bims-netuvo 2024-07-21 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2024–07–21
eleven papers selected by
Maksym V. Kopanitsa, Charles River Laboratories

Neuronal distribution in colorectal cancer: associations with clinicopathological parameters and survival.
Extracellular vesicle-packaged PIAT from cancer-associated fibroblasts drives neural remodeling by mediating m5C modification in pancreatic cancer mouse models.
GDNF-induced phosphorylation of MUC21 promotes pancreatic cancer perineural invasion and metastasis by activating RAC2 GTPase.
Chemical genetic screens reveal defective lysosomal trafficking as synthetic lethal with NF1 loss.
Mechanisms of stress-attributed breast cancer incidence and progression.
Common Benign Nerve Sheath Tumor at an Uncommon Location - Gastric Schwannoma.
A Rare Case of a Schwannoma on the Foot - Case Report.
Painless Growing Swelling on the Palm of a 4-year-old Boy: Malignant Peripheral Nerve Sheath Tumor.
Risk Factors of Lymph Node Metastasis and Prognosis in 891 Chinese Patients With Submucosal Early Gastric Carcinoma, Emphasizing Differences Between Gastric Cardiac and Noncardiac Origins.
Posterior Interosseous Nerve Syndrome due to Schwannoma - A Case Report.
Construction and validation of a prognostic model for gastric cancer patients with tumor deposits.

Mod Pathol. 2024 Jul 16. pii: S0893-3952(24)00145-5. [Epub ahead of print] 100565

Neuronal distribution in colorectal cancer: associations with clinicopathological parameters and survival.

Maartje Massen, Meike S Thijssen, Glenn Rademakers, Musa Idris, Kim A D Wouters, Jaleesa R M van der Meer, Nikkie Buekers, Desirée Huijgen, Iryna V Samarska, Matty P Weijenberg, Piet A van den Brandt, Manon van Engeland, Marion J Gijbels, Werend Boesmans, Kim M Smits, Veerle Melotte.

  Over the last years, insights in the cancer neuroscience field increased rapidly and a potential role for neurons in colorectal carcinogenesis has been recognized. However, knowledge on the neuronal distribution, subtypes, origin and associations with clinicopathological characteristics in human studies is sparse. In this study, colorectal tumor tissues from the Netherlands Cohort Study on diet and cancer (n=490) and an in-cohort validation population (n=529) were immunohistochemically stained for the pan-neuronal markers neurofilament (NF) and protein gene product 9.5 (PGP9.5) to study the association between neuronal marker expression and clinicopathological characteristics. In addition, tumor and healthy colon tissue were stained for neuronal subtype markers and their immunoreactivity in colorectal cancer (CRC) stroma was analyzed. NF and PGP9.5 positive nerve fibers were found within the tumor stroma and were mostly characterized by the neuronal subtype markers vasoactive intestinal protein (VIP) and neuronal nitric oxide synthase (nNOS), suggesting that inhibitory neurons are the most prominent neuronal subtype in CRC. NF and PGP9.5 protein expression were not consistently associated with tumor stage, sublocation, differentiation grade and median survival. NF immunoreactivity was associated with a worse CRC-specific survival in the study cohort (p=0.025), independent of other prognostic factors (HR=2.31; 95% CI 1.33-4.03; p=0.003), but these results were not observed in the in-cohort validation group. PGP9.5 on the other hand, was associated with a worse CRC-specific survival in the in-cohort validation (p=0.046) but not in the study population. This effect disappeared in multivariate analyses (HR=0.81; 95% CI 0.50-1.32; p=0.393) indicating that this effect was dependent on other prognostic factors. This study demonstrates that the tumor stroma of CRC patients mainly harbors inhibitory neurons and that NF as a single marker is significantly associated with a poorer CRC-specific survival in the study cohort but necessitates future validation.

