bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2023–05–21
ten papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute
  1. CD51 Intracellular Domain Promotes Cancer Cell Neurotropism through Interacting with Transcription Factor NR4A3 in Colorectal Cancer.
  2. Perineural invasion affects prognosis of patients undergoing colorectal cancer surgery: a propensity score matching analysis.
  3. Tertiary Lymphoid Structures (TLSs) and Stromal Blood Vessels Have Significant and Heterogeneous Impact on Recurrence, Lymphovascular and Perineural Invasion amongst Breast Cancer Molecular Subtypes.
  4. Global and single-cell proteomics view of the co-evolution between neural progenitors and breast cancer cells in a co-culture model.
  5. Perineural Invasion in Cutaneous Squamous Cell Carcinoma in a Cohort of Renal Transplant Patients Versus Immunocompetent Patients: The Irish Experience.
  6. The Secretome of Parental and Bone Metastatic Breast Cancer Elicits Distinct Effects in Human Osteoclast Activity after Activation of β2 Adrenergic Signaling.
  7. Insights into the leveraging of GABAergic signaling in cancer therapy.
  8. Various effects of the GABAergic system on cancer: the conditions and specificities of its use in the treatment of some cancers.
  9. Case Report: Adjuvant image-guided radiation therapy reduces surgical invasiveness in malignant peripheral nerve sheath tumors.
  10. Intrathoracic neurogenic tumors (ITNs): Management of solid and cystic lesions.
  1. Cancers (Basel). 2023 May 05. pii: 2623. [Epub ahead of print]15(9):
    CD51 Intracellular Domain Promotes Cancer Cell Neurotropism through Interacting with Transcription Factor NR4A3 in Colorectal Cancer.
    Tianze Huang, Yanyun Lin, Junguo Chen, Jiancong Hu, Hao Chen, Yanhong Zhang, Bin Zhang, Xiaosheng He.
      The abundant nervous system in intestine provides the basis for perineural invasion (PNI) of colorectal cancer (CRC). PNI is defined as the invasion of the nerves by cancer cells. Although PNI is already known to be an independent prognostic factor in CRC, the molecular mechanism underlying PNI remains obscure. In this study, we first demonstrated that CD51 could promote the neurotropism of tumor cells through cleavage with γ-secretase to generate an intracellular domain (ICD). Mechanistically, ICD of CD51 could bind to the transcription factor NR4A3, and act as a coactivator to promote the expression of downstream effectors, such as NTRK1, NTRK3, and SEMA3E. Pharmacological inhibition of γ-secretase impedes PNI mediated by CD51 in CRC both in vitro and in vivo and may become a potential therapeutic target for PNI in CRC.
    Keywords:  CD51; colorectal cancer; intracellular domain; perineural invasion
    DOI:  https://doi.org/10.3390/cancers15092623
  2. BMC Cancer. 2023 May 18. 23(1): 452
    Perineural invasion affects prognosis of patients undergoing colorectal cancer surgery: a propensity score matching analysis.
    Le Qin, Yixin Heng, Shenghe Deng, Junnan Gu, Fuwei Mao, Yifan Xue, Zhenxing Jiang, Jun Wang, Denglong Cheng, Ke Wu, Yinghao Cao, Kailin Cai.
       BACKGROUND: Tumour perineural invasion (PNI) is a predictor of poor prognosis, but its effect on the prognosis of patients with colorectal cancer (CRC) has not yet been elucidated.
    METHODS: This retrospective study used propensity score matching (PSM). The clinical case data of 1470 patients with surgically treated stage I-IV CRC at Wuhan Union Hospital were collected. PSM was used to analyse and compare the clinicopathological characteristics, perioperative outcomes, and long-term prognostic outcomes of the PNI(+) and PNI(-) groups. The factors influencing prognosis were screened using Cox univariate and multivariate analyses.
    RESULTS: After PSM, 548 patients were included in the study (n = 274 in each group). Multifactorial analysis showed that neurological invasion was an independent prognostic factor affecting patients' OS and DFS (hazard ratio [HR], 1.881; 95% confidence interval [CI], 1.35-2.62; P = 0.0001; HR, 1.809; 95% CI, 1.353-2.419; P < 0.001). Compared to PNI(+) patients without chemotherapy, those who received chemotherapy had a significant improvement in OS (P < 0.01). The AUROC curve of OS in the PNI(+) subgroup (0.802) was higher than that after PSM (0.743), while that of DFS in the PNI(+) subgroup (0.746) was higher than that after PSM (0.706). The independent predictors of PNI(+) could better predict the prognosis and survival of patients with PNI(+).
