Cervical Tumor Research Articles

Differentiation between Anterior and Posterior Roots Using Compound Muscle Action Potential in Intradural Extramedullary Spinal Tumor Surgery.

This study aims to determine the cutoff values for the compound muscle action potential (CMAP) stimulus in anatomically identified anterior (motor nerve) and posterior roots (sensory nerve) during cervical intradural extramedullary tumor surgery. The connection between CMAP data from nerve roots and postoperative neurological symptoms in thoracolumbar tumors was compared with data from cervical lesions. The participants of the study included 22 patients with intradural extramedullary spinal tumors (116 nerve roots). The lowest stimulation intensity to the nerve root at which muscle contraction occurs was defined as the minimal activation intensity (MAI) in the CMAP. In cervical tumors, the MAI was measured after differentiating between the anterior and posterior roots based on the anatomical placement of the dentate ligament and nerve roots. The MAIs for 20 anterior roots in eight cervical tumors were between 0.1 and 0.3 mA, whereas those for 19 posterior roots were between 0.4 and 2.0 mA. The cutoff was <0.4 mA for both the anterior and posterior roots, and sensitivity and specificity were both 100%. In thoracolumbar tumors, the nerve root was severed in 12 of 14 cases. All MAIs were determined to be at the dorsal roots as their scores were higher than the cutoff and did not indicate motor deficits. The MAIs of the anatomically identified anterior and posterior root CMAPs were found to have a cutoff value of <0.4 mA in the cervical lesions. Similar MAI cutoffs were also applicable to thoracolumbar lesions. Thus, CMAP may be useful in detecting anterior and posterior roots in spinal tumor surgery.

Lymph node-biomimetic scaffold boosts CAR-T therapy against solid tumor.

The limited infiltration and persistence of chimeric antigen receptor (CAR)-T cells is primarily responsible for their treatment deficits in solid tumors. Here, we present a three-dimensional scaffold, inspired by the physiological process of T-cell proliferation in lymph nodes. This scaffold gathers the function of loading, delivery, activation and expansion for CAR-T cells to enhance their therapeutic effects on solid tumors. This porous device is made from poly(lactic-co-glycolic acid) by a microfluidic technique with the modification of T-cell stimulatory signals, including anti-CD3, anti-CD28 antibodies, as well as cytokines. This scaffold fosters a 50-fold CAR-T cell expansion in vitro and a 15-fold cell expansion in vivo. Particularly, it maintains long-lasting expansion of CAR-T cells for up to 30 days in a cervical tumor model and significantly inhibits the tumor growth. This biomimetic delivery strategy provides a versatile platform of cell delivery and activation for CAR-T cells in treating solid tumors.

Targeting MELK improves PD-1 blockade efficiency in cervical cancer via enhancing antitumor immunity

The balance between T helper 1 (Th1)/T helper 2 (Th2) has critical function in determining intratumoral immune response and anti-PD-1 immunotherapy. The level of maternal embryonic leucine zipper kinase (MELK) is reported to correlate with infiltrating of immune cells in cancers, but the underlying molecular mechanism is not clarified. In the present study, we are aimed to elucidate the potential function of MELK in cervical cancer. We found that MELK was upregulated and acted an oncogenic role in cervical cancer. MELK overexpression shifted Th1/Th2 balance towards Th2 predisposition in mouse cervical tumors in vivo and naïve T cells from human PBMCs in vitro, while MELK knockdown exhibited opposite effects. MELK overexpression activated NF-κB signaling and promoted IL-6 secretion by cervical cancer cells. Depletion of IL-6 by neutralization antibodies abrogated the influence of MELK on Th1/2 balance. Besides, MELK modulated the antitumor activity of cytotoxic CD8+ T cells in cervical tumors, but depletion of Th2 cells by IL-4 neutralization abrogated this effect. Finally, MELK overexpression conferred tolerance to PD-1 blockade in cervical tumors, while targeting MELK by OTSSP167 significantly enhanced PD-1 blockade efficiency. Our data elucidated a novel role of MELK in regulating Th1/Th2 balance and anti-PD-1 immunotherapy in cervical cancer.

