bims-netuvo 2024-07-14 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2024–07–14
fiveteen papers selected by
Maksym V. Kopanitsa, Charles River Laboratories

The Use of Hexokinase 2-Displacing Peptides as an Anti-Neoplastic Approach for Malignant Peripheral Nerve Sheath Tumors.
TrkA + sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression.
Promotion of perineural invasion of cholangiocarcinoma by Schwann cells via nerve growth factor.
Quantitative parameters of dual-layer spectral detector computed tomography for evaluating differentiation grade and lymphovascular and perineural invasion in colorectal adenocarcinoma.
The multifaceted role of beta-blockers in overcoming cancer progression and drug resistance: Extending beyond cardiovascular disorders.
Identification of perineural invasion at imaging staging as a novel potential risk factor in rectal cancer: A case report.
Low back pain with axillary mass in a perimenopausal woman: A case of schwannomatosis mimicking metastasis.
Prognostic Evaluation of Piezo2 Channels in Mammary Gland Carcinoma.
Bioelectric pharmacology of cancer: A systematic review of ion channel drugs affecting the cancer phenotype.
Modeling mechanisms of chemotherapy-induced peripheral neuropathy and chemotherapy transport using induced pluripotent stem cell-derived sensory neurons.
Analgesic Effect of Auricular Vagus Nerve Stimulation on Oxaliplatin-induced Peripheral Neuropathic Pain in a Rodent Model.
Salbutamol, a Short Acting Beta-2 Agonist, Reduces Risk and Improves Prognosis of Prostate Cancer.
Multifaceted interactions between cancer cells and glial cells in brain metastasis.
Relationships between nine neuropsychiatric disorders and cervical cancer: insights from genetics, causality and shared gene expression patterns.
Recent advances in small molecule Nav 1.7 inhibitors for cancer pain management.

Cells. 2024 Jul 08. pii: 1162. [Epub ahead of print]13(13):

The Use of Hexokinase 2-Displacing Peptides as an Anti-Neoplastic Approach for Malignant Peripheral Nerve Sheath Tumors.

Francesco Ciscato, Ionica Masgras, Alessandro Gori, Marco Fantuz, Greta Bergamaschi, Denis Komarov, Martina La Spina, Shiva Ghasemi-Firouzabadi, Marco Pizzi, Angelo Paolo Dei Tos, Federica Chiara, Alessandro Carrer, Andrea Rasola.

  Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive sarcomas that can arise both sporadically and in patients with the genetic syndrome Neurofibromatosis type 1 (NF1). Prognosis is dismal, as large dimensions, risk of relapse, and anatomical localization make surgery poorly effective, and no therapy is known. Hence, the identification of MPNST molecular features that could be hit in an efficient and selective way is mandatory to envision treatment options. Here, we find that MPNSTs express high levels of the glycolytic enzyme Hexokinase 2 (HK2), which is known to shield cancer cells from noxious stimuli when it localizes at MAMs (mitochondria-associated membranes), contact sites between mitochondria and endoplasmic reticulum. A HK2-targeting peptide that dislodges HK2 from MAMs rapidly induces a massive death of MPNST cells. After identifying different matrix metalloproteases (MMPs) expressed in the MPNST microenvironment, we have designed HK2-targeting peptide variants that harbor cleavage sites for these MMPs, making such peptides activatable in the proximity of cancer cells. We find that the peptide carrying the MMP2/9 cleavage site is the most effective, both in inhibiting the in vitro tumorigenicity of MPNST cells and in hampering their growth in mice. Our data indicate that detaching HK2 from MAMs could pave the way for a novel anti-MPNST therapeutic strategy, which could be flexibly adapted to the protease expression features of the tumor microenvironment.

Keywords:  Neurofibromatosis type 1; hexokinase 2; hexokinase 2 targeting peptides; malignant peripheral nerve sheath tumors

DOI:  https://doi.org/10.3390/cells13131162
bioRxiv. 2024 Jun 25. pii: 2024.06.20.599869. [Epub ahead of print]

TrkA + sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression.