Keywords:  (enteric) nervous system; Colorectal cancer; neurofilament; neuronal subtypes; prognosis; protein gene product 9.5

DOI:  https://doi.org/10.1016/j.modpat.2024.100565
Sci Transl Med. 2024 Jul 17. 16(756): eadi0178

Extracellular vesicle-packaged PIAT from cancer-associated fibroblasts drives neural remodeling by mediating m5C modification in pancreatic cancer mouse models.

Shangyou Zheng, Chonghui Hu, Qing Lin, Tingting Li, Guolin Li, Qing Tian, Xiang Zhang, Tianhao Huang, Yuancheng Ye, Rihua He, Changhao Chen, Yu Zhou, Rufu Chen.

Perineural invasion (PNI) is a biological characteristic commonly observed in pancreatic cancer. Although PNI plays a key role in pancreatic cancer metastasis, recurrence, and poor postoperative survival, its mechanism is largely unclarified. Clinical sample analysis and endoscopic ultrasonographic elasticity scoring indicated that cancer-associated fibroblasts (CAFs) were closely related to the occurrence of PNI. Furthermore, CAF-derived extracellular vesicles (EVs) were involved in PNI in dorsal root ganglion coculture and mouse sciatic nerve models. Next, we demonstrated that CAFs promoted PNI through extracellular vesicle transmission of PNI-associated transcript (PIAT). Mechanistically, PIAT specifically bound to YBX1 and blocked the YBX1-Nedd4l interaction to inhibit YBX1 ubiquitination and degradation. Furthermore, PIAT enhanced the binding of YBX1 and PNI-associated mRNAs in a 5-methylcytosine (m5C)-dependent manner. Mutation of m5C recognition motifs in YBX1 or m5C sites in downstream target genes reversed PIAT-mediated PNI. Consistent with these findings, analyses using a KPC mouse model demonstrated that the PIAT/YBX1 axis enhanced PNI through m5C modification. Clinical data suggested that the PIAT expression in the serum EVs of patients with pancreatic cancer was associated with the degree of neural invasion and prognosis. Our study revealed the important role of the PIAT/YBX1 signaling axis in the tumor microenvironment (TME) in promoting tumor cell PNI and provided a new target for precise interference with CAFs and RNA methylation in the TME to suppress PNI in pancreatic cancer.

DOI: https://doi.org/10.1126/scitranslmed.adi0178
Oncogene. 2024 Jul 17.

GDNF-induced phosphorylation of MUC21 promotes pancreatic cancer perineural invasion and metastasis by activating RAC2 GTPase.

Yutong Chen, Weiyu Zhang, Yan Zeng, Pengfei Yang, Yaning Li, Xinyue Liang, Kecheng Liu, Hai Lin, Yalan Dai, Jiancong Zhou, Bingqi Hou, Zhenting Ma, Yujing Lin, Wenzheng Pang, Linjuan Zeng.

Perineural invasion (PNI) is an adverse prognostic feature of pancreatic ductal adenocarcinoma (PDAC). However, the understanding of the interactions between tumors and neural signaling within the tumor microenvironment is limited. In the present study, we found that MUC21 servers as an independent risk factor for poor prognosis in PDAC. Furthermore, we demonstrated that MUC21 promoted the metastasis and PNI of PDAC cells by activating JNK and inducing epithelial-mesenchymal transition (EMT). Mechanistically, glial cell-derived neurotrophic factor, secreted by Schwann cells, phosphorylates the intracellular domain S543 of MUC21 via CDK1 in PDAC cells, facilitating the interaction between MUC21 and RAC2. This interaction leads to membrane anchoring and activation of RAC2, which in turn activates the JNK/ZEB1/EMT axis, ultimately enhancing the metastasis and PNI of PDAC cells. Our results present a novel mechanism of PNI, suggesting that MUC21 is a potential prognostic marker and therapeutic target for PDAC.

DOI: https://doi.org/10.1038/s41388-024-03102-4
J Cell Sci. 2024 Jul 17. pii: jcs.262343. [Epub ahead of print]

Chemical genetic screens reveal defective lysosomal trafficking as synthetic lethal with NF1 loss.

