bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2022‒04‒17
eleven papers selected by
Maksym V. Kopanitsa
The Francis Crick Institute

  1. Nat Commun. 2022 Apr 13. 13(1): 1985
      Neuronal nerve processes in the tumor microenvironment were highlighted recently. However, the origin of intra-tumoral nerves remains poorly known, in part because of technical difficulties in tracing nerve fibers via conventional histological preparations. Here, we employ three-dimensional (3D) imaging of cleared tissues for a comprehensive analysis of sympathetic innervation in a murine model of pancreatic ductal adenocarcinoma (PDAC). Our results support two independent, but coexisting, mechanisms: passive engulfment of pre-existing sympathetic nerves within tumors plus an active, localized sprouting of axon terminals into non-neoplastic lesions and tumor periphery. Ablation of the innervating sympathetic nerves increases tumor growth and spread. This effect is explained by the observation that sympathectomy increases intratumoral CD163+ macrophage numbers, which contribute to the worse outcome. Altogether, our findings provide insights into the mechanisms by which the sympathetic nervous system exerts cancer-protective properties in a mouse model of PDAC.
  2. Int J Mol Sci. 2022 Mar 29. pii: 3775. [Epub ahead of print]23(7):
      α-Synuclein (α-syn) is a protein involved in neuronal degeneration. However, the family of synucleins has recently been demonstrated to be involved in the mechanisms of oncogenesis by selectively accelerating cellular processes leading to cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers, with a specifically high neurotropism. The molecular bases of this biological behavior are currently poorly understood. Here, α-synuclein was analyzed concerning the protein expression in PDAC and the potential association with PDAC neurotropism. Tumor (PDAC) and extra-tumor (extra-PDAC) samples from 20 patients affected by PDAC following pancreatic resections were collected at the General Surgery Unit, University of Pisa. All patients were affected by moderately or poorly differentiated PDAC. The amount of α-syn was compared between tumor and extra-tumor specimen (sampled from non-affected neighboring pancreatic areas) by using in situ immuno-staining with peroxidase anti-α-syn immunohistochemistry, α-syn detection by using Western blotting, and electron microscopy by using α-syn-conjugated immuno-gold particles. All the methods consistently indicate that each PDAC sample possesses a higher amount of α-syn compared with extra-PDAC tissue. Moreover, the expression of α-syn was much higher in those PDAC samples from tumors with perineural infiltration compared with tumors without perineural infiltration.
    Keywords:  Western blotting; electron microscopy; electron-microscopy; neuroinvasion; pancreatic ductal adenocarcinoma; ultrastructural stoichiometry; α-synuclein
  3. FASEB Bioadv. 2022 Apr;4(4): 225-234
      Activation of the sympathetic nervous system releases catecholamines that can interact with β-adrenergic receptors on tumor cells. Preclinical models have shown that the signaling processes initiated by activation of β-adrenergic receptors increase tumorigenesis, stimulate cell proliferation, and inhibit apoptosis. Indeed, preclinical studies have also shown that β-adrenergic blockade can decrease tumor burden. Researchers have been studying the effects of β-adrenergic receptor blockers on tumor cells and how they may slow the progression of melanoma, basal cell carcinoma, and squamous cell carcinoma. Moreover, clinical data have shown improved prognosis in patients with skin cancer who take β-blockers. This review discusses the mechanisms of β-adrenergic signaling in cancer and immune cells, details preclinical models of sympathetic blockade, and considers clinical evidence of the effects of β-adrenergic blockade in skin cancers.
    Keywords:  adrenergic system; basal cell carcinoma; melanoma; skin cancer; squamous cell carcinoma; sympathetic nervous system; β‐adrenergic; β‐adrenergic signaling; β‐blockers
  4. J Gastrointest Cancer. 2022 Apr 11.
      BACKGROUND: Tumor deposits (TDs) are associated with adverse prognostic factors and decreased survival in colon cancer. However, there is no information of their survival impact in rectal cancer with neoadjuvant chemoradiotherapy (n-CRT).METHODS: Retrospective study in 223 patients with rectal cancer with n-CRT. A survival analysis of factors associated with decreased overall survival (OS) including TDs was performed.