Chromatin accessibility complex subunit 1 enhances tumor growth by regulating the oncogenic transcription of YAP in breast and cervical cancer.

As a component of chromatin remodeling complex, chromatin accessibility complex subunit 1 (CHRAC1) is critical in transcription and DNA replication. However, the significance of CHRAC1 in cancer progression has not been investigated extensively. This research aimed to determine the function of CHRAC1 in breast and cervical cancer and elucidate the molecular mechanism. The Bio-ID method was used to identify the interactome of transcriptional activator Yes-associated protein (YAP) and the binding between YAP and CHRAC1 was verified by immunofluorescence. CCK8, colony formation and subcutaneous xenograft assays were conducted to explore the function of CHRAC1 in cancer cell proliferation. RNA-seq analysis and RT-PCR were used to analyze the transcription program change after CHRAC1 ablation. The diagnostic value of CHRAC1 was analyzed by TCGA database and further validated by immunohistochemistry staining. In the current study, we found that the chromatin remodeler CHRAC1 was a potential YAP interactor. CHRAC1 depletion suppressed breast and cervical cancer cell proliferation and tumor growth. The potential mechanism may be that CHRAC1 interacts with YAP to facilitate oncogenic transcription of YAP target genes in Hippo pathway, thereby promoting tumorigenesis. CHRAC1 was elevated in cervical and breast cancer biopsies and the upregulation correlated with shorter survival, poor pathological stages and metastasis of cancer patients. Moreover, CHRAC1 expression was statistically associated with YAP in breast and cervical cancer biopsies. These findings highlight that CHRAC1 contributes to cancer progression through regulating the oncogenic transcription of YAP, which makes it a potential therapeutic target for cancer treatment.

Abstract IA005: PET imaging predictors of response to chemoradiotherapy in cervical cancer

Abstract Although HPV transformed tumors are presumed to be radiation sensitive, approximately one third of locally advanced cervical cancer patients fail the current standard of care (concurrent cisplatin and radiation therapy). Work in our laboratory has combined the results of functional imaging with 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET) imaging together with bioinformatic analyses of associated translational correlates to define new predictors of resistance to DNA damaging therapies. Results of this work demonstrate that cervical tumors with increased FDG uptake on pretreatment FDG-PET imaging are characterized by myeloid predominant inflammatory infiltrates, including immature monocytes and macrophages. Co-culture of cervical tumor cells with macrophages is associated with increased glucose uptake and pro-survival signaling in tumor cells mediated through macrophage derived IL-6 and signaling through the JAK-STAT pathway. We are currently using a combination of single cell sequencing and spatially resolved approaches to further define PET associated and chemoradiation induced changes in cervix tumor cell metabolism and the immune tumor microenvironment with the goal of defining new targets for personalized therapies. Importantly, cervical cancers retain and transcribe portions of the HPV genome. At the end of the talk, we will review recent work in our lab that highlights the impact of HPV associated gene expression, including splice variants, on the response to DNA damaging agents. Citation Format: Julie K. Schwarz. PET imaging predictors of response to chemoradiotherapy in cervical cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA005.

Unveiling the natural history of paralysis in metastatic cervical spinal tumor: An experimental study

IntroductionDespite the relatively low prevalence of metastatic cervical spinal tumor, these entities give rise to more profound complications than thoracic and lumbar spinal tumor. However, it is regrettable that experimental investigation has thus far shown a dearth of attention to metastatic cervical spinal tumor. Research questionWhat is the conceptualization and realization of quadriparesis resulting from metastatic cervical spinal tumor? Material and methodsUsing Fischer 344 rats as the experimental cohort, this study orchestrated the engraftment of tumor cells procured from the 13762 MAT B III cell line (RRID: CVCL_3475), which represents mammary adenocarcinoma. These cells were engrafted into the vertebrae of the cervical spine. A comprehensive inquiry encompassing behavioral assessments, histological evaluations, and microangiographic analyses conducted after the aforementioned cellular transplantation was subsequently pursued. ResultsThe incidence of cervical paralysis was 61.1%. Notably, the evolution of paralysis was unfurled by two distinctive temporal phases within its natural history. A meticulous histological examination facilitated delineation of the tumor's posterior expansion within the spinal canal. Simultaneously, the tumor exhibited anterior and lateral encroachment on the spinal cord, inducing compression from all sides. Augmented by microangiographic investigations, conspicuous attenuation of stained blood vessels within the affected anterior horn and funiculus of the spinal cord was observed. Discussion and conclusionThe pathological advancement of paralysis stemming from metastatic cervical spinal tumor is now apprehended to unfurl through a biphasic phase. The initial phase is characterized by gradual unfurling spanning several days, juxtaposed against the second phase marked by swift and accelerated progression.

