bims-netuvo 2022-08-14 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2022–08–14
eleven papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute

Emerging Roles of the Nervous System in Gastrointestinal Cancer Development.
Sensory neuron dysfunction in orthotopic mouse models of colon cancer.
Computed tomography-based radiomics nomogram for the preoperative prediction of perineural invasion in colorectal cancer: a multicentre study.
Serum Extracellular Vesicle Stratifin Is a Biomarker of Perineural Invasion in Patients With Colorectal Cancer and Predicts Worse Prognosis.
Benign Neurogenic Tumors.
Combination of clinical and spectral-CT parameters for predicting lymphovascular and perineural invasion in gastric cancer.
TIMP1 derived from pancreatic cancer cells stimulates Schwann cells and promotes the occurrence of perineural invasion.
The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence.
PD-L1 Expression in Colorectal Adenocarcinoma Is Associated With the Tumor Immune Microenvironment and Epithelial-Mesenchymal Transition.
Metastasis of melanoma in non-sentinel nodes in patients with metastatic sentinel node. Can we avoid complementary lymphadenectomy?
Effect of exercise on tumor markers - Is exercise anti-tumorigenic in humans?: A scoping review of preliminary clinical investigations.

Cancers (Basel). 2022 Jul 30. pii: 3722. [Epub ahead of print]14(15):

Emerging Roles of the Nervous System in Gastrointestinal Cancer Development.

Chunhua Wan, Xiaoqin Yan, Baoying Hu, Xinhua Zhang.

  Our understanding of the fascinating connection between nervous system and gastrointestinal (GI) tumorigenesis has expanded greatly in recent years. Recent studies revealed that neurogenesis plays an active part in GI tumor initiation and progression. Tumor-driven neurogenesis, as well as neurite outgrowth of the pre-existing peripheral nervous system (PNS), may fuel GI tumor progression via facilitating cancer cell proliferation, chemoresistance, invasion and immune escape. Neurotransmitters and neuropeptides drive the activation of various oncogenic pathways downstream of neural receptors within cancer cells, underscoring the importance of neural signaling pathways in GI tumor malignancy. In addition, neural infiltration also plays an integral role in tumor microenvironments, and contributes to an environment in favor of tumor angiogenesis, immune evasion and invasion. Blockade of tumor innervation via denervation or pharmacological agents may serve as a promising therapeutic strategy against GI tumors. In this review, we summarize recent findings linking the nervous system to GI tumor progression, set the spotlight on the molecular mechanisms by which neural signaling fuels cancer aggressiveness, and highlight the importance of targeting neural mechanisms in GI tumor therapy.

Keywords:  chronic stress; gastrointestinal cancer; nervous system; neurogenesis; neurotransmitter; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers14153722
J Neuroinflammation. 2022 Aug 12. 19(1): 204

Sensory neuron dysfunction in orthotopic mouse models of colon cancer.

Mihály Balogh, Jixiang Zhang, Caitlyn M Gaffney, Neha Kalakuntla, Nicholas T Nguyen, Ronnie T Trinh, Clarissa Aguilar, Hoang Vu Pham, Bojana Milutinovic, James M Nichols, Rajasekaran Mahalingam, Andrew J Shepherd.

  Reports of neurological sequelae related to colon cancer are largely restricted to rare instances of paraneoplastic syndromes, due to autoimmune reactions. Systemic inflammation associated with tumor development influences sensory neuron function in other disease models, though the extent to which this occurs in colorectal cancer is unknown. We induced orthotopic colorectal cancer via orthotopic injection of two colorectal cancer cell lines (MC38 and CT26) in two different mouse strains (C57BL/6 and Balb/c, respectively). Behavioral tests of pain sensitivity and activity did not detect significant alterations in sensory sensitivity or diminished well-being throughout tumor development. However, immunohistochemistry revealed widespread reductions in intraepidermal nerve fiber density in the skin of tumor-bearing mice. Though loss of nerve fiber density was not associated with increased expression of cell injury markers in dorsal root ganglia, lumbar dorsal root ganglia neurons of tumor-bearing animals showed deficits in mitochondrial function. These neurons also had reduced cytosolic calcium levels in live-cell imaging and reduced spontaneous activity in multi-electrode array analysis. Bulk RNA sequencing of DRGs from tumor-bearing mice detected activation of gene expression pathways associated with elevated cytokine and chemokine signaling, including CXCL10. This is consistent with the detection of CXCL10 (and numerous other cytokines, chemokines and growth factors) in MC38 and CT26 cell-conditioned media, and the serum of tumor-bearing mice. Our study demonstrates in a pre-clinical setting that colon cancer is associated with latent sensory neuron dysfunction and implicates cytokine/chemokine signaling in this process. These findings may have implications for determining risk factors and treatment responsiveness related to neuropathy in colorectal cancer.

