bims-netuvo 2023-08-13 papers

Issue of 2023‒08‒13
seven papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute

Cells. 2023 Aug 03. pii: 1996. [Epub ahead of print]12(15):

Unveiling the Neural Environment in Cancer: Exploring the Role of Neural Circuit Players and Potential Therapeutic Strategies.

Tuan Minh Nguyen, Dinh Thi Minh Ngoc, Jung-Hye Choi, Chang-Hoon Lee.

The regulation of the immune environment within the tumor microenvironment has provided new opportunities for cancer treatment. However, an important microenvironment surrounding cancer that is often overlooked despite its significance in cancer progression is the neural environment surrounding the tumor. The release of neurotrophic factors from cancer cells is implicated in cancer growth and metastasis by facilitating the infiltration of nerve cells into the tumor microenvironment. This nerve-tumor interplay can elicit cancer cell proliferation, migration, and invasion in response to neurotransmitters. Moreover, it is possible that cancer cells could establish a network resembling that of neurons, allowing them to communicate with one another through neurotransmitters. The expression levels of players in the neural circuits of cancers could serve as potential biomarkers for cancer aggressiveness. Notably, the upregulation of certain players in the neural circuit has been linked to poor prognosis in specific cancer types such as breast cancer, pancreatic cancer, basal cell carcinoma, and stomach cancer. Targeting these players with inhibitors holds great potential for reducing the morbidity and mortality of these carcinomas. However, the efficacy of anti-neurogenic agents in cancer therapy remains underexplored, and further research is necessary to evaluate their effectiveness as a novel approach for cancer treatment. This review summarizes the current knowledge on the role of players in the neural circuits of cancers and the potential of anti-neurogenic agents for cancer therapy.

Keywords: neoneurogenesis; nerve–cancer crosstalk; neurotransmitter; prognosis

DOI: https://doi.org/10.3390/cells12151996

Cancers (Basel). 2023 Jul 25. pii: 3758. [Epub ahead of print]15(15):

Radical Tumor Denervation Activates Potent Local and Global Cancer Treatment.

John D Mitsou, Vivian Tseveleki, Foteinos-Ioannis Dimitrakopoulos, Konstantinos Konstantinidis, Haralabos Kalofonos.

This preliminary study seeks to determine the effect of R&P denervation on tumor growth and survival in immunocompetent rats bearing an aggressive and metastatic breast solid tumor. A novel microsurgical approach was applied "in situ", aiming to induce R&P denervation through the division of every single nerve fiber connecting the host with the primary tumor via its complete detachment and re-attachment, by resecting and reconnecting its supplying artery and vein (anastomosis). This preparation, known as microsurgical graft or flap, is radically denervated by definition, but also effectively delays or even impedes the return of innervation for a significant period of time, thus creating a critical and therapeutic time window. Mammary adenocarcinoma cells (HH-16.cl4) were injected into immunocompetent Sprague Dawley adult rats. When the tumors reached a certain volume, the subjects entered the study. The primary tumor, including a substantial amount of peritumoral tissue, was surgically isolated on a dominant artery and vein, which was resected and reconnected using a surgical microscope (orthotopic tumor auto-transplantation). Intending to simulate metastasis, two or three tumors were simultaneously implanted and only one was treated, using the surgical technique described herein. Primary tumor regression was observed in all of the microsurgically treated subjects, associated with a potent systemic anticancer effect and prolonged survival. In stark contrast, the subjects received a close to identical surgical operation; however, with the intact neurovascular connection, they did not achieve the therapeutic result. Animals bearing multiple tumors and receiving the same treatment in only one tumor exhibited regression in both the "primary" and remote- untreated tumors at a clinically significant percentage, with regression occurring in more than half of the treated subjects. A novel therapeutic approach is presented, which induces the permanent regression of primary and, notably, remote tumors, as well as, evidently, the naturally occurring metastatic lesions, at a high rate. This strategy is aligned with the impetus that comes from the current translational research data, focusing on the abrogation of the neuro-tumoral interaction as an alternative treatment strategy. More data regarding the clinical significance of this are expected to come up from a pilot clinical trial that is ongoing.

