bims-netuvo 2022-06-12 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2022–06–12
ten papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute

Peak density of immature nerve cells occurs with high-grade dysplasia in intraductal papillary mucinous neoplasms of the pancreas.
High nerve density in breast cancer is associated with poor patient outcome.
Contrast-enhanced CT based radiomics in the preoperative prediction of perineural invasion for patients with gastric cancer.
The Role of Schwann Cells in Cancer.
An Investigation of the Pathology Report of Bladder Cancer Patients with Radical Cystectomy in Southern Iran, 2013-2018: A Cross-Sectional Study.
Expression of M3 muscarinic acetylcholine receptors in gastric cancer.
Sleep Disruption and Cancer: Chicken or the Egg?
Stem Cell-Based Models for Studying the Effects of Cancer and Cancer Therapies on the Peripheral Nervous System.
Stress-induced epinephrine promotes epithelial-to-mesenchymal transition and stemness of CRC through the CEBPB/TRIM2/P53 axis.
Pancreatic Cancer and Microenvironments: Implications of Anesthesia.

J Pathol. 2022 Jun 10.

Peak density of immature nerve cells occurs with high-grade dysplasia in intraductal papillary mucinous neoplasms of the pancreas.

Vincent Quoc-Huy Trinh, Joseph Thomas Roland, Jahg Wong, Frank Revetta, Krutika Patel, Chanjuan Shi, Kathleen E DelGiorno, Bruce D Carter, Marcus Chuan Beng Tan.

  The development of neural structures within tumors is now considered vital for carcinogenesis. However, the time course of this development in human pre-invasive neoplasia has been incompletely described. Therefore, we performed a detailed analysis of nerves across the neoplastic spectrum in resected intraductal papillary mucinous neoplasms (IPMN) of the pancreas. Histology and multiplexed immunochemistry demonstrated that nerve density increased from low grade (LG) to high grade dysplasia (HG) but did not further increase once invasive IPMN (INV IPMN) was present. Higher nerve density correlated with increasing expression of nerve growth factor (NGF) by the tumor cells. Intra-tumoral nerves were immature and lacked markers of sympathetic, parasympathetic, and sensory lineages. Here, we show for the first time the presence of neural precursor cells (NPCs) within the stroma of pancreatic tumors. The density of these doublecortin (DCX)-positive NPCs increased from LG to HG, but not from HG to INV IPMN. We conclude that peak neural density of tumors is reached in high grade dysplasia (often termed carcinoma in situ) rather than after invasion. These findings suggest that nerve-tumor interactions are important in IPMN progression and may serve as the basis for future mechanistic studies and novel therapeutic modalities. This article is protected by copyright. All rights reserved.

Keywords:  Intraductal Papillary Mucinous Neoplasms; Neoplasms; Nerves; Neural Factors; Pancreas

DOI:  https://doi.org/10.1002/path.5978
FASEB Bioadv. 2022 Jun;4(6): 391-401

High nerve density in breast cancer is associated with poor patient outcome.

Dong Li, Li Na Hu, Si Min Zheng, Ting La, Li Yuan Wei, Xiao Jun Zhang, Zhen Hua Zhang, Jun Xing, Li Wang, Ruo Qi Li, Qin Zhu, Rick F Thorne, Yu Chen Feng, Hubert Hondermarck, Xu Dong Zhang, Li Li, Jin Nan Gao.

