bims-netuvo 2023-11-19 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2023–11–19
eleven papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute

Neuroscience and oncology: state-of-the-art and new perspectives.
Tumor- and Nerve-Derived Axon Guidance Molecule Promotes Pancreatic Ductal Adenocarcinoma Progression and Metastasis through Macrophage Reprogramming.
Tumor-derived GABA promotes lung cancer progression by influencing TAMs polarization and neovascularization.
A meta-analysis of the association between post-traumatic stress disorder and cancer risk.
Correction: Felsenstein M. et al. Perineural Invasion in Pancreatic Ductal Adenocarcinoma (PDAC): A Saboteur of Curative Intended Therapies? J. Clin. Med. 2022, 11, 2367.
Cardiac tumor comprising a malignant peripheral nerve sheath tumor and spontaneous atrial osseous metaplasia in a sheep.
A rare case of multifocal schwannomatosis with multiple lesions of the median nerve.
A retrospective study on subcutaneous malignant peripheral nerve sheath tumors in 14 domestic rabbits (Oryctolagus cuniculus) treated surgically between 2008 and 2021.
Giant benign intrathoracic schwannoma: a decade-long progression towards fatality.
Non-sentinel lymph node metastases risk factors in patients with breast cancer with one or two sentinel lymph node macro-metastases.
Primary lipoblastic nerve sheath tumor in an inguinal lymph node mimicking metastatic tumor: a case report and literature review.

Curr Opin Neurol. 2023 Dec 01. 36(6): 544-548

Neuroscience and oncology: state-of-the-art and new perspectives.

Frank Winkler.

PURPOSE OF REVIEW: Emerging discoveries suggest that both the central (CNS) and peripheral (PNS) nervous system are an important driver of cancer initiation, promotion, dissemination, and therapy resistance, not only in the brain but also in multiple cancer types throughout the body. This article highlights the most recent developments in this emerging field of research over the last year and provides a roadmap for the future, emphasizing its translational potential.
RECENT FINDINGS: Excitatory synapses between neurons and cancer cells that drive growth and invasion have been detected and characterized. In addition, a plethora of paracrine, mostly tumor-promoting neuro-cancer interactions are reported, and a neuro-immuno-cancer axis emerges. Cancer cell-intrinsic neural properties, and cancer (therapy) effects on the nervous system that cause morbidity in patients and can establish harmful feedback loops receive increasing attention. Despite the relative novelty of these findings, therapies that inhibit key mechanisms of this neuro-cancer crosstalk are developed, and already tested in clinical trials, largely by repurposing of approved drugs.
SUMMARY: Neuro-cancer interactions are manyfold, have multiple clinical implications, and can lead to novel neuroscience-instructed cancer therapies and improved therapies of neurological dysfunctions and cancer pain. The development of biomarkers and identification of most promising therapeutic targets is crucial.

DOI: https://doi.org/10.1097/WCO.0000000000001207
bioRxiv. 2023 Oct 27. pii: 2023.10.24.563862. [Epub ahead of print]

Tumor- and Nerve-Derived Axon Guidance Molecule Promotes Pancreatic Ductal Adenocarcinoma Progression and Metastasis through Macrophage Reprogramming.

Noelle R J Thielman, Vanessa Funes, Sanjana Davuluri, Hector E Ibanez, Wei-Chih Sun, Juan Fu, Keyu Li, Stephen Muth, Xingyi Pan, Kenji Fujiwara, Dwayne Thomas, MacKenzie Henderson, Selina Shiqing Teh, Qingfeng Zhu, Elizabeth Thompson, Elizabeth M Jaffee, Alex Kolodkin, Fengxi Meng, Lei Zheng.