Qizhi Qin, Sowmya Ramesh, Zhao Li, Lingke Zhong, Masnsen Cherief, Mary Archer, Xin Xing, Neelima Thottappillil, Mario Gomez-Salazar, Mingxin Xu, Manyu Zhu, Leslie Chang, Ankit Uniyal, Khadijah Mazhar, Monisha Mittal, Edward F McCarthy, Carol D Morris, Benjamin Levi, Yun Guan, Thomas L Clemens, Theodore J Price, Aaron W James.

Bone pain is a presenting feature of bone cancers such as osteosarcoma (OS), relayed by skeletal-innervating peripheral afferent neurons. Potential functions of tumor-associated sensory neurons in bone cancers beyond pain sensation are unknown. To uncover neural regulatory functions, a chemical-genetic approach in mice with a knock-in allele for TrkA was used to functionally perturb sensory nerve innervation during OS growth and disease progression. TrkA inhibition in transgenic mice led to significant reductions in sarcoma-associated sensory innervation and vascularization, tumor growth and metastasis, and prolonged overall survival. Single-cell transcriptomics revealed that sarcoma denervation was associated with phenotypic alterations in both OS tumor cells and cells within the tumor microenvironment, and with reduced calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) signaling. Multimodal and multi-omics analyses of human OS bone samples and human dorsal root ganglia neurons further implicated peripheral innervation and neurotrophin signaling in OS tumor biology. In order to curb tumor-associated axonal ingrowth, we next leveraged FDA-approved bupivacaine liposomes leading to significant reductions in sarcoma growth, vascularity, as well as alleviation of pain. In sum, TrkA-expressing peripheral neurons positively regulate key aspects of OS progression and sensory neural inhibition appears to disrupt calcitonin receptor signaling (CALCR) and VEGF signaling within the sarcoma microenvironment leading to significantly reduced tumor growth and improved survival. These data suggest that interventions to prevent pathological innervation of osteosarcoma represent a novel adjunctive therapy to improve clinical outcomes and survival.

DOI: https://doi.org/10.1101/2024.06.20.599869
J Gastrointest Oncol. 2024 Jun 30. 15(3): 1198-1213

Promotion of perineural invasion of cholangiocarcinoma by Schwann cells via nerve growth factor.

Xingwang Qian, Enchi Liu, Chong Zhang, Ruo Feng, Nguyen Tran, Wenlong Zhai, Fazhan Wang, Zhihai Qin.

   Background: Cholangiocarcinoma (CCA), a highly lethal tumor of the hepatobiliary system originating from bile duct epithelium, can be divided into the intrahepatic, hilar, and extrahepatic types. Due to its insidious onset and atypical early clinical symptoms, the overall prognosis is poor. One of the important factors contributing to the poor prognosis of CCA is the occurrence of perineural invasion (PNI), but the specific mechanisms regarding how it contributes to the occurrence of PNI are still unclear. The main purpose of this study is to explore the molecular mechanism leading to the occurrence of PNI and provide new ideas for clinical treatment.
Methods: CCA cell lines and Schwann cells (SCs) were stimulated to observe the changes in cell behavior. SCs cocultured with tumor supernatant and SCs cultured in normal medium were subjected to transcriptome sequencing to screen the significantly upregulated genes. Following this, the two types of tumor cells were cultured with SC supernatant, and the changes in behavior of the tumor cells were observed. Nonobese diabetic-severe combined immunodeficiency disease (NOD-SCID) mice were injected with cell suspension supplemented with nerve growth factor (NGF) via the sciatic nerve. Four weeks later, the mice were euthanized and the tumor sections were removed and stained.
Results: Nerve invasion by tumor cells was common in CCA tissues. SCs were observed in tumor tissues, and the number of SCs in tumor tissues and the degree of PNI were much higher than were those in normal tissues or tissues without PNI. The overall survival time was shorter in patients with CCA with PNI than in patients without PNI. SCs were enriched in CCA tissues, indicating the presence of PNI and associated with poor prognosis in CCA patients. CCA was found to promote NGF secretion from SCs in vitro. After the addition of exogenous NGF in CCA cell culture medium, the proliferation activity and migration ability of CCA cells were significantly increased, suggesting that SCs can promote the proliferation and migration of CCA through the secretion of NGF. NGF, in turn, was observed to promote epithelial-mesenchymal transition in CCA through tropomyosin receptor kinase A (TrkA), thus promoting its progression. Tumor growth in mice shows that NGF can promote PNI in CCA.
Conclusions: In CCA, tumor cells can promote the secretion of NGF by SCs, which promotes the progression of CCA and PNI by binding to its high-affinity receptor TrkA, leading to poor prognosis.

