bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2022–10–09
thirteen papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute
  1. Radiotherapy exacerbates tumor-promoting innervation and nerve signaling in rectal cancer.
  2. The Boring Schwann Cells: Tumor Me-TAST-asis along Nerves.
  3. Tumor microenvironment adrenergic nerves blockade liposomes for cancer therapy.
  4. Single-cell RNA sequencing uncovers a neuron-like macrophage subset associated with cancer pain.
  5. Neurotransmitter signaling: a new frontier in colorectal cancer biology and treatment.
  6. Tissue-resident glial cells associate with tumoral vasculature and promote cancer progression.
  7. [Hematopoietic regulation and tumor control by the peripheral nervous system].
  8. Oncostatin M receptor is overexpressed in oral squamous cell carcinoma and connected to poor prognosis.
  9. A case of head and neck cutaneous squamous cell carcinoma highlighting aggressive perineural features.
  10. [Prognostic values of stromal tumor-infiltrating lymphocytes and lymphocyte-activation gene-3 in advanced gastric adenocarcinoma].
  11. Sciatic nerve schwannoma complicated by nerve bundle membrane effusion: Two case reports and a literature review.
  12. Morphine stimulates cervical cancer cells and alleviates cytotoxicity of chemotherapeutic drugs via opioid receptor-dependent and -independent mechanisms.
  13. A case of intestinal schwannoma initially suspected by transvaginal ultrasound.
  1. Int J Radiat Oncol Biol Phys. 2022 Oct 03. pii: S0360-3016(22)03415-0. [Epub ahead of print]
    Radiotherapy exacerbates tumor-promoting innervation and nerve signaling in rectal cancer.
    Taylor P Uccello, Maggie L Lecsh, Nicholas A Ullman, Sarah A Kintzel, Lauren B Gradzewicz, Trishna Velagaleti, Fergal J Fleming, Bradley N Mills, Joseph D Murphy, Jesse Garrett-Larsen, Haoming Qiu, Michael G Drage, Jian Ye, Nicholas W Gavras, Carl J Johnston, Tanzy M T Love, Elizabeth A Repasky, David C Linehan, Edith M Lord, Scott A Gerber.
       PURPOSE: Many solid tumors present with perineural invasion (PNI), and innervation correlates with worsened prognosis. The effects that commonly administered therapies such as radiation therapy (RT) have on PNI status remain unknown. Here we investigated the contribution of RT on the nervous system and elucidated the implications that increased nerve signaling can have on tumor burden using our previously developed orthotopic murine model of rectal cancer (RC) and our targeted and clinically relevant short course radiation therapy (SCRT) regimen.
    METHODS: Medical charts for RC patients treated at XXXX were obtained and PNI status was analyzed. Human data was accompanied by an orthotopic murine model of RC. Briefly, luciferase-expressing murine colon-38 tumor cells (MC38-luc) were injected orthotopically into the rectal wall of C57BL6 mice. Targeted SCRT (5 Gray (Gy) per fraction for five consecutive fractions) was administered to the tumor. Intratumoral innervation was determined by immunohistochemistry (IHC), local norepinephrine (NE) concentration was quantified by ELISA, and Beta-Adrenergic receptor (BAR) expression was assessed by flow cytometry. Chronic NE signaling was mirrored by daily isoproterenol treatment and the effect on tumor burden was determined by overall survival, presence of metastatic lesions, and tumor size. Isoproterenol signaling was inhibited by administration of propranolol.
    RESULTS: Human RC patients with PNI have decreased overall survival compared to patients without PNI. In our mouse model, SCRT induced the expression of genes involved in neurogenesis, increased local NE secretion, and upregulated BAR expression. Treating mice with isoproterenol resulted in decreased overall survival, increased rate of metastasis, and reduced SCRT efficacy. Interestingly, the isoproterenol-induced decrease in SCRT efficacy could be abrogated by blocking the BAR through the use of propranolol, suggesting a direct role of BAR stimulation on impairing SCRT responses.
    CONCLUSIONS: Our results indicate that while SCRT is a valuable treatment, it is accompanied by adverse effects on the nervous system that may impede the efficacy of therapy and promote tumor burden. Therefore, we could speculate that therapies aimed at targeting this signaling cascade or impairing nerve growth in combination with SCRT may prove beneficial in future cancer treatment.
    DOI:  https://doi.org/10.1016/j.ijrobp.2022.09.080
  2. Cancer Discov. 2022 Oct 05. 12(10): 2240-2243
    The Boring Schwann Cells: Tumor Me-TAST-asis along Nerves.