Axon guidance molecules were found to be the gene family most frequently altered in pancreatic ductal adenocarcinoma (PDA) through mutations and copy number changes. However, the exact molecular mechanism regarding PDA development remained unclear. Using genetically engineered mouse models to examine one of the axon guidance molecules, semaphorin 3D (SEMA3D), we found a dual role for tumor-derived SEMA3D in malignant transformation of pancreatic epithelial cells and a role for nerve-derived SEMA3D in PDA development. This was demonstrated by the pancreatic-specific knockout of the SEMA3D gene from the KRAS G12D and TP53 R 172 H mutation knock-in, PDX1-Cre (KPC) mouse model which demonstrated a delayed tumor initiation and growth comparing to the original KPC mouse model. Our results showed that SEMA3D knockout skews the macrophages in the pancreas away from M2 polarization, providing a potential mechanistic role of tumor-derived SEMA3D in PDA development. The KPC mice with the SEMA3D knockout remained metastasis-free, however, died from primary tumor growth. We then tested the hypothesis that a potential compensation mechanism could result from SEMA3D which is naturally expressed by the intratumoral nerves. Our study further revealed that nerve-derived SEMA3D does not reprogram macrophages directly, but reprograms macrophages indirectly through ARF6 signaling and lactate production in PDA tumor cells. SEMA3D increases tumor-secreted lactate which is sensed by GPCR132 on macrophages and subsequently stimulates pro-tumorigenic M2 polarization in vivo. Tumor intrinsic- and extrinsic-SEMA3D induced ARF6 signaling through its receptor Plexin D1 in a mutant KRAS-dependent manner. Consistently, RNA sequencing database analysis revealed an association of higher KRAS MUT expression with an increase in SEMA3D and ARF6 expression in human PDAs. Moreover, multiplex immunohistochemistry analysis showed an increased number of M2-polarized macrophages proximal to nerves in human PDA tissue expressing SEMA3D. Thus, this study suggests altered expression of SEMA3D in tumor cells lead to acquisition of cancer-promoting functions and the axon guidance signaling originating from nerves is "hijacked" by tumor cells to support their growth. Other axon guidance and neuronal development molecules may play a similar dual role which is worth further investigation.
One sentence summary: Tumor- and nerve-derived SEMA3D promotes tumor progression and metastasis through macrophage reprogramming in the tumor microenvironment.
STATEMENT OF SIGNIFICANCE: This study established the dual role of axon guidance molecule, SEMA3D, in the malignant transformation of pancreatic epithelial cells and of nerve-derived SEMA3D in PDA progression and metastasis. It revealed macrophage reprogramming as the mechanism underlying bothroles. Together, this research elucidated how inflammatory responses promote invasive PDA progression and metastasis through an oncogenic process.

DOI: https://doi.org/10.1101/2023.10.24.563862
Int Immunopharmacol. 2023 Nov 15. pii: S1567-5769(23)01544-8. [Epub ahead of print]126 111217

Tumor-derived GABA promotes lung cancer progression by influencing TAMs polarization and neovascularization.

Yanjun Dong, Guishi Wang, Dengke Nie, Yanxin Xu, Xue Bai, Changyong Lu, Fengyin Jian, Huijuan Wang, Xianjie Zheng.

   BACKGROUND: Gamma-aminobutyric acid (GABA), a common neurotransmitter, has been found in various cancers but its origin and its role in the tumor immune microenvironment remains unclear.
METHODS: Here, we reported the expression of glutamate decarboxylase 1 (GAD1, converting glutamate into GABA) in lung cancer tissues based on the publicly available database, and explored the effects and underlying mechanism of GABA on lung cancer progression.
RESULTS: Compared with normal tissues, GAD1 was aberrantly overexpressed in lung adenocarcinoma (LUAD) based on TCGA database. Furthermore, the LUAD patients' overall survival was negatively correlated with the GAD1 expression levels. Our work found that a GABAa receptor inhibitor had a therapeutic effect on mouse tumors and significantly reduced tumor size and weight. Further experiments showed that GABA derived from tumor cells promoted tumor progression not by directly affecting cancer cells but by affecting macrophages polarization in the tumor microenvironment. We found that GABA inhibited the NF-κB pathway and STAT3 pathway to prevent macrophages from polarizing towards M1 type, while promoting macrophage M2 polarization by activating the STAT6 pathway. GABA was also found to promote tumor neovascularization by increasing the expression of FGF2 in macrophages.
CONCLUSIONS: These results suggest that GABA affects tumor progression by regulating macrophage polarization, and targeting GABA and its signaling pathway may represent a potential therapy for lung cancer.

