the antagonist AZ-23. As positive feedback, the decreased pain reversed the nerve-to-cancer Ca2+ crosstalk-related cell cycle, dramatically inhibiting tumor growth. All experiments confirmed the improved pain threshold and enhanced tumor inhibition. The study may inspire multidisciplinary researchers to focus on the cancer-nerve crosstalk for treating cancer and accompanied neuropathic diseases. This article is protected by copyright. All rights reserved.
    Keywords:  cancer-nerve crosstalk; layered double hydroxide nanoshells; metastatic bone tumor; pain sensitization
  3. Andrologia. 2022 Mar 01. e14395
      The role of perineural invasion detected by puncture biopsy of prostate cancer remains controversial. We performed a meta-analysis to assess the relationship between positive perineural invasion at prostate biopsy and positive surgical margins (PSM) after radical prostatectomy. We searched a number of relevant electronic databases including Web of Science, Medline, PubMed, Embase, and the Cochrane Library until 31 March 2021. STATA 15.1 software was used to analyse all data for this article. The quality of these studies was assessed by the Newcastle-Ottawa Scale (ranged from 0 to 9 stars). Finally, we selected 13 high-quality studies in our meta-analysis, which contain 8283 patients. Overall pooled analysis proposed that biopsy perineural invasion was related to a higher risk of the positive surgical margins after radical prostatectomy in prostate cancer (RR: 1.73; 95% CI: 1.56-1.92; z = 10.30, p = 0.000). Moreover, the outcomes of the publication bias checkout testified that without significant bias arose (Egger's test: 0.086 > 0.05; Begg's test: 0.59 > 0.05). The existing evidence indicates that higher incidence of positive surgical margins in patients who had perineural invasion was detected in prostate biopsy.
    Keywords:  biopsy perineural invasion; positive surgical margin; prostate cancer; radical prostatectomy
  4. Asian J Surg. 2022 Mar 01. pii: S1015-9584(22)00149-X. [Epub ahead of print]
      BACKGROUND/OBJECTIVE: Pancreatic neuroendocrine tumors (P-NETs) are highly heterogeneous with wide spectrum of biological behaviors and growth patterns. Here, we aimed to assess the impact of tumor grading on P-NETs prognosis and survival outcomes.METHODS: Patients with P-NET were recruited to determine correlations between grades and clinicopathological factors, survival outcomes and prognostic factors.
    RESULT: A total of 152 patients with P-NETs were enrolled. G1 P-NET were associated with significantly lower rates of perineural invasion, lymphovascular invasion, lymph node involvement and distant metastasis. The pancreatic head was the most common location of P-NETs. The 1-year, 5-year and 10-year overall survival rates of the patients were 94.4%, 89.1% and 78.8%, respectively. Majority of pancreatic neuroendocrine carcinoma (P-NEC) were unresectable (90.9%), and P-NECs patients had poor survival rates (1-year, 20% and no 5-year). Male sex, tumor size ≥2.5 cm, perineural invasion, lymph node invasion, metastasis, and advanced stage were significantly associated with poorer survival outcomes. Tumor grade and sex were independent survival predictors. Moreover, tumor grade was the most powerful prognostic factor.
    CONCLUSIONS: Tumor grade, sex, perineural invasion, tumor size, lymph node involvement, metastasis, and stage are survival predictors for patients with P-NETs. Tumor grade is the most powerful independent prognostic factor.
    Keywords:  Grade; Neuroendocrine carcinoma; Neuroendocrine tumor; Prognosis; Survival
  5. J Cell Physiol. 2022 Mar 03.
      Breast cancer is the most common and deadliest type of cancer in women. Stress exposure has been associated with carcinogenesis and the stress released neurotransmitters, noradrenaline and adrenaline, and their cognate receptors, can participate in the carcinogenesis process, either by regulating tumor microenvironment or by promoting systemic changes. This work intends to provide an overview of the research done in this area and try to unravel the role of adrenergic ligands in the context of breast carcinogenesis. In the initiation phase, adrenergic signaling may favor neoplastic transformation of breast epithelial cells whereas, during cancer progression, may favor the metastatic potential of breast cancer cells. Additionally, adrenergic signaling can alter the function and activity of other cells present in the tumor microenvironment towards a protumor phenotype, namely macrophages, fibroblasts, and by altering adipocyte's function. Adrenergic signaling also promotes angiogenesis and lymphangiogenesis and, systemically, may induce the formation of preneoplastic niches, cancer-associated cachexia and alterations in the immune system which contribute for the loss of quality of life of breast cancer patients and their capacity to fight cancer. Most studies points to a major contribution of β2 -adrenoceptor activated pathways on these effects. The current knowledge of the mechanistic pathways activated by β2 -adrenoceptors in physiology and pathophysiology, the availability of selective drugs approved for clinical use and a deeper knowledge of the basic cellular and molecular pathways by which adrenergic stimulation may influence cancer initiation and progression, opens the possibility to use new therapeutic alternatives to improve efficacy of breast cancer treatments.