    CONCLUSIONS: PNI significantly affects the long-term survival and prognosis of patients with CRC undergoing surgery and is an independent risk factor for OS and DFS in patients with CRC undergoing surgery. Postoperative chemotherapy significantly improved the OS of PNI(+) patients.
    Keywords:  Colorectal cancer; Disease-free survival; Overall survival; Perineural invasion; Propensity score matching
    DOI:  https://doi.org/10.1186/s12885-023-10936-w
  3. Cells. 2023 04 17. pii: 1176. [Epub ahead of print]12(8):
    Tertiary Lymphoid Structures (TLSs) and Stromal Blood Vessels Have Significant and Heterogeneous Impact on Recurrence, Lymphovascular and Perineural Invasion amongst Breast Cancer Molecular Subtypes.
    Alina Cristina Barb, Mihaela Pasca Fenesan, Marilena Pirtea, Madalin Marius Margan, Larisa Tomescu, Eugen Melnic, Anca Maria Cimpean.
       BACKGROUND: Tertiary lymphoid structures (TLSs) mediate local antitumor immunity, and interest in them significantly increased since cancer immunotherapy was implemented. We examined TLS- tumor stromal blood vessel interplay for each breast cancer (BC) molecular subtype related to recurrence, lymphovascular invasion (LVI), and perineural invasion (PnI).
    METHODS: TLSs were quantified on hematoxylin and eosin stain specimens followed by CD34/smooth muscle actin (SMA) double immunostaining for stromal blood vessel maturation assessment. Statistical analysis linked microscopy to recurrence, LVI, and PnI.
    RESULTS: TLS negative (TLS-) subgroups in each BC molecular subtype (except to Luminal A) have higher LVI, PnI, and recurrence. A significant rise in LVI and PnI were observed for the HER2+/TLS- subgroup (p < 0.001). The triple negative breast cancer (TNBC)/TLS- subgroup had the highest recurrence and invasion risk which was also significantly related to tumor grade. PnI but not LVI significantly influenced recurrence in the TNBC/TLS+ subgroup (p < 0.001). TLS-stromal blood vessel interrelation was different amongst BC molecular subtypes.
    CONCLUSION: BC invasion and recurrence are strongly influenced by TLS presence and stromal blood vessels, especially for HER2 and TNBC BC molecular subtypes.
    Keywords:  TLS; breast cancer molecular subtypes; immature blood vessels; lymphovascular invasion; mature blood vessels; perineural invasion; recurrence; tertiary lymphoid structure
    DOI:  https://doi.org/10.3390/cells12081176
  4. bioRxiv. 2023 May 05. pii: 2023.05.03.539050. [Epub ahead of print]
    Global and single-cell proteomics view of the co-evolution between neural progenitors and breast cancer cells in a co-culture model.
    Ole Vidhammer Bjørnstad, Manuel Carrasco, Kenneth Finne, Ingeborg Winge, Cecilie Askeland, Jarle B Arnes, Gøril Knutsvik, Dimitrios Kleftogiannis, Joao A Paulo, Lars A Akslen, Heidrun Vethe.
      Tumor neurogenesis, a process by which new nerves invade tumors, is a growing area of interest in cancer research. Nerve presence has been linked to aggressive features of various solid tumors, including breast and prostate cancer. A recent study suggested that the tumor microenvironment may influence cancer progression through recruitment of neural progenitor cells from the central nervous system. However, the presence of neural progenitors in human breast tumors has not been reported. Here, we investigate the presence of Doublecortin (DCX) and Neurofilament-Light (NFL) co-expressing (DCX+/NFL+) cells in patient breast cancer tissue using Imaging Mass Cytometry. To map the interaction between breast cancer cells and neural progenitor cells further, we created an in vitro model mimicking breast cancer innervation, and characterized using mass spectrometry-based proteomics on the two cell types as they co- evolved in co-culture. Our results indicate stromal presence of DCX+/NFL+ cells in breast tumor tissue from a cohort of 107 patient cases, and that neural interaction contribute to drive a more aggressive breast cancer phenotype in our co-culture models. Our results support that neural involvement plays an active role in breast cancer and warrants further studies on the interaction between nervous system and breast cancer progression.
    DOI:  https://doi.org/10.1101/2023.05.03.539050
  5. Dermatol Surg. 2023 May 12.
    Perineural Invasion in Cutaneous Squamous Cell Carcinoma in a Cohort of Renal Transplant Patients Versus Immunocompetent Patients: The Irish Experience.