  Active crosstalk between the nervous system and breast cancer cells has been experimentally demonstrated in vitro and in animal models. However, low frequencies of peripheral nerve presence in human breast cancers reported in previous studies (~30% of cases) potentially negate a major role of the nervous system in breast cancer development and progression. This study aimed to clarify the incidence of nerves within human breast cancers and to delineate associations with clinicopathological features. Immunohistochemical staining was conducted in formalin-fixed paraffin-embedded breast cancer tissue sections using antibodies against the pan-neuronal markers protein gene product 9.5 and growth-associated protein 43, and the sympathetic nerve-specific marker tyrosine hydroxylase. Nerve trunks and isolated nerve fibers were quantitated. The chi-squared test was used to determine the associations between nerve counts and clinicopathological parameters. The log-rank test was used to compare differences in patient progression-free survival (PFS) and overall survival (OS). The overall frequency of peripheral nerves in breast cancers was 85%, a markedly higher proportion than reported previously. Of note, most nerves present in breast cancers were of the sympathetic origin. While high density of nerve trunks or isolated nerve fibers was associated with poor PFS and OS of patients, high nerve trunk density appeared also to predict poor patient PFS independently of lymph node metastasis. Innervation of breast cancers is a common event correlated with poor patient outcomes. These findings support the notion that the nervous system plays an active role in breast cancer pathogenesis.

Keywords:  breast cancer; cancer neuroscience; innervation; nerves; tumor microenvironment

DOI:  https://doi.org/10.1096/fba.2021-00147
Eur J Radiol. 2022 Jun 03. pii: S0720-048X(22)00243-1. [Epub ahead of print]154 110393

Contrast-enhanced CT based radiomics in the preoperative prediction of perineural invasion for patients with gastric cancer.

Haoze Zheng, Qiao Zheng, Mengmeng Jiang, Ce Han, Jinling Yi, Yao Ai, Congying Xie, Xiance Jin.

   PURPOSE: To investigate the feasibility and accuracy of radiomics models based on contrast-enhanced CT (CECT) in the prediction of perineural invasion (PNI), so as to stratify high-risk recurrence and improve the management of patients with gastric cancer (GC) preoperatively.
METHODS: Total of 154 GC patients underwent D2 lymph node dissection with pathologically confirmed GC and preoperative CECT from an open-label, investigator-sponsored trial (NCT01711242) were enrolled. Radiomics features were extracted from contoured images and selected using Mann-Whitney U test and the least absolute shrinkage and selection operator (LASSO) after inter-class correlation coefficient (ICC) analysis. Models based on radiomics features (R), clinical factors (C) and combined parameters (R + C) were built and evaluated using Support Vector Machine (SVM) and logistic regression to predict the PNI for patients with GC preoperatively.
RESULTS: Total of 11 radiomics features were selected for final analysis, along with two clinical factors. The area under curve (AUC) of models based on R, C, and R + C with logistic regression and SVM were 0.77 vs. 0.83, 0.71 vs.0.70, 0.86 vs. 0.90, and 0.73 vs.0.80, 0.62 vs. 0.64, 0.77 vs. 0.82 in the training and testing cohorts, respectively. SVM(R + C) achieved a best AUC of 0.82(0.69-0.94) in the test cohorts with a sensitivity, specificity and accuracy of 0.63, 0.91, and 0.77, respectively.
CONCLUSIONS: The performance of these models indicates that radiomics features alone or combined with clinical factors provide a feasible way to classify patients preoperatively and improve the management of patients with GC.

Keywords:  Area under curve; Contrast-enhanced CT; Gastric cancer; Perineural invasion; Radiomics

DOI:  https://doi.org/10.1016/j.ejrad.2022.110393
Adv Biol (Weinh). 2022 Jun 04. e2200089

The Role of Schwann Cells in Cancer.

Sylvie Deborde, Richard J Wong.

  Schwann cells (SCs) are the most abundant cell type in the nerves in the peripheral nervous system and compose a family of subtypes that are endowed with a variety of different functions. SCs facilitate the transmission of neural impulses, provide nutrients and protection for neurons, guide axons in nerve repair, and regulate immune functions. In the context of cancer, recent studies have revealed an active role of SCs in promoting cancer cell invasion, modulating immune responses, and transmitting pain sensation.