Keywords:  Colon cancer; DRG neuron; Neuropathic pain; Neuropathy; Paraneoplastic neuropathy

DOI:  https://doi.org/10.1186/s12974-022-02566-z
Abdom Radiol (NY). 2022 Aug 12.

Computed tomography-based radiomics nomogram for the preoperative prediction of perineural invasion in colorectal cancer: a multicentre study.

Qiaoling Chen, Yanfen Cui, Ting Xue, Hui Peng, Manman Li, Xinghua Zhu, Shaofeng Duan, Hongmei Gu, Feng Feng.

   PURPOSE: To develop and validate a computed tomography (CT) radiomics nomogram from multicentre datasets for preoperative prediction of perineural invasion (PNI) in colorectal cancer.
METHODS: A total of 299 patients with histologically confirmed colorectal cancer from three hospitals were enrolled in this retrospective study. Radiomic features were extracted from the whole tumour volume. The least absolute shrinkage and selection operator logistic regression was applied for feature selection and radiomics signature construction. Finally, a radiomics nomogram combining the radiomics score and clinical predictors was established. The receiver operating characteristic curve and decision curve analysis (DCA) were used to evaluate the predictive performance of the radiomics nomogram in the training cohort, internal validation and external validation cohorts.
RESULTS: Twelve radiomics features extracted from the whole tumour volume were used to construct the radiomics model. The area under the curve (AUC) values of the radiomics model in the training cohort, internal validation cohort, external validation cohort 1, and external validation cohort 2 were 0.82 (0.75-0.90), 0.77 (0.62-0.92), 0.71 (0.56-0.85), and 0.73 (0.60-0.85), respectively. The nomogram, which combined the radiomics score with T category and N category by CT, yielded better performance in the training cohort (AUC = 0.88), internal validation cohort (AUC = 0.80), external validation cohort 1 (AUC = 0.75), and external validation cohort 2 (AUC = 0.76). DCA confirmed the clinical utility of the nomogram.
CONCLUSIONS: The CT-based radiomics nomogram has the potential to accurately predict PNI in patients with colorectal cancer.

Keywords:  Colorectal cancer; Computed tomography; Nomogram; Perineural invasion; Radiomics

DOI:  https://doi.org/10.1007/s00261-022-03620-3
Front Oncol. 2022 ;12 912584

Serum Extracellular Vesicle Stratifin Is a Biomarker of Perineural Invasion in Patients With Colorectal Cancer and Predicts Worse Prognosis.

Wenyun Hou, Meng Pan, Yi Xiao, Wei Ge.

  Previous studies have shown that the presence of perineural invasion (PNI) is associated with a significantly worse prognosis in colorectal cancer (CRC) patients. In this study, we performed a detailed analysis of the diversity of extracellular vesicles (EV) between NPNI (non-PNI) and PNI using quantitative proteomics and aim to investigate the mechanisms underlying PNI in colorectal cancer. Quantitative proteomics technology was used to identify the proteome of serum-purified EVs from CRC patients with and without PNI (PNI and non-PNI (NPNI) groups, respectively) and healthy volunteers. Mass spectrometry data were verified by ELISA and Western blot analyses. The proteomic profile of serum EVs from the PNI group differed from that of those in the NPNI group. Serum-derived EVs from the PNI promoted more significant cellular mobility than EVs derived from the NPNI group. EV stratifin (SFN) expression levels demonstrated an area under the receiver operating characteristic curve values of 0.84 for discriminating patients with PNI from NPNI patients. Moreover, EV SFN expression levels were an independent predictor of CRC prognosis. In this study, we identified SFN as a potential biomarker for the diagnosis of PNI in stage II CRC patients.

Keywords:  colorectal cancer; epithelial-mesenchymal transition; extracellular vesicles; perineural invasion; proteomics

DOI:  https://doi.org/10.3389/fonc.2022.912584
Surg Clin North Am. 2022 Aug;pii: S0039-6109(22)00042-1. [Epub ahead of print]102(4): 679-693

Benign Neurogenic Tumors.

Jeffrey M Farma, Andrea S Porpiglia, Elaine T Vo.