Keywords:  Perineural invasion (PNI); Schwann cells (SCs); cholangiocarcinoma (CCA); nerve growth factor (NGF)

DOI:  https://doi.org/10.21037/jgo-24-309
Eur J Radiol. 2024 Jun 28. pii: S0720-048X(24)00310-3. [Epub ahead of print]178 111594

Quantitative parameters of dual-layer spectral detector computed tomography for evaluating differentiation grade and lymphovascular and perineural invasion in colorectal adenocarcinoma.

Jinghua Chen, Lei Ni, Jingjing Gong, Jie Wu, Tingting Qian, Mengjia Wang, Jian Huang, Kefu Liu.

   PURPOSE: To explore the predictive value of dual-layer spectral detector CT (SDCT) quantitative parameters for determining differentiation grade, lymphovascular invasion (LVI) and perineural invasion (PNI) in colorectal adenocarcinoma (CRAC) patients.
METHODS: A total of 106 eligible patients with CRAC were included in this study. Spectral parameters, including CT values at 40 and 100 keV, the effective atomic number (Zeff), the iodine concentration (IC), the slope of the spectral Hounsfield unit (HU) curve (λHU), and the normalized iodine concentration (NIC) in the arterial phase (AP) and venous phase (VP), were compared according to the differentiation grade and the status of LVI and PNI. The diagnostic accuracies of the quantitative parameters with statistical significance were determined via receiver operating characteristic (ROC) curves, and the area under the curve (AUC) was calculated.
RESULTS: There were 57 males and 49 females aged 43-86 (69 ± 10) years. The measured values of the spectral quantitative parameters of the CRAC were consistent within the observer (ICC range: 0.800-0.926). The 40 keV-AP, IC-AP, NIC-AP, 40 keV-VP, and IC-VP were significantly different among the different differentiation grades in the CRAC (P = 0.040, AUC = 0.673; P = 0.035, AUC = 0.684; P = 0.031, AUC = 0.639; P = 0.044, AUC = 0.663 and P = 0.035, AUC = 0.666, respectively). A statistically significant difference was observed in 40 keV-VP, 100 keV-VP, Zeff-VP, IC-VP, and λHU-VP between LVI-positive and LVI-negative patients (P = 0.003, AUC = 0.688; P = 0.015, AUC = 0.644; P = 0.001, AUC = 0.688; P = 0.001, AUC = 0.703 and P = 0.003, AUC = 0.677, respectively). There were no statistically significant differences in the values of the spectral parameters of the PNI state of patients with CRAC (P > 0.05).
CONCLUSION: The quantitative parameters of SDCT had good diagnostic efficacy in differentiating between different grades and statuses of LVI in patients with CRAC; however, SDCT did not have value for identifying the state of PNI.

Keywords:  Colorectal carcinoma; Differentiation; Dual-layer spectral detector CT; Lymphovascular invasion; Perineural invasion

DOI:  https://doi.org/10.1016/j.ejrad.2024.111594
FASEB J. 2024 Jul 15. 38(13): e23813

The multifaceted role of beta-blockers in overcoming cancer progression and drug resistance: Extending beyond cardiovascular disorders.

Simona Cavalu, Sameh Saber, Ahmed E Amer, Rabab S Hamad, Mustafa Ahmed Abdel-Reheim, Elsayed A Elmorsy, Amir Mohamed Abdelhamid.

