bims-netuvo 2023-02-05 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2023–02–05
twelve papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute

Neuronal-Activity Dependent Mechanisms of Small Cell Lung Cancer Progression.
Cancer-nerve interplay in cancer progression and cancer-induced bone pain.
Area postrema neurons mediate interleukin-6 function in cancer-associated cachexia.
Cancer aggravation due to persistent pain signals with the increased expression of pain-related mediators in sensory neurons of tumor-bearing mice.
Tumor-associated nonmyelinating Schwann cell-expressed PVT1 promotes pancreatic cancer kynurenine pathway and tumor immune exclusion.
Single-cell RNA sequencing reveals intratumoral heterogeneity and potential mechanisms of malignant progression in prostate cancer with perineural invasion.
Abdominal Schwannoma Mimicking Lymph Node Metastasis in Rectal Cancer.
Repeated activation of Trpv1-positive sensory neurons facilitates tumor growth associated with changes in tumor-infiltrating immune cells.
Elucidation of the mechanisms underlying tumor aggravation by the activation of stress-related neurons in the paraventricular nucleus of the hypothalamus.
Primary Intraosseous Malignant Peripheral Nerve Sheath Tumor of the Humerus: Report of a Rare Case.
Myofibroma mimicking peripheral nerve sheath tumour with ulnar nerve compression symptoms.
Influence of beta-blockers and other non-cancer drugs on outcomes after pancreatic cancer resection.

bioRxiv. 2023 Jan 20. pii: 2023.01.19.524430. [Epub ahead of print]

Neuronal-Activity Dependent Mechanisms of Small Cell Lung Cancer Progression.

Solomiia Savchuk, Kaylee Gentry, Wengang Wang, Elana Carleton, Belgin Yalçın, Yin Liu, Elisa C Pavarino, Jenna LaBelle, Angus M Toland, Pamelyn J Woo, Fangfei Qu, Mariella G Filbin, Mark A Krasnow, Bernardo L Sabatini, Julien Sage, Michelle Monje, Humsa S Venkatesh.

Neural activity is increasingly recognized as a critical regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth both through paracrine mechanisms and through electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses, while perisynaptic neurotransmitter signaling drives breast cancer brain metastasis growth. Outside of the CNS, innervation of tumors such as prostate, breast, pancreatic and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression. However, the extent to which the nervous system regulates lung cancer progression, either in the lung or when metastatic to brain, is largely unexplored. Small cell lung cancer (SCLC) is a lethal high-grade neuroendocrine tumor that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that, similar to glioma, metastatic SCLC cells in the brain co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Optogenetic stimulation of cortical neuronal activity drives proliferation and invasion of SCLC brain metastases. In the brain, SCLC cells exhibit electrical currents and consequent calcium transients in response to neuronal activity, and direct SCLC cell membrane depolarization is sufficient to promote the growth of SCLC tumors. In the lung, vagus nerve transection markedly inhibits primary lung tumor formation, progression and metastasis, highlighting a critical role for innervation in overall SCLC initiation and progression. Taken together, these studies illustrate that neuronal activity plays a crucial role in dictating SCLC pathogenesis in both primary and metastatic sites.

DOI: https://doi.org/10.1101/2023.01.19.524430
J Bone Miner Metab. 2023 Jan 30.

Cancer-nerve interplay in cancer progression and cancer-induced bone pain.

Toshiyuki Yoneda, Masahiro Hiasa, Tatsuo Okui, Kenji Hata.

   INTRODUCTION: Cancer-induced bone pain (CIBP) is one of the most common and debilitating complications associated with bone metastasis. Although our understanding of the precise mechanism is limited, it has been known that bone is densely innervated, and that CIBP is elicited as a consequence of increased neurogenesis, reprogramming, and axonogenesis in conjunction with sensitization and excitation of sensory nerves (SNs) in response to the noxious stimuli that are derived from the tumor microenvironment developed in bone. Recent studies have shown that the sensitized and excited nerves innervating the tumor establish intimate communications with cancer cells by releasing various tumor-stimulating factors for tumor progression.
APPROACHES: In this review, the role of the interactions of cancer cells and SNs in bone in the pathophysiology of CIBP will be discussed with a special focus on the role of the noxious acidic tumor microenvironment, considering that bone is in nature hypoxic, which facilitates the generation of acidic conditions by cancer. Subsequently, the role of SNs in the regulation of cancer progression in the bone will be discussed together with our recent experimental findings.
CONCLUSION: It is suggested that SNs may be a newly-recognized important component of the bone microenvironment that contribute to not only in the pathophysiology of CIBP but also cancer progression in bone and dissemination from bone. Suppression of the activity of bone-innervating SNs, thus, may provide unique opportunities in the treatment of cancer progression and dissemination, as well as CIBP.