  Neurogenic tumors arise from cells of the nervous system. These tumors can be found anywhere along the distribution of the sympathetic and parasympathetic nervous system and are categorized based on cell of origin: ganglion cell, paraganglion cell, and nerve sheath cells. Ganglion cell-derived tumors include neuroblastomas, ganglioneuroblastomas, and ganglioneuromas. Paraganglion cell-derived tumors include paragangliomas and pheochromocytomas. Nerve sheath cell-derived tumors include schwannomas (neurilemmomas), neurofibromas, and neurofibromatosis. Most of these are benign; however, they can cause local compressive symptoms. Surgery is the mainstay of treatment, if clinically indicated. Nonetheless, a thorough preoperative workup is essential, especially for catecholamine-secreting tumors.

Keywords:  Benign neurogenic tumors; Neurofibroma; Paraganglioma; Pheochromocytoma; Schwannoma

DOI:  https://doi.org/10.1016/j.suc.2022.04.007
Diagn Interv Imaging. 2022 Aug 04. pii: S2211-5684(22)00140-1. [Epub ahead of print]

Combination of clinical and spectral-CT parameters for predicting lymphovascular and perineural invasion in gastric cancer.

Tiezhu Ren, Wenjuan Zhang, Shenglin Li, Liangna Deng, Caiqiang Xue, Zhengxiao Li, Suwei Liu, Jiachen Sun, Junlin Zhou.

   PURPOSE: The purpose of this study was to investigate the utility of combining clinical and spectral computed tomography (CT) parameters for the preoperative evaluation of lymphovascular invasion (LVI) and perineural invasion (PNI) in gastric cancers (GCs).
MATERIALS AND METHODS: Patients with gastric adenocarcinoma who underwent spectral-CT examination were retrospectively examined. All diagnoses were confirmed by pathology, and the patients were divided into positive and negative groups based on LVI/PNI occurrence. Clinical characteristics, including demographic information, serum tumor markers, and gastroscopic pathological information, were collected. The effective atomic number (Zeff), iodine concentration (IC), and water concentration were measured in the arterial (AP) and venous phase (VP). Differences between the two groups were searched for using independent sample t-test, Mann-Whitney U test, or chi-square (χ2) test and diagnostic performances of the different variables were evaluated using receiver operating characteristic (ROC) curve.
RESULTS: A total of 121 patients (96 men, 25 women; mean age: 59 ± 8.7 [SD] years, range: 36-82 years) with gastric adenocarcinoma were included in the study. The serum level of the tumor marker CA125, as well as Zeff and IC in the LVI/PNI-positive group, were significantly higher than in the negative group, and the histological grade and Borrmann type differed between the two groups (all P < 0.05). The discriminating capability analysis demonstrated that CA125 exhibited a favorable performance, and the VP parameters' diagnostic efficacy was superior to that of the AP parameters. The efficacy of the combination of clinical and spectral-CT parameters was superior to that of individual parameters (all AUC > 0.85). The clinical parameters combined with Zeff and IC in the AP and VP exhibited a high evaluation efficacy (AUC = 0.890 [95% CI: 0.826-0.955]; F1 score = 0.888; accuracy = 84.3% [102/121; 95% CI: 76.7-89.8]; sensitivity = 86.2% [75/87; 95% CI: 76.8-92.4]; specificity = 79.4% [27/34; 95% CI: 61.6-90.1]).
CONCLUSIONS: Clinical and spectral-CT parameters exhibit considerable capabilities in the preoperative evaluation of LVI and PNI in GCs. The combination of clinical and spectral-CT parameters effectively predicts LVI and PNI in GCs.

Keywords:  Gastric cancer; Lymphovascular invasion; Perineural invasion; Spectral CT

DOI:  https://doi.org/10.1016/j.diii.2022.07.004
Cancer Lett. 2022 Aug 09. pii: S0304-3835(22)00347-0. [Epub ahead of print] 215863

TIMP1 derived from pancreatic cancer cells stimulates Schwann cells and promotes the occurrence of perineural invasion.

Zhenfeng Tian, Guangsheng Ou, Mingxin Su, Ruomeng Li, Lele Pan, Xingyi Lin, Jinmao Zou, Shangxiang Chen, Yaqing Li, Kaihong Huang, Yinting Chen.