  Beta-blockers are commonly used medications that antagonize β-adrenoceptors, reducing sympathetic nervous system activity. Emerging evidence suggests that beta-blockers may also have anticancer effects and help overcome drug resistance in cancer treatment. This review summarizes the contribution of different isoforms of beta-adrenoceptors in cancer progression, the current preclinical and clinical data on associations between beta-blockers use and cancer outcomes, as well as their ability to enhance responses to chemotherapy and other standard therapies. We discuss proposed mechanisms, including effects on angiogenesis, metastasis, cancer stem cells, and apoptotic pathways. Overall, results from epidemiological studies and small clinical trials largely indicate the beneficial effects of beta-blockers on cancer progression and drug resistance. However, larger randomized controlled trials are needed to firmly establish their clinical efficacy and optimal utilization as adjuvant agents in cancer therapy.

Keywords:  angiogenesis; apoptosis; beta‐blockers; cancer; drug resistance; metastasis

DOI:  https://doi.org/10.1096/fj.202400725RR
Radiol Case Rep. 2024 Sep;19(9): 3626-3630

Identification of perineural invasion at imaging staging as a novel potential risk factor in rectal cancer: A case report.

Sara Del Tufo, Umberto Atripaldi, Antonella Nicastro, Iacopo Panarese, Davide Ciardiello, Valerio Nardone, Francesco Selvaggi, Roberto Grassi, Salvatore Cappabianca, Erika Martinelli, Alfonso Reginelli.

  Treatment of rectal cancer has improved over the years thanks to a multidisciplinary approach. A correct staging has a fundamental role for risk stratification and to define the best treatment for each patient. Unfortunately, approximately 30% of patients with locally advanced rectal cancers will experience tumor recurrence. Thus, the identification of novel clinical-pathological and radiological prognostic factors represents an urgent unmet clinical need. Here we report the case of a patient with radically resected localized rectal cancer who developed an impressive early pelvic recurrence. To better understand the clinical scenario, we have studied the possible factors related to the aggressiveness of the disease. The only poor prognosticfactor that was evidenced at histological report was perineural invasion. Therefore, we questioned whether we could evaluate perineural invasion with imaging, similar to head and neck tumors. Learning from this clinical case, we believe that improving the risk stratification and radiology reporting is necessary to provide the best care for the patient and allow for a better prognosis prediction. Of course, our data should be considered as hypothesis generating and should be further investigated and validated in larger and prospective studies.

Keywords:  Biomarkers; MRI; Perineural invasion; Rectal cancer; Staging

DOI:  https://doi.org/10.1016/j.radcr.2024.05.031
Radiol Case Rep. 2024 Sep;19(9): 3710-3714

Low back pain with axillary mass in a perimenopausal woman: A case of schwannomatosis mimicking metastasis.

Abhikanta Khatiwada, Sharada K C, Aashish Bastakoti, Bibek Koirala, Aalok Kumar Yadav.

  Schwannomatosis is a rare neurocutaneous syndrome characterized by the presence of multiple schwannomas along the peripheral nerves, distinctly excluding the vestibular nerves. It is recognized as the third principal form of neurofibromatosis, alongside neurofibromatosis types 1 and 2. In this report, we discuss the case of a 45-year-old woman who initially sought medical attention for low back pain and swelling in her left axilla. Her magnetic resonance imaging revealed multiple enhancing intradural extramedullary lesions, along with a mass in the right upper thoracic region and another in the left axilla, raising suspicions of metastasis. However, a comprehensive analysis that aligned imaging results with histopathological findings confirmed the diagnosis of schwannomatosis. This case highlights the importance of differentiating between various conditions that can cause multiple intradural extramedullary masses, such as nerve sheath tumors, meningiomas, and metastasis. The presence of multiple schwannomas suggests a diagnosis of either neurofibromatosis type 2 or schwannomatosis, making the distinction between these two conditions critical for appropriate management.