Keywords:  Acid-sensing ion channel 3; Acidic bone microenvironment; Bone pain; Sensory nerves; Transient receptor potential channel vanilloid subfamily member 1

DOI:  https://doi.org/10.1007/s00774-023-01401-6
bioRxiv. 2023 Jan 14. pii: 2023.01.12.523716. [Epub ahead of print]

Area postrema neurons mediate interleukin-6 function in cancer-associated cachexia.

Qingtao Sun, Daniëlle van de Lisdonk, Miriam Ferrer, Bruno Gegenhuber, Melody Wu, Jessica Tollkuhn, Tobias Janowitz, Bo Li.

Interleukin-6 (IL-6) has been long considered a key player in cancer-associated cachexia 1-15 . It is believed that sustained elevation of IL-6 production during cancer progression causes brain dysfunctions, which ultimately result in cachexia 16-20 . However, how peripheral IL-6 influences the brain remains poorly understood. Here we show that neurons in the area postrema (AP), a circumventricular structure in the hindbrain, mediate the function of IL-6 in cancer-associated cachexia in mice. We found that circulating IL-6 can rapidly enter the AP and activate AP neurons. Peripheral tumor, known to increase circulating IL-6 1-5,15,18,21-23 , leads to elevated IL-6 and neuronal hyperactivity in the AP, and causes potentiated excitatory synaptic transmission onto AP neurons. Remarkably, neutralization of IL-6 in the brain of tumor-bearing mice with an IL-6 antibody prevents cachexia, reduces the hyperactivity in an AP network, and markedly prolongs lifespan. Furthermore, suppression of Il6ra , the gene encoding IL-6 receptor, specifically in AP neurons with CRISPR/dCas9 interference achieves similar effects. Silencing of Gfral-expressing AP neurons also ameliorates the cancer-associated cachectic phenotypes and AP network hyperactivity. Our study identifies a central mechanism underlying the function of peripheral IL-6, which may serve as a target for treating cancer-associated cachexia.

DOI: https://doi.org/10.1101/2023.01.12.523716
Mol Brain. 2023 Feb 03. 16(1): 19

Cancer aggravation due to persistent pain signals with the increased expression of pain-related mediators in sensory neurons of tumor-bearing mice.

Kenichi Tanaka, Takashige Kondo, Michiko Narita, Takeru Muta, Sara Yoshida, Daisuke Sato, Yukari Suda, Yusuke Hamada, Takatsune Shimizu, Naoko Kuzumaki, Minoru Narita.

  A growing body of evidence suggests that intractable pain reduces both the quality of life and survival in cancer patients. In the present study, we evaluated whether chronic pain stimuli could directly affect cancer pathology using tumor-bearing mice. For this purpose, we used two different models of chronic pain in mice, neuropathic pain and persistent postsurgical pain, with Lewis lung carcinoma (LLC) as tumor cells. We found that tumor growth was dramatically promoted in these pain models. As well as these pain models, tumor growth of LLC, severe osteosarcoma (AXT) and B16 melanoma cells was significantly promoted by concomitant activation of sensory neurons in AAV6-hM3Dq-injected mice treated with the designer drug clozapine-N-oxide (CNO). Significant increases in mRNA levels of vascular endothelial growth factor-A (Vegfa), tachykinin precursor 1 (Tac1) and calcitonin-related polypeptide alpha (Calca) in the ipsilateral side of dorsal root ganglion of AAV6-hM3Dq-injected mice were observed by concomitant activation of sensory neurons due to CNO administration. Moreover, in a model of bone cancer pain in which mice were implanted with AXT cells into the right femoral bone marrow cavity, the survival period was significantly prolonged by repeated inhibition of sensory neurons of AAV6-hM4Di-injected mice by CNO administration. These findings suggest that persistent pain signals may promote tumor growth by the increased expression of sensory-located peptides and growth factors, and controlling cancer pain may prolong cancer survival.