    Keywords:  adrenoceptors; breast cancer; stress; systemic effects; tumor microenvironment
  6. World J Surg Oncol. 2022 Feb 27. 20(1): 58
      BACKGROUND: To investigate the relationship between tumor deposits (TDs) with the clinicopathological characteristics tumor-infiltrating lymphocytes (TILs) and prognosis of gastric cancer. Further analysis was done on the relationship between the number and maximum diameter of TDs with the clinicopathological characteristics and prognosis of gastric cancer.METHODS: The pathological findings of 369 patients with gastric cancer were retrospectively analyzed to observe the expression of TDs and the levels of stromal TILs. The relationship between TDs, clinicopathological characteristics, and levels of stromal TILs was compared using the chi-square test. Kaplan-Meier was used for survival analysis, and the log-rank test was used to determine the relationship between TDs and disease-free survival, cancer-specific survival, and overall survival. The prognostic value of TDs was assessed using multivariate Cox proportional hazards regression analysis. For further analysis, the optimal cutoff values for the number and maximum diameter of TDs were selected based on the receiver operating characteristic (ROC) curve.
    RESULTS: TDs were significantly associated with sex, lymphovascular invasion, perineural invasion, pathological T,N stage, and clinical stage (all P < 0.05). TILs levels are lower in TDs(+) group and higher in TDs(-) group. Compared with TDs(-) groups, TDs(+) group had poor disease-free survival, cancer-specific survival, and overall survival. TDs are negatively correlated with TILs, and TILs levels are lower in TDs(+) group and higher in TDs(-) group (P < 0.05). The samples are divided into the number of TDs (< 4 and ≥ 4) and the maximum diameter of TDs (< 7 mm and ≥ 7 mm). The number of TDs was significantly associated with pathological N stage (P < 0.05). The maximum diameter of TDs was significantly correlated with Lauren classification (P < 0.05) .TDs ≥ 4 had lower DFS, CSS, and OS (P < 0.05). The maximum diameter of TDs was not statistically significant with prognosis (P > 0.05).
    CONCLUSION: TDs are independent prognosis predictors of gastric cancer. In the tumor microenvironment, TDs and TILs interact with each other to regulate the development of gastric cancer, thus affecting gastric cancer prognosis of patients. The number of TDs ≥ 4 has a worse prognosis compared to the number of TDs < 4.
    Keywords:  Prognosis; Tumor deposits; Tumor-infiltrating lymphocytes
  7. Ann Diagn Pathol. 2022 Feb 24. pii: S1092-9134(22)00032-6. [Epub ahead of print]58 151930
      BACKGROUND AND OBJECTIVE: The use of the tumor microenvironment as a target in creating treatment modalities and as a biomarker in predicting treatment response has become increasingly important. Tumor-infiltrating lymphocytes (TILs), located in the tumor microenvironment, are the fundamental elements of the specific immunological response against tumor cells and have prognostic importance in many types of cancer.MATERIALS AND METHODS: Between January 2010 and June 2021, 350 patients who were operated on in our hospital and met the study criteria were included in the study. TILs and tumor-infiltrating lymphocyte volume (TILV) were evaluated in hematoxylin-eosin sections of the patients.
    RESULTS: Presence of high stromal TILs was associated with improved survival (p = 0.036), distant metastasis (p = 0.009), high nuclear and histological grade (p < 0.001), estrogen receptor (ER) and progesterone receptor (PR) negativity (p < 0.001), high Ki-67 proliferation index (<0.001), HER2 expression (p = 0.026) level, perineural invasion (p = 0.048), adjuvant chemotherapy (p = 0.005) and radiotherapy (p = 0.055) treatment. High TILV was associated with high nuclear and histological grade (p < 0.001), ER and PR negativity (p < 0.001), HER2 positivity (p = 0.013), high Ki-67 proliferation index (p = 0.001) and high tumor size (p = 0.0011). There was no significant relationship between survival (p = 0.343), distant metastasis (p = 0.632), lymph node metastasis (p = 0.141) and sTIL volume.