Keywords:  Intradural extramedullary lesions; Nerve sheath tumor; Neurofibromatosis; Neurofibromatosis type 2; Schwannoma

DOI:  https://doi.org/10.1016/j.radcr.2024.05.062
Cancers (Basel). 2024 Jun 29. pii: 2413. [Epub ahead of print]16(13):

Prognostic Evaluation of Piezo2 Channels in Mammary Gland Carcinoma.

Raquel Martín-Sanz, Aline Rodrigues-Françoso, Yolanda García-Mesa, Francisco Javier García-Alonso, María Asunción Gómez-Muñoz, Sandra Malmierca-González, Rocío Salazar-Blázquez, Olivia García-Suárez, Jorge Feito.

  In the last decade, a group of Ca2+ channels called Piezo were discovered, demonstrating a decisive role in the cellular response to mechanical stimuli and being essential in the biological behavior of cells regarding the extracellular compartment. Several investigations have suggested a potential role in carcinogenesis, with a tumor suppressor role in some cases but increased expression in several high-grade neoplasms. Regarding Piezo2 expression in mammary gland neoplasms, a protective role for Piezo2 was initially suggested, but a subsequent study demonstrated a relationship between Piezo2 expression and the highly aggressive triple-negative phenotype of breast carcinoma. A cohort of 125 patients with clinical follow-up was chosen to study Piezo2 expression and clarify its clinical implications using the same immunohistochemical evaluation performed for other breast carcinoma parameters. Fisher's exact test was chosen to identify potential relationships between the different variables. A significant association was found with the Ki67 proliferation index, but not with mitoses. The tendency of most proliferative tumors was to have an increased score for Piezo2. A similar association was found between Piezo2 expression and perineural invasion.

Keywords:  Piezo2; breast cancer; immunohistochemistry; mechano-signaling; piezo channels

DOI:  https://doi.org/10.3390/cancers16132413
Prog Biophys Mol Biol. 2024 Jul 05. pii: S0079-6107(24)00062-2. [Epub ahead of print]191 25-39

Bioelectric pharmacology of cancer: A systematic review of ion channel drugs affecting the cancer phenotype.

Karina Kofman, Michael Levin.

  Cancer is a pernicious and pressing medical problem; moreover, it is a failure of multicellular morphogenesis that sheds much light on evolutionary developmental biology. Numerous classes of pharmacological agents have been considered as cancer therapeutics and evaluated as potential carcinogenic agents; however, these are spread throughout the primary literature. Here, we briefly review recent work on ion channel drugs as promising anti-cancer treatments and present a systematic review of the known cancer-relevant effects of 109 drugs targeting ion channels. The roles of ion channels in cancer are consistent with the importance of bioelectrical parameters in cell regulation and with the functions of bioelectric signaling in morphogenetic signals that act as cancer suppressors. We find that compounds that are well-known for having targets in the nervous system, such as voltage-gated ion channels, ligand-gated ion channels, proton pumps, and gap junctions are especially relevant to cancer. Our review suggests further opportunities for the repurposing of numerous promising candidates in the field of cancer electroceuticals.

Keywords:  Bioelectricity; Cancer; Electroceutical; Ion channel; Ion pump; Meta-analysis; Metastasis; Pharmacology

DOI:  https://doi.org/10.1016/j.pbiomolbio.2024.07.005
Neuropharmacology. 2024 Jul 05. pii: S0028-3908(24)00231-4. [Epub ahead of print]258 110062

Modeling mechanisms of chemotherapy-induced peripheral neuropathy and chemotherapy transport using induced pluripotent stem cell-derived sensory neurons.

Christina Mortensen, Mikkel Thy Thomsen, Katherina C Chua, Helen S Hammer, Flemming Nielsen, Oliver Pötz, Asa Fex Svenningsen, Deanna L Kroetz, Tore Bjerregaard Stage.