Keywords:  Cancer pain; Cancer-neuron interaction; Sensory neuron; Survival; Tumor growth

DOI:  https://doi.org/10.1186/s13041-023-01001-5
Sci Adv. 2023 Feb 03. 9(5): eadd6995

Tumor-associated nonmyelinating Schwann cell-expressed PVT1 promotes pancreatic cancer kynurenine pathway and tumor immune exclusion.

Chengcao Sun, Youqiong Ye, Zhi Tan, Yuan Liu, Yajuan Li, Wei Hu, Ke Liang, Sergey D Egranov, Lisa Angela Huang, Zhao Zhang, Yaohua Zhang, Jun Yao, Tina K Nguyen, Zilong Zhao, Andrew Wu, Jeffrey R Marks, Abigail S Caudle, Aysegul A Sahin, Jianjun Gao, Seth T Gammon, David Piwnica-Worms, Jian Hu, Paul J Chiao, Dihua Yu, Mien-Chie Hung, Michael A Curran, George A Calin, Haoqiang Ying, Leng Han, Chunru Lin, Liuqing Yang.

One of the major obstacles to treating pancreatic ductal adenocarcinoma (PDAC) is its immunoresistant microenvironment. The functional importance and molecular mechanisms of Schwann cells in PDAC remains largely elusive. We characterized the gene signature of tumor-associated nonmyelinating Schwann cells (TASc) in PDAC and indicated that the abundance of TASc was correlated with immune suppressive tumor microenvironment and the unfavorable outcome of patients with PDAC. Depletion of pancreatic-specific TASc promoted the tumorigenesis of PDAC tumors. TASc-expressed long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was triggered by the tumor cell-produced interleukin-6. Mechanistically, PVT1 modulated RAF proto-oncogene serine/threonine protein kinase-mediated phosphorylation of tryptophan 2,3-dioxygenase in TASc, facilitating its enzymatic activities in catalysis of tryptophan to kynurenine. Depletion of TASc-expressed PVT1 suppressed PDAC tumor growth. Furthermore, depletion of TASc using a small-molecule inhibitor effectively sensitized PDAC to immunotherapy, signifying the important roles of TASc in PDAC immune resistance.

DOI: https://doi.org/10.1126/sciadv.add6995
Front Genet. 2022 ;13 1073232

Single-cell RNA sequencing reveals intratumoral heterogeneity and potential mechanisms of malignant progression in prostate cancer with perineural invasion.

Bao Zhang, Shenghan Wang, Zhichao Fu, Qiang Gao, Lin Yang, Zhentao Lei, Yuqiang Shi, Kai Le, Jie Xiong, Siyao Liu, Jiali Zhang, Junyan Su, Jing Chen, Mengyuan Liu, Beifang Niu.

  Background: Prostate cancer (PCa) is the second most common cancer among men worldwide. Perineural invasion (PNI) was a prominent characteristic of PCa, which was recognized as a key factor in promoting PCa progression. As a complex and heterogeneous disease, its true condition is difficult to explain thoroughly with conventional bulk RNA sequencing. Thus, an improved understanding of PNI-PCa progression at the single-cell level is needed. Methods: In this study, we performed scRNAseq on tumor tissues of three PNI-PCa patients. Principal component analysis (PCA) and Uniform manifold approximation and projection (UMAP) were used to reduce dimensionality and visualize the cellular composition of tumor tissues. The differently expressed genes among each cluster were identified by EdgeR. GO enrichment analysis was used to understand the roles of genes within the clusters. Pseudotime cell trajectory was used to reveal the molecular pathways underlying cell fate decisions and identify genes whose expression changed as the cells underwent transition. We applied CellPhoneDB to identify cell-cell interactions among the epithelial and neural cells in PNI-PCa. Results: Analysis of the ∼17,000 single-cell transcriptomes in three PNI prostate cancer tissues, we identified 12 major cell clusters, including neural cells and two epithelial subtypes with different expression profiles. We found that basal/intermediate epithelial cell subtypes highly expressed PCa progression-related genes, including PIGR, MMP7, and AGR2. Pseudotime trajectory analysis showed that luminal epithelial cells could be the initiating cells and transition to based/intermediate cells. Gene ontology (GO) enrichment analysis showed that pathways related to cancer progressions, such as lipid catabolic and fatty acid metabolic processes, were significantly enriched in basal/intermediate cells. Our analysis also suggested that basal/intermediate cells communicate closely with neural cells played a potential role in PNI-PCa progression. Conclusion: These results provide our understanding of PNI-PCa cellular heterogeneity and characterize the potential role of basal/intermediate cells in the PNI-PCa progression.