  Perineural invasion (PNI) occurs in most pancreatic ductal adenocarcinomas (PDACs). The relationship between cancer cells and peripheral nerves, however, is unknown. Therefore, we focused on the cooperation of PDAC cells and peripheral nerve astrocytes, Schwann cells (SCs), in PNI. The mutual tumor-supportive secretory cytokines between SCs (sNF96.2) and PDAC cells (PANC-1, BxPC-3) were screened by human cytokine arrays and verified. The prognostic value of selected cytokines and SC-associated markers was confirmed in PDAC patients. TIMP1 and CCL7 were found to form a paracrine feedback loop between PDAC cells and SCs. PDAC cell-derived TIMP1 promotes SCs proliferation and migration via CD63/PI3K/AKT signaling. CCL7 secreted from SCs enhances PDAC cell migration, invasion and expression of TIMP1 via CCR2/STAT3. PDAC cell-SC cooperation in PNI was blocked when TIMP1 knockdown in vitro and in vivo. Finally, TIMP1, CCL7 and SC-associated markers were correlated with PNI and prognosis in PDAC patients. In conclusion, SCs collaborate with PDAC cells through the TIMP1-CCL7 paracrine feedback loop to promote PNI. TIMP1 knockdown in PDAC cells suppresses PNI. Strategies to disrupt the TIMP1-CCL7 feedback loop might be developed to inhibit PNI in PDAC.

Keywords:  Cytokine secretion; Nerve; Nerve infiltration; Pancreatic ductal adenocarcinoma; Tumor metastasis

DOI:  https://doi.org/10.1016/j.canlet.2022.215863
Cell Biol Toxicol. 2022 Aug 12.

The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence.

Masae Iwasaki, Hailin Zhao, Cong Hu, Junichi Saito, Lingzhi Wu, Aislinn Sherwin, Masashi Ishikawa, Atsuhiro Sakamoto, Donal Buggy, Daqing Ma.

  Anaesthetics may modify colorectal cancer cell biology which potentially affects long-term survival. This study aims to compare propofol and sevoflurane regarding with the direct anaesthetic effects on cancer malignancy and the indirect effects on host immunity in a cancer xenograft mode of mice. Cultured colon cancer cell (Caco-2) was injected subcutaneously to nude mice (day 1). Mice were exposed to either 1.5% sevoflurane for 1.5 h or propofol (20 μg g-1; ip injection) with or without 4 μg g-1 lipopolysaccharide (LPS; ip) from days 15 to 17, compared with those without anaesthetic exposure as controls. The clinical endpoints including tumour volumes over 70 mm3 were closely monitored up to day 28. Tumour samples from the other cohorts were collected on day 18 for PCR array, qRT-PCR, western blotting and immunofluorescent assessment. Propofol treatment reduced tumour size (mean ± SD; 23.0 ± 6.2mm3) when compared to sevoflurane (36.0 ± 0.3mm3) (p = 0.008) or control (23.6 ± 4.7mm3). Propofol decreased hypoxia inducible factor 1α (HIF1α), interleukin 1β (IL1β), and hepatocyte growth factor (HGF) gene expressions and increased tissue inhibitor of metalloproteinases 2 (TIMP-2) gene and protein expression in comparison to sevoflurane in the tumour tissue. LPS suppressed tumour growth in any conditions whilst increased TIMP-2 and anti-cancer neutrophil marker expressions and decreased macrophage marker expressions compared to those in the LPS-untreated groups. Our data indicated that sevoflurane increased cancer development when compared with propofol in vivo under non-surgical condition. Anaesthetics tested in this study did not alter the effects of LPS as an immune modulator in changing immunocyte phenotype and suppressing cancer development.

Keywords:  Anaesthetic effects; Propofol; Sevoflurane; Tumour progression

DOI:  https://doi.org/10.1007/s10565-022-09747-9
Am J Clin Pathol. 2022 Aug 08. pii: aqac077. [Epub ahead of print]

PD-L1 Expression in Colorectal Adenocarcinoma Is Associated With the Tumor Immune Microenvironment and Epithelial-Mesenchymal Transition.

Ilke Evrim Secinti, Tumay Ozgur, Isa Dede.