(Nano)biotechnological approaches in the treatment of cervical cancer: integration of engineering and biology.

Cervical cancer is one of the most malignant gynaecological tumors characterised with the aggressive behaviour of the tumor cells. In spite of the development of different strategies for the treatment of cervical cancer, the tumor cells have developed resistance to conventional therapeutics. On the other hand, nanoparticles have been recently applied for the treatment of human cancers through delivery of drugs and facilitate tumor suppression. The stimuli-sensitive nanostructures can improve the release of therapeutics at the tumor site. In the present review, the nanostructures for the treatment of cervical cancer are discussed. Nanostructures can deliver both chemotherapy drugs and natural compounds to increase anti-cancer activity and prevent drug resistance in cervical tumor. Moreover, the genetic tools such as siRNA can be delivered by nanoparticles to enhance their accumulation at tumor site. In order to enhance selectivity, the stimuli-responsive nanoparticles such as pH- and redox-responsive nanocarriers have been developed to suppress cervical tumor. Moreover, nanoparticles can induce photo-thermal and photodynamic therapy to accelerate cell death in cervical tumor. In addition, nanobiotechnology demonstrates tremendous potential in the treatment of cervical cancer, especially in the context of tumor immunotherapy. Overall, metal-, carbon-, lipid- and polymer-based nanostructures have been utilized in cervical cancer therapy. Finally, hydrogels have been developed as novel kinds of carriers to encapsulate therapeutics and improve anti-cancer activity.

Tumor mineralization-based cancer diagnosis and therapy

Biomineralization is a phenomenon that involves the deposition of inorganic ions onto organic substrates, resulting in the formation of hard tissue materials. Tumor mineralization, on the other hand, encompasses two key aspects: tumor calcification and tumor iron mineralization. The occurrence of spontaneous tumor calcification and regional lymph node calcification in colorectal cancer, lung cancer, and glioblastoma has been established as a favorable prognostic factor in clinical settings. Building upon this understanding, we propose the concept and advance the development of a compound that artificially induces bionic mineralization around the surface of cancer cells. This process has demonstrated exceptional efficacy in inhibiting the growth and metastasis of cervical, breast, and lung tumors. Moreover, it has exhibited outstanding performance in the early-stage diagnosis of cancer. Consequently, we anticipate that this concept holds significant potential for cancer-targeted mineralization therapy and diagnosis, offering a novel avenue for the development of anticancer drugs.

Heterogeneous Response of Tumor Cell Lines to Inhibition of Aspartate β-hydroxylase.

Background: Cancer development involves alterations in key cellular pathways, with aspartate β-hydroxylase (ASPH) emerging as an important player in tumorigenesis. ASPH is upregulated in various cancer types, where it promotes cancer progression mainly by regulating the Notch1 and SRC pathways. Methods: This study explored the responses of various human cervical, pharyngeal, and breast tumor cell lines to second- and third-generation ASPH inhibitors (MO-I-1151 and MO-I-1182) using proliferation, migration, and invasion assays; western blotting; and cell cycle analysis. Results: ASPH inhibition significantly reduced cell proliferation, migration, and invasion and disrupted both the canonical and noncanonical Notch1 pathways. The noncanonical pathway was particularly mediated by AKT signaling. Cell cycle analysis revealed a marked reduction in cyclin D1 expression, further confirming the inhibitory effect of ASPH inhibitors on cell proliferation. Additional analysis revealed G0/G1 arrest and restricted progression into S phase, highlighting the regulatory impact of ASPH inhibitors on the cell cycle. Furthermore, ASPH inhibition induced distinctive alterations in nuclear morphology. The high heterogeneity in the responses of individual tumor cell lines to ASPH inhibitors, both quantitatively and qualitatively, underscores the complex network of mechanisms that are regulated by ASPH and influence the efficacy of ASPH inhibition. The effects of ASPH inhibitors on Notch1 pathway activity, cyclin D1 expression, and nuclear morphology contribute to the understanding of the multifaceted effects of these inhibitors on cancer cell behavior. Conclusion: This study not only suggests that ASPH inhibitors are effective against tumor cell progression, in part through the induction of cell cycle arrest, but also highlights the diverse and heterogeneous effects of these inhibitors on the behavior of tumor cells of different origins.