    CONCLUSION: TILs are an indicator of an anti-tumor immune response, and tumor suppressor efficiency is increased by chemotherapy and immunotherapy treatments. It is one of the factors that determine the success of the treatment. The tumor-infiltrating lymphocyte is an important parameter that can help determine the patient groups to be treated with chemotherapy, prevent unnecessary complications, and be quickly evaluated in all laboratories without any expense.
    Keywords:  Breast; Prognosis; Tumor-infiltrating lymphocyte; Tumor-infiltrating lymphocyte volume
  8. Ann Surg Oncol. 2022 Mar 01.
      BACKGROUND: Limited information is available on the relevant prognostic variables after surgery for patients with pancreatic ductal adenocarcinoma (PDAC) subjected to neoadjuvant chemotherapy (NACT). NACT is known to induce a spectrum of histological changes in PDAC. Different grading regression systems are currently available; unfortunately, they lack precision and accuracy. We aimed to identify a new quantitative prognostic index based on tumor morphology.PATIENTS AND METHODS: The study population was composed of 69 patients with resectable or borderline resectable PDAC treated with preoperative NACT (neoadjuvant group) and 36 patients submitted to upfront surgery (upfront-surgery group). A comprehensive histological assessment on hematoxylin and eosin (H&E) stained sections evaluated 20 morphological parameters. The association between patient survival and morphological variables was evaluated to generate a prognostic index.
    RESULTS: The distribution of morphological parameters evaluated was significantly different between upfront-surgery and neoadjuvant groups, demonstrating the effect of NACT on tumor morphology. On multivariate analysis for patients that received NACT, the predictors of shorter overall survival (OS) and disease-free survival (DFS) were perineural invasion and lymph node ratio. Conversely, high stroma to neoplasia ratio predicted longer OS and DFS. These variables were combined to generate a semiquantitative prognostic index based on both OS and DFS, which significantly distinguished patients with poor outcomes from those with a good outcome. Bootstrap analysis confirmed the reproducibility of the model.
    CONCLUSIONS: The pathologic prognostic index proposed is mostly quantitative in nature, easy to use, and may represent a reliable tumor regression grading system to predict patient outcomes after NACT followed by surgery for PDAC.
  9. PLoS Comput Biol. 2022 Feb 28. 18(2): e1009912
      Accurate quantification of nerves in cancer specimens is important to understand cancer behaviour. Typically, nerves are manually detected and counted in digitised images of thin tissue sections from excised tumours using immunohistochemistry. However the images are of a large size with nerves having substantial variation in morphology that renders accurate and objective quantification difficult using existing manual and automated counting techniques. Manual counting is precise, but time-consuming, susceptible to inconsistency and has a high rate of false negatives. Existing automated techniques using digitised tissue sections and colour filters are sensitive, however, have a high rate of false positives. In this paper we develop a new automated nerve detection approach, based on a deep learning model with an augmented classification structure. This approach involves pre-processing to extract the image patches for the deep learning model, followed by pixel-level nerve detection utilising the proposed deep learning model. Outcomes assessed were a) sensitivity of the model in detecting manually identified nerves (expert annotations), and b) the precision of additional model-detected nerves. The proposed deep learning model based approach results in a sensitivity of 89% and a precision of 75%. The code and pre-trained model are publicly available at
  10. Anticancer Res. 2022 Mar;42(3): 1247-1261
      BACKGROUND/AIM: The aim of the present investigation was to characterize the growth pattern and antigen profile of peripheral nerve sheath tumors (PNST) in a large series of tumors obtained from patients with Neurofibromatosis type 1 (NF1) focusing on morphological characteristics of diffuse plexiform neurofibroma (DPNF).MATERIALS AND METHODS: Tissue micro-array (TMA) analysis was applied to study 520 formalin-fixed, paraffin-embedded human PNST of 385 patients with confirmed NF1 diagnosis. PNST originated from all areas of the body and were classified as cutaneous neurofibroma (CNF, n=114), diffuse neurofibroma (DNF, n=109), DPNF (n=108), plexiform neurofibroma (PNF, n=110), and malignant peripheral nerve sheath tumor (MPNST, n=22). Histomorphology and antigen expression patterns of the tumors were determined [S100, epithelial membrane antigen (EMA), CD90, mast cell tryptase, and neurofilament].