Stephanie J Bouley, Andrew V Grassetti, Robert J Allaway, Matthew D Wood, Helen W Hou, India R Burdon Dasbach, William Seibel, Jimmy Wu, Scott A Gerber, Konstantin H Dragnev, James A Walker, Yolanda Sanchez.

  Neurofibromatosis type 1, a genetic disorder caused by germline mutations in NF1, predisposes patients to the development of tumors, including cutaneous and plexiform neurofibromas (CNs and PNs), optic gliomas, astrocytomas, juvenile myelomonocytic leukemia, high-grade gliomas, and malignant peripheral nerve sheath tumors (MPNSTs), which are chemotherapy- and radiation-resistant sarcomas with poor survival. Loss of NF1 also occurs in sporadic tumors such as glioblastoma (GBM), melanoma, breast, ovarian, and lung cancers. We performed a high-throughput screen for compounds that were synthetic lethal with NF1 loss, which identified several leads, including the small molecule Y102. Treatment of cells with Y102 perturbed autophagy, mitophagy, and lysosome positioning in NF1-deficient cells. A dual proteomics approach identified the BORC complex, which is required for lysosome positioning and trafficking, as a potential target of Y102. Knockdown of a BORC complex subunit using siRNA recapitulated the phenotypes observed with Y102 treatment. Our findings demonstrate that the BORC complex may be a promising therapeutic target for NF1-deficient tumors.

Keywords:  NF1; RAS; synthetic lethal; mitochondria; lysosomes; BORC

DOI:  https://doi.org/10.1242/jcs.262343
Cancer Causes Control. 2024 Jul 16.

Mechanisms of stress-attributed breast cancer incidence and progression.

Elizabeth Reznik, Ava Torjani.

  Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths in women, with psychosocial stress commonly cited by patients as one of its causes. While there is conflicting epidemiological evidence investigating the association between psychosocial stress and breast cancer incidence and progression, there is reason to believe that interventions aimed at reducing stress pharmacologically or psychologically may improve breast cancer outcomes. The aim of this review is to discuss the molecular and biological mechanisms of stress-attributed breast cancer incidence and progression, including the induction of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), as well as decreased immune function and stress hormone-induced resistance to chemotherapy. Moreover, these mechanisms have been cited as potential therapeutic targets of pharmacologic and psychological interventions that may improve the care, well-being and survival of breast cancer patients. Further research is recommended to investigate whether interventions in the primary care setting for women with risk factors for breast cancer development may lead to a decreased incidence of invasive breast tumors.

Keywords:  Breast cancer; HPA axis; Incidence; Progression; Psychosocial stress; Sympathetic nervous system

DOI:  https://doi.org/10.1007/s10552-024-01884-2
Cureus. 2024 Jun;16(6): e62569

Common Benign Nerve Sheath Tumor at an Uncommon Location - Gastric Schwannoma.

Manjesh K A, Nagarjun Nelluri, Ankith R Narra, Sreedhar R Kota, Kishore Abuji.

  Gastric schwannomas are rare types of gastrointestinal mesenchymal tumours that are slow-growing and mostly benign. They are usually asymptomatic. In some cases, nonspecific gastric symptoms, palpable mass, and bleeding can be seen. A definitive diagnosis requires pathological and immunohistochemical examination, and surgical resection offers an excellent prognosis with uncommon recurrence. We present a case of a 62-year-old woman who underwent exploratory laparotomy and wedge resection with preoperative diagnosis as gastrointestinal stromal tumor and postoperatively diagnosed as schwannoma on histopathology.

Keywords:  benign peripheral nerve sheath tumor; gastric schwannoma; gastrointestinal stromal tumor (gist); mesenchymal tumour; rare gastric tumor

DOI:  https://doi.org/10.7759/cureus.62569
Rev Bras Ortop (Sao Paulo). 2024 Jul;59(Suppl 1): e88-e90

A Rare Case of a Schwannoma on the Foot - Case Report.