Keywords:  Schwann cells; cancer; nerve repair; reprogramming

DOI:  https://doi.org/10.1002/adbi.202200089
Med J Islam Repub Iran. 2021 ;pii: 176. [Epub ahead of print]35

An Investigation of the Pathology Report of Bladder Cancer Patients with Radical Cystectomy in Southern Iran, 2013-2018: A Cross-Sectional Study.

Ali Ariafar, Shahryar Zeighami, Mehdi Salehipour, Faisal Ahmed, Sara Saeedi, Hossein-Ali Nikbakht.

  Background: The oncological outcomes of bladder cancer are directly associated with disease pathology and surgical technique. Therefore, we investigated the pathologic factors of radical cystectomy (RC) specimens. Methods: In this retrospective study, 365 patients who underwent RC between March 2013 to March 2018 in hospitals affiliated to Shiraz University were enrolled. The patients' clinicopathological parameters, such as tumor type, tumor grade, carcinoma in situ, lymph node (LN) involvement, lymphovascular invasion (LVI), perineural invasion (PNI), and age, were recorded from their pathology reports. For comparison of variables, an independent t test was used. P < 0.05 was regarded as significant. The statistical software SPSS version 22 was used to examine the data. Results: The participants' mean age was 64.52 ± 11.54 years, and 320 (87.7%) patients were men and 45 (12.3%) were women. The mean dissected LN was 9.69 ± 8.70 nodes and 1.06 ±3.49 of the dissected LNs were involved by tumor. PNI and perivesical invasion were presented in 148 (40.5%) and 96 (26.3%) patients, respectively. Ureteral, urethral, and prostate involvements were seen in 23 (6.3%), 50 (13.7%), and 66 (18.1%) patients. Most patients had pathologic tumor stage 2 (36.4%). Factors such as LVI, PNI, perivesical invasion, and prostate involvement, were strongly correlated with positive LN (P ≤ 0.05). Conclusion: The examination of the RC specimen is critical for patient care, outcome, and justification of adjuvant therapy. Factors such as LVI, perineural invasion, perivesical invasion, and prostate involvement were strongly correlated with positive LN.

Keywords:   Bladder Cancer ; Lymph Node ; Pathology ; Radical Cystectomy

DOI:  https://doi.org/10.47176/mjiri.35.176
Rom J Morphol Embryol. 2021 Oct-Dec;62(4):62(4): 1001-1010

Expression of M3 muscarinic acetylcholine receptors in gastric cancer.

Alina Maria Mehedinţeanu, Cecil Sorin Mirea, Puiu Olivian Stovicek, Michael Schenker, Marius Ionuţ Stancu, Ana Maria Ciurea, Liliana Streba, Anca Maria Istrate-Ofiţeru, Teodor Nicuşor Sas, Cristin Constantin Vere.

INTRODUCTION: Gastric cancer represents a real public health problem as far as incidence, aggressiveness and unfavorable prognosis are concerned. The autonomous nervous system might be one of the major factors involved in the onset, progression, and metastasis, both sympathetically and parasympathetically. The increased activation of the M3 muscarinic acetylcholine receptors (mAChRs) triggers pro-oncogenic mechanisms, especially at a gastric level, through the activation of the Hippo signaling pathway and the increase of the nerve growth factor.
PATIENTS, MATERIALS AND METHODS: In this study, biopsy or postoperative gastric resection pieces have been evaluated by histopathological (HP) and immunohistochemical (IHC) examination in a group of 77 gastric patients and 23 patients without an oncological diagnosis. To quantify the IHC signal, also considering the HP aspect, light microscopy images were obtained.
RESULTS: The M3 mAChR expression analysis has been correlated with the different gastric adenocarcinoma differentiation degrees (G1-G3). M3 mAChR presence has been observed also in the non-malignant gastric tissue, but it was significantly increased in the tumor tissue. The highest receptor expression was recorded in patients with a poorly-differentiated (G3) adenocarcinoma, these expressions decreasing with the increase of the differentiation degree towards moderately-differentiated (G2) and well-differentiated (G1).
CONCLUSIONS: Surgical or pharmacological parasympathetic activity inhibition could decrease the development and progression of gastric tumors and could improve the gastric cancer patient's prognosis.