Clinical outcomes of excisional surgery for cervical spine tumors

Clinical outcomes of excisional surgery for cervical spine tumors

Cases of Cervical Extramedullary Recurrent Malignant Solitary Fibrous Tumors Treated Multimodally with Pazopanib Hydrochloride

Cases of Cervical Extramedullary Recurrent Malignant Solitary Fibrous Tumors Treated Multimodally with Pazopanib Hydrochloride

Automatically detecting anchor cells and clustering for scRNA-seq data using scTSNN.

Advancing in single-cell RNA sequencing techniques enhances the resolution of cell heterogeneity study. Density-based unsupervised clustering has the potential to detect the representative anchor points and the number of clusters automatically. Meanwhile, discovering the true cell type of scRNA-seq data in the unsupervised scenario is still challenging. To this end, we proposed a tensor shared nearest neighbor anchor clustering for scRNA-seq data, named scTSNN, which first makes use of the tensor affinity learning module to mine the local-global balanced topological structures among cells, next designs density-based shared nearest neighbor measurement method to automatically detect anchor cells, finally partitions the non-anchor cells to obtain the clustering results. Validated on synthetic datasets and scRNA-seq datasets, scTSNN not only exactly detects the complicated structures but also has better performance in accuracy and robustness compared with the state-of-the-art methods. Moreover, case studies on mammalian cells and cervical cancer tumor cells demonstrate the selected anchor cells of scTSNN benefit the cell pseudotime inference and rare cell identification, which show good application and research value of scTSNN.

Identification and Quantification of Radiotherapy-related Protein Expression in Cancer Tissues Using the Qupath Software and Prediction of Treatment Response.

Automated measurement of immunostained samples can enable more convenient and objective prediction of treatment outcome from radiotherapy. We aimed to validate the performance of the QuPath image analysis software in immune cell markers detection by comparing QuPath cell counting results with those of physician manual cell counting. CD8- and FoxP3-stained cervical, CD8-stained oropharyngeal, and Ku70-stained prostate cancer tumor sections were analyzed in 104 cervical, 92 oropharyngeal, and 58 prostate cancer patients undergoing radiotherapy at our Institution. QuPath and manual counts were highly correlated. When divided into two groups using ROC curves, the agreement between QuPath and manual counts was 89.4% for CD8 and 88.5% for FoxP3 in cervical cancer, 87.0% for CD8 in oropharyngeal cancer and 80.7% for Ku70 in prostate cancer. In cervical cancer, the high CD8 group based on QuPath counts had a better prognosis and the low CD8 group had a significantly worse prognosis [p=0.0003; 5-year overall survival (OS), 65.9% vs. 34.7%]. QuPath counts were more predictive than manual counts. Similar results were observed for FoxP3 in cervical cancer (p=0.002; 5-year OS, 62.1% vs. 33.6%) and CD8 in oropharyngeal cancer (p=0.013; 5-year OS, 80.2% vs. 47.2%). In prostate cancer, high Ku70 group had worse and low group significantly better outcome [p=0.007; 10-year progression-free survival (PFS), 56.0% vs. 93.8%]. QuPath showed a strong correlation with manual counting, confirming its utility and accuracy and potential applicability in clinical practice.