Keywords:  GABA; Lung cancer; Neovascularization; Polarization; TAMs

DOI:  https://doi.org/10.1016/j.intimp.2023.111217
Front Psychiatry. 2023 ;14 1281606

A meta-analysis of the association between post-traumatic stress disorder and cancer risk.

Juanjuan Yang, Wei Jiang.

   Background: Several studies have investigated the link between post-traumatic stress disorder (PTSD) and cancer risk but reported mixed results. The objective of our study was to investigate the association between PTSD and cancer risk.
Methods: Studies published in English about the relationship between PTSD and cancer incidence were systematically searched. We performed a meta-analysis to estimate the relative risks (RR) and 95% confidence intervals (CI) for cancer incidence.
Result: A total of 3,129 articles were screened. Finally, 8 articles and 11 studies were included in the meta-analysis. We found that PTSD was not associated with cancer risk compared with controls. For site-specific cancer, our results showed that women with PTSD were associated with higher risk of ovarian cancer than controls. However, PTSD was not associated with the risk of gastrointestinal cancer, breast cancer and lung cancer.
Conclusion: These analyzes based on studies published in English suggest that PTSD is associated with ovarian cancer risk, although the evidence base is very limited. Future studies are needed to investigate the mechanisms that PTSD diagnosis influenced cancer incidence depending on types of cancer.

Keywords:  PTSD; breast cancer; cancer incidence; ovarian cancer; stress

DOI:  https://doi.org/10.3389/fpsyt.2023.1281606
J Clin Med. 2023 Nov 06. pii: 6947. [Epub ahead of print]12(21):

Correction: Felsenstein M. et al. Perineural Invasion in Pancreatic Ductal Adenocarcinoma (PDAC): A Saboteur of Curative Intended Therapies? J. Clin. Med. 2022, 11, 2367.

Matthäus Felsenstein, Flora Lindhammer, Mathilde Feist, Karl Herbert Hillebrandt, Lea Timmermann, Christian Benzing, Brigitta Globke, Dario Zocholl, Mengwen Hu, Uli Fehrenbach, Bruno Valentin Sinn, Uwe Pelzer, Igor Maximillian Sauer, Johann Pratschke, Thomas Malinka.

In the original publication [...].

DOI: https://doi.org/10.3390/jcm12216947
J Vet Med Sci. 2023 Nov 14.

Cardiac tumor comprising a malignant peripheral nerve sheath tumor and spontaneous atrial osseous metaplasia in a sheep.

Ryo Ando, Norika Okada, Shogo Sato, Chihiro Kanno, Yosuke Maeda, Nuttipa Iamohbhars, Boonkanit Markbordee, Chun-Ho Park, Fumiaki Takahashi, Hiroaki Kawaguchi.

  Primary cardiac tumors in animals are very rare. The purpose of this report was to describe the first case of a cardiac tumor comprising a malignant peripheral nerve sheath tumor and spontaneous atrial osseous metaplasia in a Corriedale sheep. Histologically, the tumor in the bilateral atrial pericardium consisted of dense cellular components comprising tumor cells and a sparse cellular area, and non-neoplastic mature bone tissue. The tumor cells were spindle-shaped, round, or polygonal, and proliferating, with fascicular, storiform, palisading, and sheet patterns. Immunohistochemically, the tumor cells were positive for vimentin, S-100, occasionally positive for myeline basic protein, glial fibrillary acidic protein, neurofilament, neuron specific enolase, and neuron growth factor receptor suggesting that they originated from the nervous system. On the basis of these findings, the final diagnosis was a malignant peripheral nerve sheath tumor and spontaneous atrial osseous metaplasia.

Keywords:  cardiac tumor; heart; malignant peripheral nerve sheath tumor (MPNST); osseous metaplasia; sheep

DOI:  https://doi.org/10.1292/jvms.23-0247
Hand Surg Rehabil. 2023 Nov 09. pii: S2468-1229(23)00572-8. [Epub ahead of print]

A rare case of multifocal schwannomatosis with multiple lesions of the median nerve.