DOI: https://doi.org/10.47162/RJME.62.4.12
Front Neurosci. 2022 ;16 856235

Sleep Disruption and Cancer: Chicken or the Egg?

Adrian Berisha, Kyle Shutkind, Jeremy C Borniger.

  Sleep is a nearly ubiquitous phenomenon across the phylogenetic tree, highlighting its essential role in ensuring fitness across evolutionary time. Consequently, chronic disruption of the duration, timing, or structure of sleep can cause widespread problems in multiple physiological systems, including those that regulate energy balance, immune function, and cognitive capacity, among others. Many, if not all these systems, become altered throughout the course of cancer initiation, growth, metastatic spread, treatment, and recurrence. Recent work has demonstrated how changes in sleep influence the development of chronic diseases, including cancer, in both humans and animal models. A common finding is that for some cancers (e.g., breast), chronic disruption of sleep/wake states prior to disease onset is associated with an increased risk for cancer development. Additionally, sleep disruption after cancer initiation is often associated with worse outcomes. Recently, evidence suggesting that cancer itself can affect neuronal circuits controlling sleep and wakefulness has accumulated. Patients with cancer often report difficulty falling asleep, difficulty staying asleep, and severe fatigue, during and even years after treatment. In addition to the psychological stress associated with cancer, cancer itself may alter sleep homeostasis through changes to host physiology and via currently undefined mechanisms. Moreover, cancer treatments (e.g., chemotherapy, radiation, hormonal, and surgical) may further worsen sleep problems through complex biological processes yet to be fully understood. This results in a "chicken or the egg" phenomenon, where it is unclear whether sleep disruption promotes cancer or cancer reciprocally disrupts sleep. This review will discuss existing evidence for both hypotheses and present a framework through which the interactions between sleep and cancer can be dissociated and causally investigated.

Keywords:  HPA axis; anti-tumor immunity; cancer; hypocretin/orexin; inflammation; sleep disruption; stress; sympathetic nervous system

DOI:  https://doi.org/10.3389/fnins.2022.856235
Adv Biol (Weinh). 2022 Jun 04. e2200009

Stem Cell-Based Models for Studying the Effects of Cancer and Cancer Therapies on the Peripheral Nervous System.

Mikayla N Richter, Faranak Fattahi.

  In recent years, the complexity of cancer and cancer therapies and their interactions with the peripheral nervous system have come into focus, but limitations in experimental models have remained a significant challenge in the field. As evidence, there are currently no therapies approved that target cancer-peripheral nervous system or cancer therapy-peripheral nervous system interactions as an anti-neoplastic or anti-neurotoxic agent, respectively. Human pluripotent stem cells offer an appealing model system that, unlike rodent models, is compatible with high throughput, high content applications; techniques that reflect modern drug discovery methodologies. Thus, utilizing the key advantages of stem cell-based models in tandem with the strengths of traditional animal models offers a complementary and interdisciplinary strategy to advance cancer and cancer therapy-peripheral nervous system research and drug discovery. In this review, the current status of the cancer-peripheral nervous system and cancer therapy-peripheral nervous system research is discussed, examples where stem cell-based models have been implemented are described, and avenues where stem cell-based models may further advance the field are proposed.

Keywords:  cancer neuroscience; iatrogenic neuropathies; nerve-tumor crosstalk; peripheral neuropathies

DOI:  https://doi.org/10.1002/adbi.202200009
J Transl Med. 2022 Jun 07. 20(1): 262

Stress-induced epinephrine promotes epithelial-to-mesenchymal transition and stemness of CRC through the CEBPB/TRIM2/P53 axis.