Lymphoepithelioma-like carcinoma of the cervix: Diagnostics, treatment, monitoring

Lymphoepithelioma-like carcinoma of the cervix (LELC) is a rare subtype of squamous cell carcinoma. This is a case report of a 40-year-old female patient diagnosed with LELC. The tumor is clinically presented as an exophytic mass on the front lip of the cervix. Magnetic resonance imaging (MRI) of the pelvis revealed a cervical tumor mass with a diameter of 21 mm. The findings of the preoperative pathohistological analysis of the biopsy tissue indicated LELC. The disease was clinically and radiologically staged as IB1 stage according to the 2009 FIGO classification, and the patient underwent surgical treatment. A total radical hysterectomy with pelvic lymphadenectomy was performed, followed by external beam radiotherapy. The patient was regularly monitored with the last check-up on February 2024 (36 months) and MRI control of the pelvis and abdomen without signs of recurrence of the underlying disease. The patient is in good general condition, without subjective complaints and side effects of the applied therapy.

Rebalancing TGF-β/PGE2 breaks RT-induced immunosuppressive barriers by enhancing tumor-infiltrated dendritic cell homing.

A better understanding of how tumor microenvironments shape immune responses after radiotherapy (RT) is required to improve patient outcomes. This study focuses on the observation that dendritic cells (DCs) infiltrating irradiated cervical tumors are retained in transforming growth factor (TGF)-β-abundant regions. We report that TGF-β secretion from cervical cancer cells was increased by irradiation in a dose-dependent manner and that this significantly suppressed the expression of allostimulatory markers and Th1 cytokines in DCs. To investigate further, we blocked the TGF-β signal in DCs and observed that RT had a dose-dependent immune-promoting effect, improving DC maturation. This suggested that proinflammatory mediators may also be induced by RT, but their effects were being counteracted by the simultaneously increased levels of TGF-β. Prostaglandin E2 (PGE2), a proinflammatory molecule, was shown to be one such mediator. Adjusting the TGF-β/PGE2 ratio by inhibiting TGF-β rebooted RT-induced DC cytoskeletal organization by stimulating myosin light chain (MLC) phosphorylation. Consequently, the homing of intra-tumorally infiltrated DCs to tumor-draining lymph nodes was enhanced, leading to the induction of more robust cytotoxic T cells. Ultimately, rebalancing the TGF-β/PGE2 ratio amplified the therapeutic effects of RT, resulting in increased intra-tumoral infiltration and activation of CD8+ T cells, and improved tumor control and overall survival rate in mice. DC depletion experiments verified that the improvement in tumor control is directly correlated with the involvement of DCs via the PGE2-MLC pathway. This study emphasizes the importance of maintaining a balanced cytokine environment during RT, particularly hypofractionated RT; and it is advisable to block TGF-β while preserving PGE2 in the tumor microenvironment in order to better stimulate DC homing and DC -T priming.

Giant Invasive Schwannomas of C1 Root – Technical Challenges and Report of the First Two Cases in Literature

Abstract Giant invasive schwannomas (GISs) have been defined as different from other spinal schwannomas. C1 schwannomas are rare and often described with other high cervical tumors. GISs of C1 have not been previously described. Two cases of GIS are reported. In both patients, presenting with myelopathy, the lesions were extradural and intradural with posterior, lateral, and anterior extensions, compressing the cervicomedullary junction (CMJ) and displacing it. The V3-4 segments of the vertebral artery (VA) were closely associated. A posterolateral approach was used to initially expose and debulk the extradural portion of the lesion, which allowed access to the intradural component. The latter was followed anterior and/or posterior to the CMJ and excised completely. The tumors were dissected at the VA. Bleeding from the perivertebral venous plexus was controlled using topical hemostats. A small bit of tumor was left in a blind area anterior to the C1 arch in one patient. There were no complications and both patients improved in the postoperative period. GIS of the C1 are rare lesions in a difficult location. Complex relationships to the CMJ, lower cranial nerves, VA, and bony spine need a careful preoperative understanding of the anatomy and planning of surgery.