José Carlos Sousa Miradouro, Tiago Costa, Nuno Silva, João Afonso.

  A Schwannoma is an infrequent lesion. This tumor derives from the myelin sheath of the peripheral nerves; in most cases, it is benign and rarely presents in the foot and ankle region. Patients affected by this type of pathology are usually asymptomatic. Still, they sometimes have sensory or motor neurologic symptoms if the tumor is large enough to cause direct or indirect compression of the affected nerve. A 55-year-old male patient presented to our department with non-traumatic swelling and pain in the lateral aspect of the right foot and leg. A magnetic resonance imaging (MRI) scan of the right leg revealed a well-circumscribed lesion, measuring 2,5 by 1 cm, showing hypointensity on T1 sequences and hyperintensity on T2, compatible with a superficial peroneal nerve sheath cells tumor. Surgical excision of the lesion was performed, and the histopathological examination confirmed the initial suspicion-Schwannoma of the superficial peroneal nerve. The postoperative period was uneventful, with progressive improvement of pain and complete functional recovery without neurological deficits. Rigorous clinical examination associated to MRI scans allow adequate diagnosis as well as the exclusion of other pathologies with similar clinical presentation. Thus, the surgeon has to be aware of all the data for an effective diagnosis and treatment in this type of rare pathology that cannot be neglected.

Keywords:  foot; nerve sheath neoplasms; peroneal nerve; schwannoma

DOI:  https://doi.org/10.1055/s-0042-1756150
Rev Bras Ortop (Sao Paulo). 2024 Jul;59(Suppl 1): e104-e108

Painless Growing Swelling on the Palm of a 4-year-old Boy: Malignant Peripheral Nerve Sheath Tumor.

Recep Öztürk, Kemal Kösemehmetoğlu, Fisun Ardıç Yükrük, Bedii Şafak Güngör.

  In this study, we present a 4-year-old male patient with a slowly growing painless mass in the palm of his left hand for 2 years. Although musculoskeletal tumors are rare, hand localized tumors are even rarer in pediatric patients. The fact that very few (less than one in ten) tumors are malignant and there are dozens of subtypes, each with different treatment management, shows the importance of the management of these lesions. Appropriate diagnosis and management of soft tissue masses, especially insidious malignant tumors, is vital. Due to the rarity of soft tissue tumors, adequate guidelines for their management are limited. The purpose of this report is to present an example of the approach to one of the soft tissue tumors.

Keywords:  child; diagnosis, differential; sarcoma; soft tissue neoplasms

DOI:  https://doi.org/10.1055/s-0043-1771005
Am J Surg Pathol. 2024 Jul 19.

Risk Factors of Lymph Node Metastasis and Prognosis in 891 Chinese Patients With Submucosal Early Gastric Carcinoma, Emphasizing Differences Between Gastric Cardiac and Noncardiac Origins.

Yuqing Cheng, Mingzhan Du, Yaohui Wang, Ting Li, Chongfang He, Xiaoli Zhou, Min Lin, Qin Huang.