Keywords:  epithelial basal/intermediate cells; intercellular communication; intratumor heterogeneity; neural cells; progression; prostate cancer with perineural invasion; single-cell RNA sequencing

DOI:  https://doi.org/10.3389/fgene.2022.1073232
Cureus. 2022 Dec;14(12): e33096

Abdominal Schwannoma Mimicking Lymph Node Metastasis in Rectal Cancer.

Enxhi Kotrri, Derek Jonker, Rebecca Auer, Gordon Locke.

  Schwannomas are rare benign tumors that are often asymptomatic and identified incidentally on imaging studies undertaken for another purpose. Schwannomas arising from the vestibular nerve are the most common site of identification; however, schwannomas can arise extracranially in any peripheral nerve tissue. Here, we present a case study of a patient with a localized rectal adenocarcinoma who was found to have a retroperitoneal schwannoma initially felt to be a lymph node metastasis of his rectal cancer. The diagnosis of schwannoma was confirmed via biopsy, which resulted in changes to the patient's overall management including radiotherapy volumes and recommendation against neoadjuvant or adjuvant systemic therapy.

Keywords:  abdominal schwannoma; lymph node (ln); lymph node metastasis; metastasis; radiation oncology; rectal cancer; schwannoma

DOI:  https://doi.org/10.7759/cureus.33096
Biochem Biophys Res Commun. 2023 Jan 24. pii: S0006-291X(23)00106-7. [Epub ahead of print]648 36-43

Repeated activation of Trpv1-positive sensory neurons facilitates tumor growth associated with changes in tumor-infiltrating immune cells.

Kenichi Tanaka, Takashige Kondo, Michiko Narita, Takeru Muta, Sara Yoshida, Daisuke Sato, Yukari Suda, Yusuke Hamada, Hiroyuki Tezuka, Naoko Kuzumaki, Minoru Narita.

  It is considered that sensory neurons extend into the tumor microenvironment (TME), which could be associated with tumor growth. However, little is known about how sensory signaling could promote tumor progression. In this study, chemogenetic activation of transient receptor potential vanilloid 1 (Trpv1)-positive sensory neurons (C-fibers) by the microinjection of AAV-hSyn-FLEX-hM3Dq-mCherry into the sciatic nerve dramatically increased tumor volume in tumor-bearing Trpv1-Cre mice. This activation in Trpv1::hM3Dq mice that had undergone tumor transplantation significantly reduced the population of tumor-infiltrating CD4+ T cells and increased the mRNA level of the M2-macrophage marker, CX3C motif chemokine receptor 1 (Cx3cr1) in immunosuppressive cells, such as tumor-associated macrophages (TAMs) and tumor-infiltrating monocytic myeloid-derived suppressor cells (M-MDSCs). Under these conditions, we found a significant correlation between the decreased expression of the M1-macrophage marker Tnf and tumor volume. These findings suggest that repeated activation of Trpv1-positive sensory neurons may facilitate tumor growth along with changes in tumor-infiltrating immune cells.

Keywords:  M2-polarization; Pain sensation; Sensory neuron; Tumor microenvironment; Tumor-associated macrophage

DOI:  https://doi.org/10.1016/j.bbrc.2023.01.075
Mol Brain. 2023 Feb 02. 16(1): 18

Elucidation of the mechanisms underlying tumor aggravation by the activation of stress-related neurons in the paraventricular nucleus of the hypothalamus.

Sara Yoshida, Yusuke Hamada, Michiko Narita, Daisuke Sato, Kenichi Tanaka, Tomohisa Mori, Hiroyuki Tezuka, Yukari Suda, Hideki Tamura, Kazunori Aoki, Naoko Kuzumaki, Minoru Narita.