    Claire Doyle, Megan Power Foley, Kira Casey, Siona Ní Raghallaigh.
      
    DOI:  https://doi.org/10.1097/DSS.0000000000003825
  6. Biomolecules. 2023 Mar 30. pii: 622. [Epub ahead of print]13(4):
    The Secretome of Parental and Bone Metastatic Breast Cancer Elicits Distinct Effects in Human Osteoclast Activity after Activation of β2 Adrenergic Signaling.
    Francisco Conceição, Daniela M Sousa, Sofia Tojal, Catarina Lourenço, Carina Carvalho-Maia, Helena Estevão-Pereira, João Lobo, Marina Couto, Mette M Rosenkilde, Carmen Jerónimo, Meriem Lamghari.
      The sympathetic nervous system (SNS), particularly through the β2 adrenergic receptor (β2-AR), has been linked with breast cancer (BC) and the development of metastatic BC, specifically in the bone. Nevertheless, the potential clinical benefits of exploiting β2-AR antagonists as a treatment for BC and bone loss-associated symptoms remain controversial. In this work, we show that, when compared to control individuals, the epinephrine levels in a cohort of BC patients are augmented in both earlier and late stages of the disease. Furthermore, through a combination of proteomic profiling and functional in vitro studies with human osteoclasts and osteoblasts, we demonstrate that paracrine signaling from parental BC under β2-AR activation causes a robust decrease in human osteoclast differentiation and resorption activity, which is rescued in the presence of human osteoblasts. Conversely, metastatic bone tropic BC does not display this anti-osteoclastogenic effect. In conclusion, the observed changes in the proteomic profile of BC cells under β-AR activation that take place after metastatic dissemination, together with clinical data on epinephrine levels in BC patients, provided new insights on the sympathetic control of breast cancer and its implications on osteoclastic bone resorption.
    Keywords:  beta-adrenergic; breast cancer; osteoclast; proteomic; sympathetic nervous system
    DOI:  https://doi.org/10.3390/biom13040622
  7. Cancer Med. 2023 May 18.
    Insights into the leveraging of GABAergic signaling in cancer therapy.
    Tian-Jiao Li, Jian Jiang, Ya-Ling Tang, Xin-Hua Liang.
      Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain of adult mammals. Several studies have demonstrated that the GABAergic system may regulate tumor development via GABA receptors, downstream cyclic adenosine monophosphate (cAMP) pathway, epithelial growth factor receptor (EGFR) pathway, AKT pathway, mitogen-activated protein kinase (MAPK) or extracellular signal-related kinases (ERK) pathway, and matrix metalloproteinase (MMP) pathway, although the exact mechanism is unclear. Pioneering studies reported that GABA signaling exists and functions in the cancer microenvironment and has an immunosuppressive effect that contributes to metastasis and colonization. This article reviews the molecular structures and biological functions of GABAergic components correlated with carcinogenesis, the mechanisms underlying GABAergic signaling that manipulate the proliferation and invasion of cancer cells, and the potential GABA receptor agonists and antagonists for cancer therapy. These molecules may provide an avenue for the development of specific pharmacological components to prevent the growth and metastasis of various cancers.
    Keywords:  GABA; GABA receptor; cancer; carcinogenesis; neurotransmitter
    DOI:  https://doi.org/10.1002/cam4.6102
  8. Curr Top Med Chem. 2023 May 15.
    Various effects of the GABAergic system on cancer: the conditions and specificities of its use in the treatment of some cancers.
    Hossein Tahmasebi Dehkordi, Sorayya Ghasemi, Masoumeh Eliyasi.
      GABA is an essential neurotransmitter in tissues other than the brain and has different functions. Cancer displays dysfunctional GABAergic system roles, comprising GAD, GABA, and GABA receptors. Both tumor-suppressing and carcinogenic characteristics of the GABAergic system have been reported in several malignancies. In the development of cancer cells, it plays oncogenesis-related roles. However, in some tumors, such as pancreatic cancer, it exhibits anti-cancer benefits in numerous human trials and animal models. As a result, GABAergic therapy may be used to treat cancer. The oxidative condition and the status of several malignant circumstances significantly influence the final GABAergic function in many tumors. Depending on the type of malignant tissue and other modifications, these roles manifest differently in malignancies. In this review, we, for the first time, concentrated on the oncogenic and tumor suppressor functions of GABA in various neoplasms, as well as its potential therapeutic implications. The significance of tumor suppressor function and the conditions that promote its function as a cancer genesis factor in cancer are discussed in this article.