Zili Zhou, Yan Shu, Haijun Bao, Shengbo Han, Zhengyi Liu, Ning Zhao, Wenzheng Yuan, Chenxing Jian, Xiaogang Shu.

   BACKGROUND: Previous studies have indicated that chronic emotional stressors likely participate in the occurrence of cancers. However, direct evidence connecting stress and colorectal cancer development remains almost completely unexplored.
METHODS: Chronic stress mouse model was used to investigate the influence of stress on tumorigenesis. Several major agonists and antagonists of adrenergic receptors were applied to investigate the effects of β-adrenergic signaling on the development of CRC. Chromatin immunoprecipitation assays (CHIP) were used to investigate the binding of p53 and CEBPB to TRIM2 promoter. Mammosphere cultures, Cell Counting Kit-8 (CCK-8) assay, colony-formation assay, scratch wound healing assays, qPCR, immunofluorescence, coimmunoprecipitation and western blotting were used to explore the effect of stress-induced epinephrine on the CEBPB/TRIM2/P53 axis and the progress of CRC cells.
RESULTS: In this study, we found that stress-induced epinephrine (EPI) promotes the proliferation, metastasis and CSC generation of CRC primarily through the β2-adrenergic receptor. Furthermore, our studies also confirmed that chronic stress decreased the stability of p53 protein by promoting p53 ubiquitination. Results of transcriptome sequencing indicated that TRIM2 was overexpressed in cells treated with EPI. Further studies indicated that TRIM2 could regulate the stability of p53 protein by promoting p53 ubiquitination. Finally, we further proved that CEBPB was regulated by EPI and acts as the upstream transcription factor of TRIM2.
CONCLUSIONS: Our studies proved that stress-induced EPI promotes the development and stemness of CRC through the CEBPB/TRIM2/P53 axis.

Keywords:  CRC; Epinephrine; P53; Stress; TRIM2

DOI:  https://doi.org/10.1186/s12967-022-03467-8
Cancers (Basel). 2022 May 28. pii: 2684. [Epub ahead of print]14(11):

Pancreatic Cancer and Microenvironments: Implications of Anesthesia.

Hou-Chuan Lai, Yi-Wei Kuo, Yi-Hsuan Huang, Shun-Ming Chan, Kuang-I Cheng, Zhi-Fu Wu.

  Pancreatic malignancy is a lethal neoplasm, as well as one of the leading causes of cancer-associated mortality, having a 5-year overall survival rate of less than 10%. The average life expectancy of patients with advanced pancreatic cancer does not exceed six months. Although surgical excision is a favorable modality for long-term survival of pancreatic neoplasm, metastasis is initially identified in nearly 80% of the patients by the time of diagnosis, making the development of therapeutic policy for pancreatic cancer extremely daunting. Emerging evidence shows that pancreatic neoplastic cells interact intimately with a complicated microenvironment that can foster drug resistance, metastasis, or relapse in pancreatic cancer. As a result, the necessity of gaining further insight should be focused on the pancreatic microenvironment contributing to cancer progression. Numerous evidence reveals that perioperative factors, including surgical manipulation and anesthetics (e.g., propofol, volatile anesthetics, local anesthetics, epidural anesthesia/analgesia, midazolam), analgesics (e.g., opioids, non-steroidal anti-inflammatory drugs, tramadol), and anesthetic adjuvants (such as ketamine and dexmedetomidine), might alter the tumor microenvironment and cancer progression by affecting perioperative inflammatory or immune responses during cancer surgery. Therefore, the anesthesiologist plays an important role in perioperative management and may affect surgical outcomes. However, the literature on the impact of anesthesia on the pancreatic cancer microenvironment and progression is limited. This review summarizes the current knowledge of the implications of anesthesia in the pancreatic microenvironment and provides future anesthetic strategies for improving pancreatic cancer survival rates.

Keywords:  anesthesia; pancreatic cancer; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers14112684