Siri Gowda, Dharminder Dhillon, Asit Khandwala.



Keywords:  Nerve sheath tumour; Peripheral nerve; Schwannoma; Schwannomatosis

DOI:  https://doi.org/10.1016/j.hansur.2023.11.001
J Vet Med Sci. 2023 Nov 13.

A retrospective study on subcutaneous malignant peripheral nerve sheath tumors in 14 domestic rabbits (Oryctolagus cuniculus) treated surgically between 2008 and 2021.

Chih Chun Wu, Yasutsugu Miwa, Makoto Nakata, James K Chambers, Kazuyuki Uchida, Nobuo Sasaki.

  A retrospective study involving 14 pet rabbits histopathologically diagnosed with malignant peripheral nerve sheath tumors (MPNSTs) was conducted. The age at diagnosis was 4-12 years, with a median age of 8.6 years. All rabbits had solid subcutaneous tumor masses in varied locations. Surgical excision of the tumors was performed in all cases. Recurrence was observed in 10 cases (71%), and postoperative metastasis to the lung was suspected in 4 cases (29%). The postoperative mean and median survival times were 11 months and 9 months, respectively. Hence, MPNSTs should be considered in the differential diagnosis for subcutaneous masses in rabbits and it is essential to inform the owners of the potentially high recurrence and metastasis rates.

Keywords:  Oryctolagus cuniculus; malignant peripheral nerve sheath tumor; rabbit

DOI:  https://doi.org/10.1292/jvms.23-0230
J Cardiothorac Surg. 2023 Nov 14. 18(1): 328

Giant benign intrathoracic schwannoma: a decade-long progression towards fatality.

Michiyo Miyawaki, Takashi Karashima, Miyuki Abe, Yohei Takumi, Takafumi Hashimoto, Ryotaro Kamohara, Atsushi Osoegawa, Kenji Sugio.

   BACKGROUND: Intrathoracic neurogenic tumors arise from sympathetic nerve trunks and intercostal nerves; more than 90% are benign. Schwannomas are the most common histological variety, but fatalities due to giant schwannomas are rare.
CASE PRESENTATION: We report a case of a 65-year-old woman who presented with chest pain and cough. Computed tomography (CT) revealed a large left chest wall mass of 130-mm in size, and the patient was referred to our department. Tumor biopsy was performed under local anesthesia, and a diagnosis of schwannoma was made. Ten years previously, a 30-mm tumor had been noted in the left third intercostal space by a previous doctor, but follow-up had been interrupted owing to depressive disorder. Although we planned to perform intercostal artery embolization followed by chest wall tumor resection, the patient did not consent to surgery due to uncontrolled depression. After four months, she developed respiratory failure caused by compression due to an enlarged tumor and died. Autopsy also revealed a benign schwannoma with no malignant findings.
CONCLUSIONS: Although schwannomas are benign tumors, there are some very rare cases in which they can become huge and life-threatening. Therefore, a benign tumor should not be neglected, and if surgery is not possible at the time of diagnosis, a regular follow up is necessary, in order not to miss the right timing for surgery.

Keywords:  Chest wall tumor; Giant tumor; Life-threatening; Schwannoma

DOI:  https://doi.org/10.1186/s13019-023-02375-2
Heliyon. 2023 Nov;9(11): e21254

Non-sentinel lymph node metastases risk factors in patients with breast cancer with one or two sentinel lymph node macro-metastases.

Liu-Yan Xu, Jing Zhao, Xuan Wang, Xin-Yan Jin, Bei-Bei Wang, Ying-Yi Fan, Xiao-Hua Pei.