    Moran Amit, Anirban Maitra.
      Perineural spread is an ominous feature of cancer. Here, Deborde and colleagues describe for the first time the biophysical coupling driving this route of tumor spread and the role of Schwann cell activation in the mobilization of cancer cells within and along the tumor-associated nerves. See related article by Deborde et al., p. 2454 (8).
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0829
  3. J Control Release. 2022 Sep 29. pii: S0168-3659(22)00644-7. [Epub ahead of print]
    Tumor microenvironment adrenergic nerves blockade liposomes for cancer therapy.
    Shuang Zhou, Jinbo Li, Jiang Yu, Yuequan Wang, Zhaomeng Wang, Zhonggui He, Defang Ouyang, Hongzhuo Liu, Yongjun Wang.
      Adrenergic nerves, which are innervated in the tumor, regulate tumor initiation, angiogenesis, and the establishment of the tumor immunosuppressive microenvironment. The study aimed to evaluate the effectiveness of propranolol liposomes (Lipo pro) in inhibiting adrenergic nerve signaling in cancer therapy. Lipo pro significantly regulated the distribution of tumor microenvironment adrenergic nerves, tumor blood vessels, and immunosuppressive microenvironment. Furthermore, it displayed considerable therapeutic effects on prostatic cancer, pancreatic ductal adenocarcinoma, and melanoma. The combination therapeutic regimen, in which Lipo pro was the primary treatment and was supplemented by chemotherapy, showed significant advantages over any single treatment, effectively restraining tumor growth in situ and metastasis, thereby prolonging the survival of mice. This study established a proof-of-concept by targeting tumor adrenergic nerve signaling for cancer therapy.
    Keywords:  Adrenergic nerves; Combination regimen; Liposome; Propranolol; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jconrel.2022.09.049
  4. Sci Adv. 2022 Oct 07. 8(40): eabn5535
    Single-cell RNA sequencing uncovers a neuron-like macrophage subset associated with cancer pain.
    Philip Chiu-Tsun Tang, Jeff Yat-Fai Chung, Jinyue Liao, Max Kam-Kwan Chan, Alex Siu-Wing Chan, Guangyao Cheng, Chunjie Li, Xiao-Ru Huang, Calvin Sze-Hang Ng, Eric W-F Lam, Dongmei Zhang, Yi-Ping Ho, Ka-Fai To, Kam-Tong Leung, Xiaohua Jiang, Ho Ko, Tin-Lap Lee, Hui-Yao Lan, Patrick Ming-Kuen Tang.
      Tumor innervation is a common phenomenon with unknown mechanism. Here, we discovered a direct mechanism of tumor-associated macrophage (TAM) for promoting de novo neurogenesis via a subset showing neuronal phenotypes and pain receptor expression associated with cancer-driven nocifensive behaviors. This subset is rich in lung adenocarcinoma associated with poorer prognosis. By elucidating the transcriptome dynamics of TAM with single-cell resolution, we discovered a phenomenon "macrophage to neuron-like cell transition" (MNT) for directly promoting tumoral neurogenesis, evidenced by macrophage depletion and fate-mapping study in lung carcinoma models. Encouragingly, we detected neuronal phenotypes and activities of the bone marrow-derived MNT cells (MNTs) in vitro. Adoptive transfer of MNTs into NOD/SCID mice markedly enhanced their cancer-associated nocifensive behaviors. We identified macrophage-specific Smad3 as a pivotal regulator for promoting MNT at the genomic level; its disruption effectively blocked the tumor innervation and cancer-dependent nocifensive behaviors in vivo. Thus, MNT may represent a precision therapeutic target for cancer pain.
    DOI:  https://doi.org/10.1126/sciadv.abn5535
  5. Oncogene. 2022 Oct 01.
    Neurotransmitter signaling: a new frontier in colorectal cancer biology and treatment.
    Francesca Battaglin, Priya Jayachandran, Carly Strelez, Annika Lenz, Sandra Algaze, Shivani Soni, Jae Ho Lo, Yan Yang, Joshua Millstein, Wu Zhang, Evanthia T Roussos Torres, Jean C Shih, Shannon M Mumenthaler, Josh Neman, Heinz-Josef Lenz.