    RESULTS: Benign PNST showed significantly more S100-positive tumor cells than MPNST (p<0.001). EMA expression was most pronounced in perineurium of DPNF. The number of mast cells in CNF, DNF and DPNF was significantly higher compared to PNF and MPNST (p<0.001 for both comparisons, Mann-Whitney U-test).
    CONCLUSION: DPNF show some distinct cellular characteristics. A high number of EMA positive cells possibly indicates the dissemination of perineural cells to the surrounding tissue. Concerning mast cell density, DPNF resemble DNF and CNS rather than PNF. Close contact of tumor cells in DPNF, DNF and CNF with the immune system is a prerequisite for permanent immunological reactions in contrast to PNF in which tumor cells are partitioned from the immune system by the perineurium and blood-nerve barrier of blood vessels. It is assumed that these morphological distinctions may reflect in part the biological differences between the entities. While PNF is a known precancerous stage in NF1 patients, DPNF are not rated as such. Furthermore, the morphologic differences between benign nerve sheath tumors may be important for the efficacy of drugs to access tumor cells.
    Keywords:  Neurofibromatosis type 1; classification; diffuse plexiform neurofibroma; neurofibroma; plexiform neurofibroma
  11. Front Pharmacol. 2022 ;13 823132
      Cannabinoid-based therapies are increasingly being used by cancer patients to treat chemotherapy-induced nausea and vomiting. Recently, cannabinoids have gained increased attention for their effects on cancer growth. Indeed, the effect of CB2 (JWH-015, JWH-133) agonists on breast cancer models have shown to reduce the size of breast cancer tumors. However, these studies assessing breast cancer progression were using CB2 agonist administered early into the cancer progression therefore assessing their effects on already established tumors is a critical need. In our study, we evaluate tumor growth using an ectopic xenograft ovarian (SKOV-3 and OVCAR-5) cancer model. The impact of chronic (30 days) administration of CB2 (JWH-133) agonist will be evaluated and started on 30 days of ectopic ovarian tumors. We will then evaluate and determine the mechanisms involved in ovarian cancer tumor growth by measuring levels of anandamide and 2-arachidonoyl glycerol as well as protein levels of CB1, CB2, ERα, ERβ, GPER, TNFα, IL-1β and IL-6 in ovarian and tumor tissues. Our results demonstrate a significant increase in ectopic ovarian tumor growth following chronic administration of JWH-133. Ovarian cancer tumor tissues chronically (30 days) treated with JWH-133 in comparison to vehicle treated groups showed an increase in endocannabinoid (AEA and 2-AG) and protein (CB2 and TNFα) levels with a decrease in GPER protein levels. Interestingly, our study emphasizes the importance of studying the impact of cannabinoid compounds on already established tumors to improve our understanding of cannabinoid-based therapies and, therefore better address clinical needs in cancer patients.
    Keywords:  2-arachidnoylglycerol; CB2 cannabinoid agonist; JWH-133; anandamide; ovarian cancer; tumor growth
  12. Front Oncol. 2022 ;12 795864
      The relationship between the anesthetic technique and cancer recurrence has not yet been clarified in cancer surgery. Surgical stress and inhalation anesthesia suppress cell-mediated immunity (CMI), whereas intravenous (IV) anesthesia with propofol and regional anesthesia (RA) are known to be protective for CMI. Surgical stress, general anesthesia (GA) with inhalation anesthesia and opioids contribute to perioperative immunosuppression and may increase cancer recurrence and decrease survival. Surgical stress and GA activate the hypothalamic-pituitary-adrenal axis and release neuroendocrine mediators such as cortisol, catecholamines, and prostaglandin E2, which may reduce host defense immunity and promote distant metastasis. On the other hand, IV anesthesia with propofol and RA with paravertebral block or epidural anesthesia can weaken surgical stress and GA-induced immunosuppression and protect the host defense immunity. IV anesthesia with propofol and RA or in combination with GA may reduce cancer recurrence and improve patient survival compared to GA alone. We review the current status of the relationship between anesthesia and breast cancer recurrence using retrospective and prospective studies conducted with animal models and clinical samples, and discuss the future prospects for reducing breast cancer recurrence and improving survival rates in breast cancer surgery.
    Keywords:  anesthetic technique; breast cancer; immune response; recurrence; survival