   BACKGROUND: and Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) constitutes a significant health problem due to the increasing prevalence and lack of therapies for treatment and prevention. While pivotal for routine cancer treatment, paclitaxel and vincristine frequently cause CIPN and impact the quality of life among cancer patients and survivors. Here, we investigate molecular mechanisms and drug transport in CIPN.
EXPERIMENTAL APPROACH: Human sensory neurons were derived from induced pluripotent stem cells (iPSC-SNs), which were characterized using flow cytometry and immunolabeling. These iPSC-SNs were exposed to different concentrations of the two microtubule-targeting agents, paclitaxel and vincristine, with and without pre-exposure to inhibitors and inducers of efflux transporters. Neuronal networks were quantified via fluorescent staining against sensory neuron markers. Transcriptional effects of the chemotherapeutics were examined using quantitative polymerase chain reactions (qPCR).
KEY RESULTS: Paclitaxel exposure resulted in axonal retraction and thickening, while vincristine caused fragmentation and abolishment of axons. Both agents increased the mRNA expression of the pain receptor, transient receptor potential vanilloid (TRPV1), and highly induced neuronal damage, as measured by activating transcription factor 3 (ATF3) mRNA. iPSC-SNs express the efflux transporters, P-glycoprotein (P-gp, encoded by ABCB1) and multidrug resistance-associated protein 1 (MPR1, encoded by ABCC1). Modulation of efflux transporters indicate that P-gp and MRP1 play a role in modulating neuronal accumulation and neurotoxicity in preliminary experiments.
CONCLUSION: and Implications: iPSC-SNs are a valuable and robust model to study the role of efflux transporters and other mechanistic targets in CIPN. Efflux transporters may play a role in CIPN pathogenesis as they regulate the disposition of chemotherapy to the peripheral nervous system, and they may present potential therapeutic targets for CIPN.

Keywords:  And neurotoxicity; Chemotherapy-induced peripheral neuropathy; Induced pluripotent stem cells; Paclitaxel; Sensory neurons; Vincristine

DOI:  https://doi.org/10.1016/j.neuropharm.2024.110062
Exp Neurobiol. 2024 Jun 30. 33(3): 129-139

Analgesic Effect of Auricular Vagus Nerve Stimulation on Oxaliplatin-induced Peripheral Neuropathic Pain in a Rodent Model.

In Seon Baek, Seunghwan Choi, Heera Yoon, Geehoon Chung, Sun Kwang Kim.

  Cancer chemotherapy often triggers peripheral neuropathy in patients, leading to neuropathic pain in the extremities. While previous research has explored various nerve stimulation to alleviate chemotherapy-induced peripheral neuropathy (CIPN), evidence on the effectiveness of noninvasive auricular vagus nerve stimulation (aVNS) remains uncertain. This study aimed to investigate the efficacy of non-invasive aVNS in relieving CIPN pain. To induce CIPN in experimental animals, oxaliplatin was intraperitoneally administered to rats (6 mg/kg). Mechanical and cold allodynia, the representative symptoms of neuropathic pain, were evaluated using the von Frey test and acetone test, respectively. The CIPN animals were randomly assigned to groups and treated with aVNS (5 V, square wave) at different frequencies (2, 20, or 100 Hz) for 20 minutes. Results revealed that 20 Hz aVNS exhibited the most pronounced analgesic effect, while 2 or 100 Hz aVNS exhibited weak effects. Immunohistochemistry analysis demonstrated increased c-Fos expression in the locus coeruleus (LC) in the brain of CIPN rats treated with aVNS compared to sham treatment. To elucidate the analgesic mechanisms involving the adrenergic descending pathway, α1-, α2-, or β-adrenergic receptor antagonists were administered to the spinal cord before 20 Hz aVNS. Only the β-adrenergic receptor antagonist, propranolol, blocked the analgesic effect of aVNS. These findings suggest that 20 Hz aVNS may effectively alleviate CIPN pain through β-adrenergic receptor activation.

Keywords:  Adrenergic receptor; Locus coeruleus; Neuropathic pain; Oxaliplatin; Vagus nerve stimulation

DOI:  https://doi.org/10.5607/en24012
Am J Clin Oncol. 2024 Jul 08.