      The brain-gut axis, a bidirectional network between the central and enteric nervous system, plays a critical role in modulating the gastrointestinal tract function and homeostasis. Recently, increasing evidence suggests that neuronal signaling molecules can promote gastrointestinal cancers, however, the mechanisms remain unclear. Aberrant expression of neurotransmitter signaling genes in colorectal cancer supports the role of neurotransmitters to stimulate tumor growth and metastatic spread by promoting cell proliferation, migration, invasion, and angiogenesis. In addition, neurotransmitters can interact with immune and endothelial cells in the tumor microenvironment to promote inflammation and tumor progression. As such, pharmacological targeting of neurotransmitter signaling represent a promising novel anticancer approach. Here, we present an overview of the current evidence supporting the role of neurotransmitters in colorectal cancer biology and treatment.
    DOI:  https://doi.org/10.1038/s41388-022-02479-4
  6. Angiogenesis. 2022 Oct 01.
    Tissue-resident glial cells associate with tumoral vasculature and promote cancer progression.
    Beatriz G S Rocha, Caroline C Picoli, Bryan O P Gonçalves, Walison N Silva, Alinne C Costa, Michele M Moraes, Pedro A C Costa, Gabryella S P Santos, Milla R Almeida, Luciana M Silva, Youvika Singh, Marcelo Falchetti, Gabriela D A Guardia, Pedro P G Guimarães, Remo C Russo, Rodrigo R Resende, Mauro C X Pinto, Jaime H Amorim, Vasco A C Azevedo, Alexandre Kanashiro, Helder I Nakaya, Edroaldo L Rocha, Pedro A F Galante, Akiva Mintz, Paul S Frenette, Alexander Birbrair.
      Cancer cells are embedded within the tissue and interact dynamically with its components during cancer progression. Understanding the contribution of cellular components within the tumor microenvironment is crucial for the success of therapeutic applications. Here, we reveal the presence of perivascular GFAP+/Plp1+ cells within the tumor microenvironment. Using in vivo inducible Cre/loxP mediated systems, we demonstrated that these cells derive from tissue-resident Schwann cells. Genetic ablation of endogenous Schwann cells slowed down tumor growth and angiogenesis. Schwann cell-specific depletion also induced a boost in the immune surveillance by increasing tumor-infiltrating anti-tumor lymphocytes, while reducing immune-suppressor cells. In humans, a retrospective in silico analysis of tumor biopsies revealed that increased expression of Schwann cell-related genes within melanoma was associated with improved survival. Collectively, our study suggests that Schwann cells regulate tumor progression, indicating that manipulation of Schwann cells may provide a valuable tool to improve cancer patients' outcomes.
    Keywords:  Genetic depletion; Glia; Perivascular cells; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10456-022-09858-1
  7. Rinsho Ketsueki. 2022 ;63(9): 991-998
    [Hematopoietic regulation and tumor control by the peripheral nervous system].
    Noboru Asada.
      The nervous system is distributed throughout all body organs and unconsciously maintains homeostasis. The peripheral nervous system, which comprises autonomic and sensory nerves, is distributed in the bone marrow, which controls hematopoiesis, and the surrounding bone tissue, which is also closely associated with hematopoiesis regulation. Recent advances in research techniques have revealed that the peripheral nervous system affects normal hematopoiesis, hematopoiesis under stress, and the regulation of hematopoietic aging. The peripheral nervous system also affects the development and progression of malignant tumors, including hematopoietic tumors and normal tissue, making the peripheral nerve regulation a potential new therapeutic target.
    Keywords:  Hematopoiesis; Nervous system; Niche; Perivascular stromal cell
    DOI:  https://doi.org/10.11406/rinketsu.63.991
  8. J Oral Pathol Med. 2022 Oct 07.
    Oncostatin M receptor is overexpressed in oral squamous cell carcinoma and connected to poor prognosis.
    Qifeng Geng, Jing Wang, Wei Zhang, Wei Zhou, Genxiong Tang, Mingyan Gu.
       BACKGROUND: Oncostatin M receptor (OSMR) is an interleukin 6 receptor with great influence on inflammation and cancer progression. However, the function of OSMR in oral squamous cell carcinoma (OSCC) remains unknown.
    METHODS: OSMR expression was explored with TIMER and TCGA databases. The mRNA and protein expressions of OSMR were detected in oral tissues. The association between OSMR expression and clinicopathological characteristics was analyzed, and the prognostic value of OSMR was determined. Immune statues of OSMR were analyzed by TIMER and TISIDB. The underlying mechanisms of OSMR in OSCC was also explored preliminarily.
    RESULTS: OSMR was dysregulated in many cancers. Both mRNA and protein levels of OSMR in OSCC tissues were significantly higher than that in normal oral tissues. OSMR expression was connected to differentiation, lymph node metastasis, TNM stage, perineural invasion and vascular invasion. OSMR expression was an independent prognostic factor associated with overall survivals. OSMR expression was significantly related to CD8+ T cell and IL6R. High OSMR expression was associated with focal adhesion, ECM receptor interaction, and JAK/STAT signaling pathway.