Keywords: abscopal effect; cancer neurobiology; microsurgery; radical denervation; tumor denervation; tumor regression

DOI: https://doi.org/10.3390/cancers15153758

Am J Transl Res. 2023 ;15(7): 4678-4686

Application of magnetic resonance neuroimaging in determining the relationship between tumors and peripheral nerves.

Chaochao Wang, Lihui Fu, Liang Liang, Jinlong Zhou.

BACKGROUND: Magnetic resonance imaging (MRI) is commonly used to analyze the relationship between tumors and nerves before surgery. However, the application value of diffusion tensor imaging (DTI), diffusion weighted imaging (DWI), and post-processing techniques needs further elucidation.PURPOSE: To assess the value of DTI, DWI, and various post-processing techniques in determining the relationship between tumors and nerves.
MATERIAL AND METHODS: The participants were 42 patients diagnosed with peripheral nerve-related tumors and 20 healthy controls. DTI and DWI scans were performed before surgery, and then DTI unidirectional maximum intensity projection (MIP) post-processing and DWI subtraction of unidirectionally encoded images for suppression of heavily isotropic objects (DWISUSHI) postprocessing techniques were used to observe the relationship between the mass and the target nerves. The mean apparent diffusion coefficient (ADC) of nerves was compared among the target neural origin group, non-target neural origin group, and healthy control group using the paired Wilcoxon rank-sum test.
RESULTS: The diagnostic coincidence rates of preoperative DTI and DWI findings with postoperative pathology were 88.1% and 100%, respectively. DTI images were of poor quality when compared to DWISUSHI (P < 0.05). The mean ADC value of the target neural origin group was greater than that of the non-target neural origin group and the healthy control group (P < 0.05).
CONCLUSION: Both DTI and DWISUSHI can stereoscopically display the relationship between peripheral nerves and tumors, but the latter contributes to better quality of the reconstructed images.

Keywords: Magnetic resonance imaging; diffusion tensor imaging; diffusion-weighted imaging; peripheral nerve

J Exp Clin Cancer Res. 2023 Aug 11. 42(1): 206

Predicting response to immunotherapy in gastric cancer via assessing perineural invasion-mediated inflammation in tumor microenvironment.

BACKGROUND: The perineural invasion (PNI)-mediated inflammation of the tumor microenvironment (TME) varies among gastric cancer (GC) patients and exhibits a close relationship with prognosis and immunotherapy. Assessing the neuroinflammation of TME is important in predicting the response to immunotherapy in GC patients.METHODS: Fifteen independent cohorts were enrolled in this study. An inflammatory score was developed and validated in GC. Based on PNI-related prognostic inflammatory signatures, patients were divided into Clusters A and B using unsupervised clustering. The characteristics of clusters and the potential regulatory mechanism of key genes were verified by RT-PCR, western-blot, immunohistochemistry and immunofluorescence in cell and tumor tissue samples.The neuroinflammation infiltration (NII) scoring system was developed based on principal component analysis (PCA) and visualized in a nomogram together with other clinical characteristics.
RESULTS: Inflammatory scores were higher in GC patients with PNI compared with those without PNI (P < 0.001). NII.clusterB patients with PNI had abundant immune cell infiltration in the TME but worse prognosis compared with patients in the NII.clusterA patients with PNI and non-PNI subgroups. Higher immune checkpoint expression was noted in NII.clusterB-PNI. VCAM1 is a specific signature of NII.clusterB-PNI, which regulates PD-L1 expression by affecting the phosphorylation of STAT3 in GC cells. Patients with PNI and high NII scores may benefit from immunotherapy. Patients with low nomogram scores had a better prognosis than those with high nomogram scores.
CONCLUSIONS: Inflammation mediated by PNI is one of the results of tumor-nerve crosstalk, but its impact on the tumor immune microenvironment is complex. Assessing the inflammation features of PNI is a potential method in predicting the response of immunotherapy effectively.