    Keywords:  Cancer treatment; GABA; GABA receptor; GABAergic system; Oncogene; Tumor suppressor
    DOI:  https://doi.org/10.2174/1568026623666230515163713
  9. Front Oncol. 2023 ;13 1129537
    Case Report: Adjuvant image-guided radiation therapy reduces surgical invasiveness in malignant peripheral nerve sheath tumors.
    Mandara M Harikar, Gianluca Ferini, Paolo Palmisciano, Muhammad Shakir, Paolo Amico, Stefano Ferraresi, Giuseppe E Umana.
       Introduction: Malignant peripheral nerve sheath tumors (MPNSTs) are a group of rare soft tissue sarcomas of mesenchymal origin. These tumors generally require extensive local excision owing to their aggressive potential. Though the role of radiotherapy is controversial, in this report, we present the case of an MPNST in the forearm that was treated with microsurgery followed by image-guided radiation therapy to achieve complete tumor disappearance at the 18-month follow-up.
    Case report: A 69-year-old woman with underlying paranoid schizophrenia was referred to our department with pain, severe swelling, and ecchymosis of her right forearm. Physical examination showed hypoesthesia in the segments innervated by the median nerve and reduced motor strength of her right hand. A gadolinium-enhanced MRI showed a large malignant peripheral nerve sheath tumor (13 x 8 x 7 cm) of the median nerve in the forearm. She underwent microsurgical en-bloc tumor resection with sparing of the median nerve. Thirty-five days postoperatively, she underwent image-guided radiotherapy (IGRT) using volumetric modulated arc therapy (VMAT). Serial MRI scans of the forearm with Gadolinium and whole-body CT scan with contrast enhancement at 30 days, 6 months, 1 year, and 18 months postoperatively documented no tumor recurrence, remnants, or metastases.
    Conclusions: In this report, we demonstrate the successful use of advanced radiotherapy techniques such as IGRT while avoiding demolitive surgery for MPNST. Though a longer follow-up is necessary, at the 18-month follow-up, the patient demonstrated good outcomes from surgical resection followed by adjuvant RT for MPNST in the forearm.
    Keywords:  image-guided radiation therapy; malignant peripheral nerve sheet tumor; radiation oncology; radiotherapy; sarcoma
    DOI:  https://doi.org/10.3389/fonc.2023.1129537
  10. Thorac Cancer. 2023 May 18.
    Intrathoracic neurogenic tumors (ITNs): Management of solid and cystic lesions.
    Giovanni Natale, Stefano Forte, Gaetana Messina, Beatrice Leonardi, Rosa Mirra, Francesco Leone, Vincenzo Di Filippo, Davide Gerardo Pica, Francesca Capasso, Mary Bove, Antonio Noro, Giorgia Opromolla, Mario Martone, Sabrina De Angelis, Alfonso Fiorelli.
       BACKGROUND: Intrathoracic neurogenic tumors (INTs) are derived from nerve tissue and grow within the chest. Preoperative diagnosis can be challenging and only complete surgical exeresis enables confirmation of the suspected diagnosis. Here, we analyzed our experience on management of paravertebral lesions with solid and cystic patterns.
    METHODS: A monocentric retrospective study was conducted, which included 25 consecutive cases of ITNs in the period from 2010 to 2022. These cases had been surgically treated by thoracoscopic resection alone, or in combination with neurosurgery in the case of dumbbell tumors. The demographic and operative data along with complications were recorded and analyzed.
    RESULTS: Twenty-five patients were diagnosed with a paravertebral lesion of which 19 (76%) had solid features and six (24%) had cystic features. The most common diagnosis was schwannoma (72%), followed by neurofibroma (20%) and malignant schwannoma (8%). In four cases (12%) the tumor showed an intraspinal extension. None of the patients had recurrence until 6 months of follow-up. Comparison between the VATS and thoracotomy procedures showed that outcome of discharge on the postoperative day, on average, was 2.61 ± 0.5 versus 3.51 ± 0.53, respectively (p-value <0.001).
    CONCLUSION: The treatment of choice for INTs is complete resection which is tailored to tumor size, location, and extension. In our study, paravertebral tumors with cystic characteristics were not associated with an intraspinal extension and did not show a different behavior from solid tumors.
    Keywords:  ITNs; neurogenic tumors; paravertebral tumors; schwannoma
    DOI:  https://doi.org/10.1111/1759-7714.14927
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