  Approximately 59 % of patients with breast cancer with one or two sentinel lymph nodes (1-2 SLN) macrometastases do not benefit from axillary lymph node dissection (ALND), which may also incur morbidities. It is necessary to evaluate the association between various clinicopathological characteristics and non-sentinel lymph node metastases (non-SLNM) in patients with breast cancer with 1-2 SLN macrometastases, and determine whether they 1-2 should avoid ALND. Eight electronic literature databases (PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journal, Wanfang, and Chinese Biomedical Literature) were searched from their inception to June 30, 2023, and two reviewers independently extracted the data and assessed the risk of bias. Association strength was summarized using odds ratios (OR) and 95 % confidence intervals (CI). Heterogeneity was accounted for using a subgroup analysis. Publication bias was evaluated using funnel plots and Egger's test. There were 25 studies with 8021 participants, and 27 potential risk factors were evaluated. The risk factors for non-SLNM in patients with 1-2 SLN macrometastatic breast cancer include the following: factors of primary tumor: multifocality (OR (95 % CI (2.63 (1.96, 3.54))), tumor size ≥ T2 (2.64 (2.22, 3.14)), tumor localization (upper outer quad) (2.06 (1.23, 3.43)), histopathological grade (G3) (2.45 (1.70, 3.52)), vascular invasion (VI) (2.60 (1.35, 4.98)), lymphovascular invasion (LVI) (2.87 (1.80, 4.56)), perineural invasion (PNI) (3.16 (1.18,8.43)). Factors of lymph nodes: method of SLNs detected (blue dye) (3.85 (1.54, 9.60)), SLN metastasis ratio ≥0.5 (2.79 (2.24, 3.48)), two positive SLNs (3.55, (2.08, 6.07)), zero negative SLN (3.72 (CI 2.50, 4.29)), extranodal extension (ENE) (4.69 (2.16, 10.18)). Molecular typing: Her-2 positive (2.08 (1.26, 3.43)), Her-2 over-expressing subtype (1.83 (1.22, 2.73)). Factors of examination/inspection: axillary lymph nodes (ALNs) positive on imaging (3.18 (1.68, 6.00)), cancer antigen 15-3 (CA15-3) (4.01 (2.33,6.89)), carcinoembryonic antigen (CEA) (2.13 (1.32-3.43)). This review identified the risk factors for non-SLNM in patients with 1-2 SLN macrometastatic breast cancer. However, additional studies are needed to confirm the above findings owing to the limited number and types of studies included.

Keywords:  Breast cancer; Meta-analysis; Non-sentinel lymph node metastases; Risk factors; Sentinel lymph node macro-metastases

DOI:  https://doi.org/10.1016/j.heliyon.2023.e21254
Front Oncol. 2023 ;13 1258769

Primary lipoblastic nerve sheath tumor in an inguinal lymph node mimicking metastatic tumor: a case report and literature review.

Chengxin Chen, Jiachen Cao, Lingxie Song, Wenjie Wang, Dandan Guo, Qi Shi, Ying Zhang, Yunzhao Chen, Chunxia Liu, Feng Li.

  Lipoblastic nerve sheath tumors of soft tissue are characterized as schwannoma tumors that exhibit adipose tissue and lipoblast-like cells with signet-ring morphology. They have been documented to arise in various anatomic locations, including the thigh, groin, shoulder, and retroperitoneum. However, to our knowledge, this tumor has not been previously reported as a lymph node primary. We present herein the first case of a benign primary lipoblastic nerve sheath tumor arising in an inguinal lymph node in a 69-year-old man. Microscopic examination revealed a multinodular tumor comprising fascicles of spindle cells, as well as adipocytic and lipoblast-like signet-ring cell component in the context of schwannoma. Despite the presence of some bizarre cells with nuclear atypia, no obvious mitotic activity or necrosis was observed. Immunohistochemical analysis showed strong and diffuse expression of S-100, SOX10, CD56, and NSE in the spindle cells as well as in the signet-ring lipoblast-like cells and the mature adipocytes. Sequencing analysis of the neoplasm identified six non-synonymous single nucleotide variant genes, specifically NF1, BRAF, ECE1, AMPD3, CRYAB, and NPHS1, as well as four nonsense mutation genes including MRE11A, CEP290, OTOA, and ALOXE3. The patient remained alive and well with no evidence of recurrence over a period of ten-year follow-up.

Keywords:  case report; lipoblast-like cells; lipoblastic nerve sheath tumor; lymph node; nuclear atypia

DOI:  https://doi.org/10.3389/fonc.2023.1258769