Differences in risk factors (RF) of lymph node metastasis (LNM) and prognosis between submucosal early gastric cardiac (SEGCC) and noncardiac (SEGNCC) carcinomas remain unclear. In this study, we investigated and compared RF of LNM and prognosis in 891 patients with radical gastrectomy for SEGCC (n=217) or SEGNCC (n=674). Compared with SEGNCC, SEGCC displayed significantly higher proportion of elderly patients (70 y or above), the elevated macroscopic type, well/moderately differentiated tubular and low-grade papillary adenocarcinomas, as well as low-grade tumor budding, but lower prevalence of the depressed macroscopic type, poorly differentiated tubular adenocarcinoma, mixed adenocarcinoma, poorly cohesive carcinoma, lymphovascular invasion (LVI), perineural invasion, and high-grade tumor budding. By univariate analysis, significant RF for LNM of the cohort included female sex, poor differentiation, SM2 invasion, LVI, intermediate-grade and high-grade tumor budding, whereas tumor size, histology type, and perineural invasion were the significant RF for LNM in SEGNCC. By multivariate analysis, significant independent RF for LNM included female sex and LVI in SEGCC but were female sex, mixed adenocarcinoma, LVI, and high-grade tumor budding in SEGNCC. The 5-year overall survival was significantly worse in SEGCC than in SEGNCC for patients with LNM, but not for those without. For overall survival, LNM was the only significant independent RF in SEGCC, whereas age 70 years or above and LNM were independent RF in SEGNCC. The results of our study provided the clinicopathologic evidence for individualized clinical management strategies for these 2 groups of patients and suggested different pathogenesis mechanisms between SEGCC and SEGNCC.

DOI: https://doi.org/10.1097/PAS.0000000000002282
Rev Bras Ortop (Sao Paulo). 2024 Jul;59(Suppl 1): e91-e93

Posterior Interosseous Nerve Syndrome due to Schwannoma - A Case Report.

Antônio Lourenço Severo, Deodoro Máximo de Alencar Neto, Marcelo Barreto Lemos, Matheus Predebon Duarte, Ivânio Tagliari.

  Posterior interosseous nerve syndrome is the most frequent syndrome of radial nerve compression, with the arcade of Frohse being the main site of compression. Its symptoms include difficulties in finger and wrist extension with possible radial deviation. Herein, we present a case of posterior interosseous syndrome caused by a schwannoma, a type of neurological tumor.

Keywords:  nerve compression syndromes; neurilemmoma; peripheral nervous system neoplasms; radial nerve; radial neuropathy

DOI:  https://doi.org/10.1055/s-0042-1749614
PeerJ. 2024 ;12 e17751

Construction and validation of a prognostic model for gastric cancer patients with tumor deposits.

Ran Xu, Yisheng Zhang, Zhengguang Wang, Ke Chen, Jun Zhao.

   Background: Tumor deposits (TD) was a significant risk factor impacting the prognosis of patients diagnosed with gastric cancer (GC), yet it was not currently incorporated into TNM staging systems. The objective of this research was to develop a predictive model for assessing the prognosis of patients with TD-positive GC.
Methods: Retrospective analysis was performed on the data of 4,972 patients treated for GC with D2 radical gastrectomy at Wannan Medical College's Yijishan Hospital between January 2012 and December 2021. The patients were categorized based on the number of TD (L1: 1, L2: 2-3, L3: ≥4) and the anatomical location of TD (Q1: single area, Q2: multiple areas). In a 3:1 ratio, patients were randomly assigned to one of two groups: training or validation.
Results: The study included a total of 575 patients who were divided into the training group (n = 432) and validation group (n = 143). Survival analysis showed that the number and anatomical location of TD had a significant impact on the prognosis of patients with TD-positive GC. Univariate analysis of the training group data revealed that tumor size, T-stage, N-stage, histological grade, number and distribution of TD, neural invasion, and postoperative chemotherapy were associated with prognosis. Multivariate Cox regression analysis identified poor histological grade, T4 stage, N3 stage, number of TD, neural invasion, and postoperative chemotherapy as independent prognostic factors for GC patients with TD. A nomogram was developed using these variables, demonstrating well predictive ability for 1, 3, and 5-year overall survival (OS) in the validation set. The DCA curve shows that the constructed model shows a large positive net gain compared to the eighth edition Tumour, Node, Metastasis (TNM) staging system.
Conclusion: The prognostic model developed for patients with TD-positive GC has a higher clinical utility compared to the eighth edition of TNM staging.

Keywords:  Adjuvant chemotherapy; Nomogram; Prognosis; Stomach tumor; Tumor deposits

DOI:  https://doi.org/10.7717/peerj.17751