    RESULTS: From 223 patients, 131 (58.7%) were men, mean age 59.8 (± 13.06) years, and 42 (18.8%) of them revealed TDs. Survival analysis of TDs showed no association with mortality. Factors associated with decreased 5-year OS were the histologic grade (p = 0.42), perineural invasion (p = 0.001), and mesorectal quality (p = 0.067). Perineural invasion (HR = 2.335, 95% CI = 1.198-4.552) remained as independent factor in the multivariate analysis.
    CONCLUSIONS: TDs were not associated with mortality in rectal cancer patients treated with n-CRT. Factors associated with decreased survival were inadequate mesorectal quality and perineural invasion.
    Keywords:  Mesorectum; Mortality; Rectal adenocarcinoma; Survival; Tumor deposits
  5. J Cancer Res Clin Oncol. 2022 Apr 12.
      PURPOSE: To analyse the risk of inguinal lymph node (ILN) metastases in T1G2 penile cancer stratified by lymphovascular invasion (LVI), perineural invasion (PNI) and tumour size.METHODS: Retrospective study of men with localised T1G2 penile cancer with non-palpable lymph nodes and no local recurrence during follow-up at six European institutional high-volume centres was performed. ILN involvement was defined as cancer detected during ultrasound-guided fine-needle aspiration cytology, core needle biopsy, dynamic sentinel lymph node biopsy, ILN dissection or inguinal recurrence during follow-up. Uni- and multivariable logistic regression analyses were performed.
    RESULTS: In the cohort of 554 men with T1G2 penile cancer, from 6 European institutions, ILN metastases were observed in 46/554 men (8%, 95% confidence interval (CI) 6-11%). Men with both, LVI- and PNI- primary cancers had the lowest risk of ILN involvement (6%) whereas men with LVI + or PNI + showed ILN metastases in 22% and 30%. In multivariable regression, men with LVI + or PNI + had higher odds for ILN metastases compared to men with LVI- and PNI- (OR 3.9, 95% CI 1.6-9.0, p value < 0.01) Tumour size was not associated with ILN risk (OR 1.01 95% CI 0.99-1.04, p = 0.17).
    CONCLUSION: Approximately, one out of ten men with T1G2 overall and one out of four men with either LVI + or PNI + still have ILN metastases despite being clinically node negative. Therefore, invasive ILN staging should strongly be recommended in T1G2 with LVI + or PNI + but importantly, must be discussed in patients with T1G2 with LVI- or PNI-.
    Keywords:  Inguinal lymph node metastases; Lymphovascular invasion; Penile cancer; Perineural invasion
  6. Asian J Surg. 2022 Apr 11. pii: S1015-9584(22)00347-5. [Epub ahead of print]
      BACKGROUND: Gallbladder mucinous adenocarcinoma (GBMAC) is a rare type of gallbladder malignant tumor, whereas little is known regarding the clinicopathological features and surgical outcomes of GBMAC.METHODS: From January 2000 till December 2015, 54 GBMAC patients who underwent curative-intent surgical resection at our institution were retrospectively reviewed. We compared the clinicopathological features and surgical outcomes of these GBMAC patients with a relatively large cohort of surgically resected conventional gallbladder adenocarcinoma (GBAC) patients without existence of mucinous components.
    RESULTS: The clinicopathological features of GBMAC were significantly different from conventional GBAC, including poorer tumor differentiation (P < 0.001), higher CA19-9 levels (P < 0.001), larger tumor sizes (P = 0.020), advanced AJCC tumor stage (P = 0.002), higher frequency of liver parenchyma invasion (P = 0.020), portal vein invasion (P = 0.003), lymph node metastasis (P = 0.016), lympho-vascular invasion (P < 0.001) and perineural invasion (P = 0.025). Relative to conventional GBAC patients, GBMAC patients showed significantly worse overall survival (OS) (29.0 vs 15.0 months; P < 0.001). Multivariate analysis confirmed the surgical margin (P = 0.046), tumor differentiation grade (P = 0.018), lymph node metastasis (P = 0.024), and presence of signet-ring cell component (P = 0.005) as independent prognostic factors influencing OS of patients with GBMAC.