    CONCLUSION: OSMR was overexpressed in OSCC and related to overall survival. OSMR expression has potential to become an effective prognostic biomarker for OSCC patients. This article is protected by copyright. All rights reserved.
    Keywords:  JAK/STAT; OSMR; oral squamous cell carcinoma; prognosis
    DOI:  https://doi.org/10.1111/jop.13371
  9. Radiol Case Rep. 2022 Dec;17(12): 4459-4461
    A case of head and neck cutaneous squamous cell carcinoma highlighting aggressive perineural features.
    Grant H Kalil, Charlotte S Taylor, Gina D Jefferson.
      Cutaneous squamous cell carcinoma (cSCC) is the second most common nonmelanoma skin cancer in the United States following basal cell carcinoma. The majority are successfully cured by surgical excision or Mohs microsurgery. A subset of cSCCs are more aggressive and likely to recur locally, spread to regional lymph nodes or even distantly, and can even result in death. High-risk features of cSCC including perineural invasion of nerve >0.1 mm in diameter and invasion beyond the subcutaneous fat are not routinely reported by Mohs microsurgery. Facial cSCC commonly involves branches of the facial nerve (VII) or trigeminal nerve (V). Clinical symptoms associated with cranial nerve VII and V involvement include pain, paresthesia of the face and tongue, facial paralysis. Assessment of nerve involvement by magnetic resonance imaging (MRI) is the most optimal imaging modality. Here, we present a case where Mohs microsurgery was performed on a facial cSCC 1.5 years prior to the development of facial paresis. We aim to highlight the interesting perineural path resulting in facial paralysis and associated symptomatology, the importance of MRI, and to remind clinicians of important high-risk features of cSCC.
    Keywords:  Cutaneous squamous cell carcinoma (cSCC); Facial paralysis; Magnetic resonance imaging (MRI); Perineural invasion; Skull base
    DOI:  https://doi.org/10.1016/j.radcr.2022.08.072
  10. Zhonghua Bing Li Xue Za Zhi. 2022 Oct 08. 51(10): 1007-1012
    [Prognostic values of stromal tumor-infiltrating lymphocytes and lymphocyte-activation gene-3 in advanced gastric adenocarcinoma].
    Z D Wu, J C Wang, H J Zhang, J Q Lin, Z Z Wu, X W Zheng, G Chen.
      Objective: To analyze density of stromal tumor-infiltrating lymphocytes (sTIL) and expression of lymphocyte-activation gene-3 (LAG-3) protein in advanced gastric adenocarcinomas, and to investigate the correlation of sTIL and LAG-3 with the prognosis in patients with advanced gastric adenocarcinoma. Methods: The clinicopathological characteristics and follow-up data of 260 patients with advanced gastric adenocarcinoma were collected at Fujian Cancer Hospital, from January 2011 to December 2014. The percentage of sTILs was reported semi-quantitatively using histological section evaluation, the LAG-3 protein was detected using immunohistochemistry, and the expression was correlated with the clinicopathological features and patient outcomes. Results: Among the 260 cases, high density of sTIL was detected in 173 cases (66.5%) while LAG-3 high expression was observed in 160 cases (61.5%). These cases were divided into four groups. Group Ⅰ: 48 cases (18.5%) were sTIL low/LAG-3 low; group Ⅱ: 52 cases (20.0%) were sTIL high/LAG-3 low; group Ⅲ: 39 cases (15.0%) were sTIL low/LAG-3 high; group Ⅳ: 121 cases (46.5%) were sTIL high/LAG-3 high. Kaplan-Meier survival analyses showed that patient prognoses were related to age, tumor size, tumor location, Lauren classification, perineural invasion, vascular invasion, TNM staging, postoperative adjuvant chemotherapy and molecular classification (P<0.05). Meanwhile, higher densities of sTIL and higher expression of LAG-3 were associated with better prognosis. Multivariate survival analysis showed age, tumor size, Lauren classification and postoperative adjuvant chemotherapy were independent prognostic factors for patient survival. The results showed a poor prognosis in low-sTIL/low-LAG-3 patients. Conclusions: Compared with low density of sTIL and low expression of LAG-3, high density of sTIL and high expression of LAG-3 are associated with better outcomes in patients with advanced gastric adenocarcinoma, respectively. Combined detecton of sTIL and LAG-3 may be more useful in gastric cancer than using either alone. Age, tumor size, Lauren classification and postoperative adjuvant chemotherapy are independent prognostic factors for patients with advanced gastric adenocarcinoma.