  A growing body of evidence suggests that excess stress could aggravate tumor progression. The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the adaptation to stress because the hypothalamic-pituitary-adrenal (HPA) axis can be activated by inducing the release of corticotropin-releasing hormone (CRH) from the PVN. In this study, we used pharmacogenetic techniques to investigate whether concomitant activation of CRHPVN neurons could directly contribute to tumor progression. Tumor growth was significantly promoted by repeated activation of CRHPVN neurons, which was followed by an increase in the plasma levels of corticosterone. Consistent with these results, chronic administration of glucocorticoids induced tumor progression. Under the concomitant activation of CRHPVN neurons, the number of cytotoxic CD8+ T cells in the tumor microenvironment was dramatically decreased, and the mRNA expression levels of hypoxia inducible factor 1 subunit α (HIF1α), glucocorticoid receptor (GR) and Tsc22d3 were upregulated in inhibitory lymphocytes, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Furthermore, the mRNA levels of various kinds of driver molecules related to tumor progression and tumor metastasis were prominently elevated in cancer cells by concomitant activation of CRHPVN neurons. These findings suggest that repeated activation of the PVN-CRHergic system may aggravate tumor growth through a central-peripheral-associated tumor immune system.

Keywords:  Cancer; Corticotropin-releasing hormone; Glucocorticoids; Tsc22d3; Tumor-associated macrophage; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1186/s13041-023-01006-0
Cureus. 2022 Dec;14(12): e33178

Primary Intraosseous Malignant Peripheral Nerve Sheath Tumor of the Humerus: Report of a Rare Case.

Wendolin J Ortiz, Maria S Salazar, John J Eager, Saleha Sajid, Mario Cervantes.

  Malignant peripheral nerve sheath tumors (MPNSTs) usually arise in the soft tissues. Intraosseous MPNSTs are rare. They may arise de novo but are typically associated with neurofibromatosis type 1 (NF1) and radiation therapy. Our patient is a 58-year-old female patient that presented with right shoulder pain. An MRI showed a shoulder mass, and percutaneous bone biopsy demonstrated morphology suggestive of an MPNST; besides, on immunohistochemistry, SOX10 was positive, and H3K27me3 expression was entirely lost. The patient underwent total resection of the right proximal humerus and endoprosthetic shoulder reconstruction, followed by radiation therapy and chemotherapy. Only a few cases in the mandible, spine, maxilla, ulna, metacarpal, tarsal, and one in the humerus have been published. In this paper, we contribute with an additional case of primary intraosseous MPNST in the humerus and a brief literature review.

Keywords:  malignant peripheral nerve sheath tumour; mpnst; proximal humerus; sarcoma; sox10

DOI:  https://doi.org/10.7759/cureus.33178
BMJ Case Rep. 2023 Feb 02. pii: e252939. [Epub ahead of print]16(2):

Myofibroma mimicking peripheral nerve sheath tumour with ulnar nerve compression symptoms.

Harvey Chim, Gayle Suk Wiesemann, Elham Nasri.

  We report a case of myofibroma encasing the ulnar nerve on the medial aspect of the left arm with motor and sensory deficit secondary to compression. Initially, the tumour appeared to be a benign peripheral nerve sheath tumour based on preoperative imaging, with clinical examination positive for left hand clawing and a positive Wartenberg's and Froment's sign. However, intraoperative dissection demonstrated that the mass did not originate from the ulnar nerve proper, lowering suspicion for a peripheral nerve sheath tumour. Histopathological analysis showed spindle cell neoplasm, consistent with myofibroma. The patient underwent hand occupational therapy subsequently, with improvement of grip strength from 5 lb to 12 lb by 4 months postoperatively and resolution of clawing of the hand postoperatively. We discuss differentiating features for this rare occurrence of solitary adult myofibroma, where the final diagnosis was only made after formal histopathological analysis.

Keywords:  Orthopaedic and trauma surgery; Orthopaedics; Peripheral nerve disease; Plastic and reconstructive surgery; Tendonopathies

DOI:  https://doi.org/10.1136/bcr-2022-252939
Br J Surg. 2023 Feb 02. pii: znac434. [Epub ahead of print]

Influence of beta-blockers and other non-cancer drugs on outcomes after pancreatic cancer resection.

Felix J Hüttner, Marius Mauch, Max Heckler, Thilo Hackert, Markus W Büchler, Pascal Probst, Markus K Diener.

DOI: https://doi.org/10.1093/bjs/znac434