Salbutamol, a Short Acting Beta-2 Agonist, Reduces Risk and Improves Prognosis of Prostate Cancer.

Steven Lehrer, Peter H Rheinstein.

OBJECTIVES: Beta-blockers, a class of drugs commonly used to manage blood pressure, have been the subject of research regarding their relationship to prostate cancer (PC) risk, prognosis, and treatment. Beta-blockers reduce risk and improve the prognosis of PC. Perioperative use of a nonselective beta-blocker improves outcomes after radical prostatectomy. However, a related class of drugs, beta-2 adrenergic agonists, has received little attention in PC.
METHODS: We studied the relationship of the beta-2 adrenergic agonist salbutamol to PC risk and survival. We analyzed Food and Drug Administration MedWatch data to determine whether salbutamol could influence the risk of PC. We used UK Biobank data to assess the effect of salbutamol on PC survival.
RESULTS: Salbutamol significantly reduces PC risk, proportional reporting ratio, and 95% CI (lower bound; upper bound): 0.131 (0.11; 0.155) and improves prognosis. Mean survival was 7.35 years for subjects not taking salbutamol, and 10.5 years for subjects taking salbutamol (P = 0.041, log-rank test. To adjust for the effect of age, we performed proportional hazards regression, survival time-dependent variable, age, and salbutamol use independent variables. Salbutamol use was significantly related to survival time (P = 0.016) and independent of the significant effect of age (P < 0.001).
CONCLUSIONS: We found a lower proportion of PCs in salbutamol-treated people, but we have not demonstrated that PC risk is reduced (there is no proof of causality). There is no causality relationship between salbutamol and the survival of patients with PC treated with salbutamol versus those not treated with the drug. Yet, there is a trend in favor of salbutamol-treated patient survival. Therefore, salbutamol and other beta-adrenergic agonists might represent a new class of drugs for the treatment of PC.

DOI: https://doi.org/10.1097/COC.0000000000001134
Cancer Sci. 2024 Jul 11.

Multifaceted interactions between cancer cells and glial cells in brain metastasis.

Kojiro Ishibashi, Eishu Hirata.

  Cancer brain metastasis has a poor prognosis, is commonly observed in clinical practice, and the number of cases is increasing as overall cancer survival improves. However, experiments in mouse models have shown that brain metastasis itself is an inefficient process. One reason for this inefficiency is the brain microenvironment, which differs significantly from that of other organs, making it difficult for cancer cells to adapt. The brain microenvironment consists of unique resident cell types such as neurons, oligodendrocytes, astrocytes, and microglia. Accumulating evidence over the past decades suggests that the interactions between cancer cells and glial cells can positively or negatively influence the development of brain metastasis. Nevertheless, elucidating the complex interactions between cancer cells and glial cells remains challenging, in part due to the limitations of existing experimental models for glial cell culture. In this review, we first provide an overview of glial cell culture methods and then examine recent discoveries regarding the interactions between brain metastatic cancer cells and the surrounding glial cells, with a special focus on astrocytes and microglia. Finally, we discuss future perspectives for understanding the multifaceted interactions between cancer cells and glial cells for the treatment of metastatic brain tumors.

Keywords:  astrocytes; brain metastasis; cancer–glia interactions; glial cell culture; microglia

DOI:  https://doi.org/10.1111/cas.16241
BMC Womens Health. 2024 Jul 08. 24(1): 394

Relationships between nine neuropsychiatric disorders and cervical cancer: insights from genetics, causality and shared gene expression patterns.

Jie Li, Jie Qi, Junqin Zhang, Yuan Zhang, Xianghua Huang.