    DOI:  https://doi.org/10.3760/cma.j.cn112151-20220412-00273
  11. Front Oncol. 2022 ;12 915982
    Sciatic nerve schwannoma complicated by nerve bundle membrane effusion: Two case reports and a literature review.
    Lian He, Yan-Ji Zhang, Shi-Li He, Jia-Ren Zhang, Jun Wu, Gao-Feng Zhang, Da-Li Wang.
      Schwannoma is a benign tumor that originates from Schwann cells in the peripheral nerve tunica or bundle of nerves and grows along the longitudinal axis of the nerve. Schwannoma can occur in multiple anatomic locations but rarely in the sciatic nerve. To our knowledge, there are no previous reports in the literature related to schwannoma combined with effusion of the nerve bundle membranes. Here, we report two cases of sciatic nerve schwannoma combined with nerve bundle membrane effusion, and the relationship between them is uncertain. We have boldly speculated about this uncertain relationship by combining the two patients' imaging manifestations to help determine the mechanism of schwannoma or effusion generation as well as a clinical treatment.
    Keywords:  MRI; case report; nerve bundle membranes effusion; schwannoma; sciatic nerve
    DOI:  https://doi.org/10.3389/fonc.2022.915982
  12. Pharmacol Res Perspect. 2022 Oct;10(5): e01016
    Morphine stimulates cervical cancer cells and alleviates cytotoxicity of chemotherapeutic drugs via opioid receptor-dependent and -independent mechanisms.
    Zhengwen Yu, Sheng Jin, Shiming Tian, Zhibao Wang.
      Morphine is frequently applied in cancer patients for pain management. However, its effects on cancer are not well understood but observed to be specific to certain cancer types. We previously revealed the stimulatory properties of morphine in esophageal carcinoma. This work addressed the effects of morphine and its underlying mechanisms in cervical cancer. Proliferation, apoptosis, and migration assays were performed to examine the effects of morphine alone and its combinatory effects with chemotherapeutic drugs. Immunoblotting and biochemical analysis were performed to determine the underlying mechanisms of morphine's action. Morphine promoted proliferation in opioid receptor-dependent manner and stimulated migration in opioid receptor-independent manner. However, morphine did not affect cervical cancer cell survival. Morphine also interfered with all tested chemotherapeutic drugs (e.g., cisplatin, 5-FU, and paclitaxel) and alleviates their efficacy. Mechanistically, morphine-stimulated growth via activating EGFR-mediated signaling pathways and is opioid-receptor-dependent; morphine-stimulated migration via activating RhoA-mediated signaling pathways and this is opioid receptor-independent. Our work suggests a strong correlation of this opioid receptor on growth factor signaling to stimulate growth and opioid receptor-independent activation of RhoA and consequent migration. Our findings have the potential to guide the clinical use of morphine for patients with cervical cancer.
    Keywords:  EGFR; RhoA; cervical cancer; morphine; opioid receptor
    DOI:  https://doi.org/10.1002/prp2.1016
  13. Radiol Case Rep. 2022 Nov;17(11): 4362-4364
    A case of intestinal schwannoma initially suspected by transvaginal ultrasound.
    Laura López-Marín, Alejandro Olloqui, Ana Villalba, José Manuel Puente, Alberto Galindo.
      Schwannomas are peripheral nerve sheath tumors. Due to their low incidence, few cases of colorectal schwannomas have been published, which increases the diagnostic challenge. The aim of this case report is to discuss the role of transvaginal ultrasound in different areas than the gynecological disorders, when on hands of properly trained professionals that perform systematized procedures. A 56-year-old woman consulted for postmenopausal genital bleeding. During transvaginal ultrasound, a colonic solid, hypervascularized mass of 23 × 26 mm was visualized. As a result of this incidental finding, the patient underwent a sigmoidectomy, with a final diagnosis of intestinal schwannoma. Transvaginal ultrasound is today one of the most useful and accurate diagnostic tools in the assessment of gynecological disorders. However, the proximity of other pelvic structures makes it possible to evaluate the presence of nongynecological conditions. This fact should encourage gynecologists to systematize the transvaginal ultrasound procedure.
    Keywords:  Diagnosis; Differential; Gastrointestinal stromal tumors; Gynecological examination; Schwannoma; Ultrasound
    DOI:  https://doi.org/10.1016/j.radcr.2022.08.028
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