    CONCLUSION: GBMAC always had more aggressive biological behaviors and poor survival outcomes even after curative surgery. GBMAC patients with the presence of signet-ring cell component showed even worse survival outcome.
    Keywords:  Curative-intent resection; Gallbladder adenocarcinoma; Gallbladder mucinous adenocarcinoma; Prognosis
  7. J Gastric Cancer. 2022 Mar;22(1): 24-34
      Purpose: Total gastrectomy (TG) with lymph node (LN) dissection is recommended for early gastric cancer (EGC) but is not indicated for endoscopic resection (ER). We aimed to identify patients who could avoid TG by establishing a scoring system for predicting lymph node metastasis (LNM) in proximal EGCs.Materials and Methods: Between January 2003 and December 2017, a total of 1,025 proximal EGC patients who underwent TG with LN dissection were enrolled. Patients who met the absolute ER criteria based on pathological examination were excluded. The pathological risk factors for LNM were determined using univariate and multivariate logistic regression analyses. A scoring system for predicting LNM was developed and applied to the validation group.
    Results: Of the 1,025 cases, 100 (9.8%) showed positive LNM. Multivariate analysis confirmed the following independent risk factors for LNM: tumor size >2 cm, submucosal invasion, lymphovascular invasion (LVI), and perineural invasion (PNI). A scoring system was created using the four aforementioned variables, and the areas under the receiver operating characteristic curves in both the training (0.85) and validation (0.84) groups indicated excellent discrimination. The probability of LNM in mucosal cancers without LVI or PNI, regardless of size, was <2.9%.
    Conclusions: Our scoring system involving four variables can predict the probability of LNM in proximal EGC and might be helpful in determining additional treatment plans after ER, functioning as a good indicator of the adequacy of treatments other than TG in high surgical risk patients.
    Keywords:  Endoscopic submucosal dissection; Gastrectomy; Lymph node metastasis; Stomach neoplasms
  8. Int J Urol. 2022 Apr 11.
      OBJECTIVES: Nerve sparing may increase positive surgical margin rate during radical prostatectomy. Our objective was to analyze the positive surgical margin rate and location as well as its impact on biochemical recurrence according to nerve sparing procedure in robot-assisted radical prostatectomy.METHODS: We included 814 patients treated with robot-assisted radical prostatectomy between 2009 and 2021, and evaluated the impact of nerve sparing on positive surgical margin and biochemical recurrence using logistic regression and Cox models.
    RESULTS: Unilateral nerve sparing and bilateral nerve sparing were performed in 152 (18.6%) cases and 118 (14.5%) cases, respectively. On multivariable analysis, in addition to nerve sparing, bilateral nerve sparing, but not unilateral nerve sparing was associated with an increased risk of positive surgical margin compared with non-nerve sparing. Positive surgical margin at any location increased the risk of biochemical recurrence. During unilateral nerve sparing, positive surgical margin in nerve sparing side, but not in non-nerve sparing side was associated with increased risk of biochemical recurrence on multivariate analysis.
    CONCLUSIONS: Taken together, surgeons need to notice an increased risk of biochemical recurrence associated with positive surgical margin when performing nerve sparing in robot-assisted radical prostatectomy, and then need to choose the patients suitable for nerve sparing.
    Keywords:  biochemical recurrence; nerve sparing; positive surgical margin; prostate cancer; robot-assisted radical prostatectomy
  9. Neuro Oncol. 2022 Apr 15. pii: noac100. [Epub ahead of print]
      BACKGROUND: Patients with neurofibromatosis type 1 (NF1) develop benign (BPNST), pre-malignant atypical (ANF), and malignant (MPNST) peripheral nerve sheath tumors. Radiological differentiation of these entities is challenging. Therefore, we aimed to evaluate the value of an MRI-based radiomics machine learning classifier for differentiation of these three entities of internal peripheral nerve sheath tumors in NF1 patients.METHODS: MRI was performed at 3T in 36 NF1 patients (20 male; age: 31±11 years). Segmentation of 117 BPNSTs, 17 MPNSTs, and 8 ANFs was manually performed using T2w SPAIR sequences. One hundred seven features per lesion were extracted using PyRadiomics and applied for BPNST vs. MPNST differentiation. A 5-feature radiomics signature was defined based on the most important features and tested for signature-based BPNST vs. MPNST classification (random forest (RF) classification, leave-one-patient-out evaluation). In a second step, signature feature expressions for BPNSTs, ANFs and MPNSTs were evaluated for radiomics-based classification for these three entities.