Near-infrared-II Ag2S quantum dot probes targeting podoplanin enhance immunotherapy in oral squamous cell carcinoma

Partial epithelial-mesenchymal transition (pEMT) plays a vital role in oral squamous cell carcinoma (OSCC) cervical lymph node metastasis and tumor immune escape as an immune barrier. However, targeted interventions for pEMT have yet to be established. In this study, we generated an αPDPN-Ag2S probe by modifying a Podoplanin(PDPN) monoclonal antibody on the surface of near infrared (NIR)-II Ag2S quantum dots (QDs) with carboxyl groups through an amide reaction. Then, we evaluated its in vivo targeting ability, therapeutic efficacy of eliminating pEMT using αPDPN-Ag2S-mediated NIR-II photoimmunotherapy (PIT) and biological safety. Here, we found that pEMT is related to CD8 + T-cell infiltration in our human OSCC tissue microarray. Compared with PdpnWT SCC7, the slower growth rate of subcutaneous graft tumors implanted with PdpnKD SCC7 was associated with a change in the tumor immune microenvironment (TIM) in an immunocompetent C3H/HeJ mouse model. In vitro, αPDPN-Ag2S plus NIR 808 nm laser irradiation induced SCC7 cell death. In vivo, NIR-II imaging results show that the αPDPN-Ag2S probe has a good active-targeting ability in a 4-nitroquinoline 1-oxide (4NQO)-induced C57 mouse OSCC model and C3H/HeJ SCC7 subcutaneous graft tumor model. Elimination of pEMT cells by NIR-II αPDPN-Ag2S probe-mediated PIT significantly reversed the local immunosuppressive tumor microenvironment and enhanced PD-1 immunotherapy efficacy. The safety profiles of αPDPN-Ag2S in BALB/c mice were also acceptable. Thus, αPDPN-Ag2S has important clinical translational value in predicting the risk of cervical lymph node metastasis. Importantly, our study proposed a new way to improve the efficacy of tumor immunotherapy.

Soluble guanylyl cyclase beta1 subunit targets epithelial-to-mesenchymal transition and downregulates Akt pathway in human endometrial and cervical cancer cells

Endometrial and cervical cancer are among the most frequently diagnosed malignancies globally. Nitric oxide receptor-soluble guanylyl cyclase (sGC) is a heterodimeric enzyme composed of two subunits, α1 and β1. Previously we showed that sGCα1 subunit promotes cell survival, proliferation, and migration, but the role of sGCβ1 subunit has not been addressed. The aim of the present work was to study the impact of sGCβ1 restoration in proliferation, survival, migration, and cell signaling in endometrial and cervical cancer cells. We found that sGCβ1 transcript levels are reduced in endometrial and cervical tumors vs normal tissues. We confirmed nuclear enrichment of sGCβ1, unlike sGCα1. Overexpression of sGCβ1 reduced cell viability and augmented apoptotic index. Cell migration and invasion were also negatively affected. All these sGCβ1-driven effects were independent of sGC enzymatic activity. sGCβ1 reduced the expression of epithelial-to-mesenchymal transition factors such as N-cadherin and β-catenin and increased the expression of E-cadherin. sGCβ1 impacted signaling in endometrial and cervical cancer cells through significant downregulation of Akt pathway affecting some of its main targets such as GSK-3β and c-Raf. Our results show for the first time that sGCβ1 exerts several antiproliferative actions in ECC-1 and HeLa cell lines by targeting key regulatory pathways.

Cervical Giant Cell Tumor Removal With an Anterolateral Approach With Vertebral Artery Transposition: 2-Dimensional Operative Video.

Cervical Giant Cell Tumor Removal With an Anterolateral Approach With Vertebral Artery Transposition: 2-Dimensional Operative Video.

Impact of pelvic radiation therapy in patients with early neuroendocrine cervical carcinoma and no residual disease in the radical hysterectomy specimen: a NeCTuR study

ObjectiveThe impact of adjuvant pelvic radiation therapy on the rate and location of recurrences was evaluated in patients with early-stage (IA1–IB2) neuroendocrine cervical carcinoma who underwent prior conization or polypectomy...