   BACKGROUND: Neuropsychiatric disorders and cervical cancer exert substantial influences on women's health. Furthermore, neuropsychiatric disorders frequently manifest as common symptoms in cancer patients, potentially increasing the risk of malignant neoplasms. This study aimed to identify neuropsychiatric disorders that are genetically and causally related to cervical cancer and to investigate the molecular mechanisms underlying these associations.
METHODS: GWAS data related to nine neuropsychiatric disorders, namely, schizophrenia, bipolar disorder, autism spectrum disorder, Parkinson's disease, anxiety, Alzheimer's disease, mood disorders, depression, and alcohol dependence, were obtained to calculate heritability (h2) and genetic correlation (rg) with cervical cancer using linkage disequilibrium score regression (LDSC). Mendelian randomization (MR) analysis of the two cohorts was employed to assess the causal effects. Shared gene expression pattern analysis was subsequently conducted to investigate the molecular mechanism underlying these significant associations.
RESULTS: Anxiety, mood disorders, depression, and alcohol dependence were genetically correlated with cervical cancer (all adjusted P < 0.05). Only depression was causally related to cervical cancer in both the discovery (ORIVW: 1.41, PIVW = 0.02) and replication cohorts (ORIVW: 1.80, PIVW = 0.03) in the MR analysis. Gene expression pattern analysis revealed that 270 genes related to depression and cervical cancer, including tumour necrosis factor (TNF), were significantly upregulated in cervical cancer patients, while vascular endothelial growth factor A (VEGFA), transcription factor AP-1 (JUN), and insulin-like growth factor I (IGF-I) were associated with prognosis in cervical cancer patients (all P < 0.05). These overlapping genes implicated the involvement of multiple biological mechanisms, such as neuron death, the PI3K-Akt signalling pathway, and human papillomavirus infection.
CONCLUSIONS: Genetic, causal and molecular evidence indicates that depression increases the risk of cervical cancer. The TNF, VEGFA, JUN, and IGF-1 genes and the neuron death, PI3K-Akt, and human papillomavirus infection signalling pathways may possibly explain this association.

Keywords:  Causal association; Cervical cancer; Depression; Gene expression patterns; Genetic correlation

DOI:  https://doi.org/10.1186/s12905-024-03234-5
Bioorg Chem. 2024 Jun 29. pii: S0045-2068(24)00510-8. [Epub ahead of print]150 107605

Recent advances in small molecule Nav 1.7 inhibitors for cancer pain management.

Xiaoquan Yu, Xingyi Zhao, Lingjun Li, Yufeng Huang, Chaoyang Cui, Qiaoguan Hu, Haoyu Xu, Bixi Yin, Xiao Chen, Dong Zhao, Yue Qiu, Yunlei Hou.

  The dorsal root ganglion (DRG) is the primary neuron responsible for transmitting peripheral pain signals to the central nervous system and plays a crucial role in pain transduction. Modulation of DRG excitability is considered a viable approach for pain management. Neuronal excitability is intricately linked to the ion channels on the neurons. The small and medium-sized DRG neurons are chiefly engaged in pain conduction and have high levels of TTX-S sodium channels, with Nav1.7 accounting for approximately 80% of the current. Voltage-gated sodium channel (VGSC or Nav) blockers are vital targets for the management of central nervous system diseases, particularly chronic pain. VGSCs play a key role in controlling cellular excitability. Clinical research has shown that Nav1.7 plays a crucial role in pain sensation, and there is strong genetic evidence linking Nav1.7 and its encoding gene SCN9A gene to painful disorders in humans. Many studies have shown that Nav1.7 plays an important role in pain management. The role of Nav1.7 in pain signaling pathways makes it an attractive target for the potential development of new pain drugs. Meanwhile, understanding the architecture of Nav1.7 may help to develop the next generation of painkillers. This review provides updates on the recently reported molecular inhibitors targeting the Nav1.7 pathway, summarizes their structure-activity relationships (SARs), and discusses their therapeutic effects on painful diseases. Pharmaceutical chemists are working to improve the therapeutic index of Nav1.7 inhibitors, achieve better analgesic effects, and reduce side effects. We hope that this review will contribute to the development of novel Nav1.7 inhibitors as potential drugs.

Keywords:  Nav1.7 inhibitors; Painful diseases; Structure-activity relationships

DOI:  https://doi.org/10.1016/j.bioorg.2024.107605