   OBJECTIVES: Colorectal carcinomas are the third-most common tumors in the world, and colorectal cancer ranks second in cancer-related deaths. Our aim in this study was to investigate the correlation between programmed cell death ligand 1 (PD-L1) expression and clinicopathologic parameters in colorectal carcinomas and their relationship to the tumor immune microenvironment, epithelial-mesenchymal transition (EMT), and microsatellite instability. We also investigated the predictive and prognostic role of PD-L1.
METHODS: One hundred patients with a diagnosis of colorectal adenocarcinoma who did not receive neoadjuvant therapy were included in the study. The relationships among the altered expression of PD-L1; vimentin; E-cadherin; mismatch repair status; and pathologic microenvironmental features, including the presence of tumor budding and CD8-positive tumor infiltrating lymphocytes (TILs), were assessed.
RESULTS: Increased PD-L1 expression in tumor cells was associated with increased TILs (P = .013), high histologic grade (P = .011), advanced pathologic T stage (P = .007), lymph node metastasis (P = .002), distant metastasis (P < .001), perineural invasion (P = .009), high bud score (P = .023), EMT (P < .001), and shorter disease-free survival (P = .029).
CONCLUSIONS: Overall, PD-L1 expression in colorectal carcinoma tumor cells is a marker of poor prognosis, and the positive correlation detected between EMT status and PD-L1 expression suggests that patients with the mesenchymal phenotype may be more likely to benefit from programmed cell death 1 protein/PD-L1 immunotherapy.

Keywords:  Colorectal cancer; Epithelial-mesenchymal transition; Prognosis; Program cell death ligand 1; Tumor budding

DOI:  https://doi.org/10.1093/ajcp/aqac077
Cir Cir. 2022 ;90(4): 525-528

Metastasis of melanoma in non-sentinel nodes in patients with metastatic sentinel node. Can we avoid complementary lymphadenectomy?

Ana L Ramírez-Ocampo, José F Gallegos-Hernández, Dulce M Hernández-Hernández, José A Abrego-Vázquez.

   BACKGROUND: Lymph mapping with sentinel node biopsy is the standard procedure for lymph node staging in patients with cutaneous melanoma with a tumor thickness of 1 mm or greater. Patients who have metastases in sentinel node must undergo complementary lymphadenectomy; however, it has not been shown to improve survival.
OBJECTIVE: To know the prevalence in our setting of metastases in the product of complementary lymphadenectomy in patients with metastatic sentinel node.
METHOD: Evaluation of a descriptive, retrospective, observational and analytical cohort of patients with metastatic sentinel node submitted to lymphadenectomy. Multivariate analysis of tumor thickness, neural invasion, location, sentinel node number, serum DHL level, lymph nodes dissected and extracapsular spread.
RESULTS: 67 patients, 35 women and 32 men with a mean of 66 years, 22% had metastases in lymph nodes from complementary lymphadenectomy, 19% of them with extracapsular spread; no relationship with the Breslow level. Extracapsular spread in the sentinel node, lymphadenectomy time, and perineural invasion in the primary tumor were prognostic factors for non-sentinel node metastasis.
CONCLUSIONS: In this series, 22% of the patients with a sentinel node-positive have metastases in the non-sentinel nodes, 19% of them with extracapsular spread, which justifies complementary lymphadenectomy.

Keywords:  Biopsia; Biopsy; Cutaneous melanoma; Ganglio centinela; Linfadenectomía; Lymphadenectomy; Melanoma cutáneo; Sentinel node

DOI:  https://doi.org/10.24875/CIRU.21000091
Crit Rev Oncol Hematol. 2022 Aug 05. pii: S1040-8428(22)00203-7. [Epub ahead of print]178 103779

Effect of exercise on tumor markers - Is exercise anti-tumorigenic in humans?: A scoping review of preliminary clinical investigations.

Dong-Woo Kang, Oscar Barnes, Matthew G Vander Heiden, Christina M Dieli-Conwright.

  It has been increasingly conceptualized that exercise may be able to suppress cancer progression itself based on the preclinical evidence suggesting various mechanisms. The challenges exist in investigating the effects of exercise on tumor progression in human settings. Circulating or tissue-driven tumor markers can be a useful and cost-effective tool in monitoring the progression of some cancers. This scoping review summarized the current evidence on the use of tumor markers in clinical exercise oncology trials. A total of 14 studies were identified, and tumor markers included prostate-specific antigen for prostate cancer, carcinoembryonic antigen and circulating tumor cells for colorectal cancer, and Ki-67 for breast cancer. Treatment settings and exercise prescriptions were highly heterogeneous, while most studies did not find significant exercise-mediated effects on tumor markers. Nevertheless, we provide an insight into the utility and considerations in using tumor markers in clinical exercise oncology research.

Keywords:  Cancer progression; Clinical trials; Exercise; Translational trials; Tumor markers

DOI:  https://doi.org/10.1016/j.critrevonc.2022.103779