    RESULTS: The mean AUC for the radiomics-based BPNST vs. MPNST differentiation was 0.94, corresponding to correct classification of on average 16/17 MPNSTs and 114/117 BPNSTs (sensitivity: 94%, specificity: 97%). Exploratory analysis with the 8 ANFs revealed intermediate radiomic feature characteristics in-between BPNST and MPNST tumor feature expression.
    CONCLUSION: In this proof-of-principle study, machine learning using MRI-based radiomics characteristics allows sensitive and specific differentiation of benign and malignant peripheral nerve sheath tumors in NF1 patients. Feature expression of pre-malignant atypical tumors were distributed in-between benign and malignant tumor feature expressions, which illustrates biological plausibility of the considered radiomics characteristics.
    Keywords:  NF1; atypical neurofibroma; machine learning; magnetic resonance imaging; malignant peripheral nerve sheath tumor
  10. Sci Rep. 2022 Apr 12. 12(1): 6094
      Androgen and androgen receptor (AR) targeted therapies are the main treatment for most prostate cancer (PC) patients. Although AR signaling inhibitors are effective, tumors can evade this treatment by transforming to an AR-negative PC via lineage plasticity. OCT1 is a transcription factor interacting with the AR to enhance signaling pathways involved in PC progression, but its role in the emergence of the AR-negative PC is unknown. We performed chromatin immunoprecipitation sequencing (ChIP-seq) in patient-derived castration-resistant AR-negative PC cells to identify genes that are regulated by OCT1. Interestingly, a group of genes associated with neural precursor cell proliferation was significantly enriched. Then, we focused on neural genes STNB1 and PFN2 as OCT1-targets among them. Immunohistochemistry revealed that both STNB1 and PFN2 are highly expressed in human AR-negative PC tissues. Knockdown of SNTB1 and PFN2 by siRNAs significantly inhibited migration of AR-negative PC cells. Notably, knockdown of PFN2 showed a marked inhibitory effect on tumor growth in vivo. Thus, we identified OCT1-target genes in AR-negative PC using a patient-derived model, clinicopathologial analysis and an animal model.
  11. Ann Surg Oncol. 2022 Apr 09.
      PURPOSE: This study aimed to explore the clinical implications and prognostic value of the number of organ/structure invasions (NOI) in patients with thymoma after curative surgical resection.METHODS: We retrospectively analyzed 306 consecutive Japanese patients with thymoma who underwent curative surgical resection. Tumor invasions of pericardium, mediastinal pleura, phrenic nerve, lung, and venous structures were examined histopathologically. Cases were classified into four subgroups according to NOI: group 0, no tumor invasion; group 1, tumor invasion into single organ/structure; group 2, tumor invasion of two organs/structures; group 3, invasion of three or more organs/structures. Associations with NOI and several clinical characteristics and their prognostic significance were analyzed.
    RESULTS: Pleural invasion was found in 100 cases (32.7%), lung invasion in 48 cases (15.7%), pericardial invasion in 46 cases (15%), phrenic nerve invasion in 29 (9.5%), and venous invasion in 22 cases (7.2%). NOI was classed as group 0 in 201 cases (65.0%), group 1 in 42 cases (13.7%), group 2 in 20 cases (6.5%), and group 3 in 43 cases (14.1%). Cases with higher NOI showed significantly worse relapse-free survival (RFS) and overall survival (OS). Cox's proportional hazard model analysis also identified NOI as a prognostic factor affecting RFS and OS.
    CONCLUSIONS: Cases with higher NOI of thymoma after radical surgical resection showed significantly worse recurrence rates and survival.