Keywords: Gastric cancer(GC); Inflammatory; Neuroinflammation infiltration(NII) score system; Perinueral invasion(PNI); Tumor microenvironment(TME)

DOI: https://doi.org/10.1186/s13046-023-02730-0

Int J Surg Case Rep. 2023 Jul 26. pii: S2210-2612(23)00693-4. [Epub ahead of print]109 108564

Mediastinal schwannoma: A case report.

Septiardhi Husodo, Farah Fatma Wati.

INTRODUCTION: Mediastinal schwannoma is a rare tumor that develops from a peripheral nerve sheath in the mediastinal.CASE PRESENTATION: An Indonesian female, 60 years old, complained of breathlessness, left chest pain, and an intermittent cough. A cystic lesion in the left lung was discovered on radiological evaluation and no evidence of malignancy or metastases were found. The patient underwent a thoracotomy and continued therapy, which included cefixime at a dose of 2 × 200 mg/day, ketorolac at a dose of 3 × 30 mg/day, ranitidine at a dose of 2 × 50 mg/day, and wound care. Histopathology examination revealed a mediastinal schwannoma. For 3 months, the patient-controlled dyspnea, left chest pain, and intermittent cough disappeared once a month.
DISCUSSION: If the tumor is large enough, a thoracoscopic procedure is advised. Because mediastinal schwannomas are benign tumors, most do not get radiotherapy, chemotherapy, and recurrence in this case has not been reported.
CONCLUSION: Tissue histopathology is used to determine the diagnosis mediastinal schwannoma, whereas radiological evaluation just confirms the diagnosis. The management is thoracotomy for large masses.

Keywords: Cancer; Mediastinal schwannoma; Thoracotomy; Tumor

DOI: https://doi.org/10.1016/j.ijscr.2023.108564

Biochem Biophys Res Commun. 2023 Aug 03. pii: S0006-291X(23)00939-7. [Epub ahead of print]677 77-80

Establishing a new model of cancer neuropathic pain in rats.

Qiwang Cao, Rui Li, Yi Yi, Pingping Luo, Xudong Song, Xuebin Yan.

To guide the treatment of malignant neuropathic pain (MNP) in clinical practice, by inoculating MADB-106 breast cancer cells into the right L4 nerve root in Sprague-Dawley rats, a rat model of MNP was established, providing basic conditions for the study of neuropathic pain and development and application of therapeutic drugs. As the tumor grew over time, it pressed the nerve roots, causing nerve damage. The spinal nerve ligation (SNL) model, which is a neuropathic pain model widely used in rats, was compared with the L4 nerve root SNL model, and histologic examination of the nerve tissue of both models was performed by electron microscopy. In addition to the infiltration and erosion of the L4 nerve by tumor cells, the tumor tissue gradually grew and compressed the L4 nerve roots, resulting in hyperalgesia of the rat's posterior foot on the operative side. Some spontaneous pain phenomena were also observed, such as constant lifting or licking of the posterior foot on the operative side under quiet conditions. Electron microscopy images showed that nerve injury was due to progressive compression by the tumor, cells of which were visualized, but the injury was lighter than that in SNL rats. Imaging showed a paravertebral tumor near the L4 nerve root in the carcinomatous neuropathic pain model rat. These results suggest that progressive compression of the nerve by a malignant tumor leads to nerve damage similar to the behavioral changes associated with chronic compression injury resulting from a loose ligature of the nerve. The cancer neuropathologic pain model at the L4 nerve root was successfully established in Sprague-Dawley rats.

Keywords: L4 nerve; MADB-106 breast cancer cells; Malignant neuropathic pain (MNP)Model

DOI: https://doi.org/10.1016/j.bbrc.2023.08.006