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The Journal of Gene Medicine Jun 2024Liver cancer is typified by a complex inflammatory tumor microenvironment, where an array of cytokines and stromal cells orchestrate a milieu that significantly...
BACKGROUND
Liver cancer is typified by a complex inflammatory tumor microenvironment, where an array of cytokines and stromal cells orchestrate a milieu that significantly influences tumorigenesis. Interleukin-17A (IL-17A), a pivotal pro-inflammatory cytokine predominantly secreted by Th17 cells, is known to play a substantial role in the etiology and progression of liver cancer. However, the precise mechanism by which IL-17A engages with hepatic stellate cells (HSCs) to facilitate the development of hepatocellular carcinoma (HCC) remains to be fully elucidated. This investigation seeks to unravel the interplay between IL-17A and HSCs in the context of HCC.
METHODS
An HCC model was established in male Sprague-Dawley rats using diethylnitrosamine to explore the roles of IL-17A and HSCs in HCC pathogenesis. In vivo overexpression of Il17a was achieved using adeno-associated virus. A suite of molecular techniques, including RT-qPCR, enzyme-linked immunosorbent assays, Western blotting, cell counting kit-8 assays and colony formation assays, was employed for in vitro analyses.
RESULTS
The study findings indicate that IL-17A is a key mediator in HCC promotion, primarily through the activation of hepatic progenitor cells (HPCs). This pro-tumorigenic influence appears to be mediated by HSCs, rather than through a direct effect on HPCs. Notably, IL-17A-induced expression of fibroblast activation protein (FAP) in HSCs emerged as a critical factor in HCC progression. Silencing Fap in IL-17A-stimulated HSCs was observed to reverse the HCC-promoting effects of HSCs.
CONCLUSIONS
The collective evidence from this study implicates the IL-17A/FAP signaling axis within HSCs as a contributor to HCC development by enhancing HPC activation. These findings bolster the potential of IL-17A as a diagnostic and preventative target for HCC, offering new avenues for therapeutic intervention.
Topics: Hepatic Stellate Cells; Animals; Interleukin-17; Carcinoma, Hepatocellular; Liver Neoplasms; Rats; Male; Rats, Sprague-Dawley; Tumor Microenvironment; Endopeptidases; Gene Expression Regulation, Neoplastic; Humans; Disease Models, Animal; Membrane Proteins; Cell Line, Tumor
PubMed: 38860366
DOI: 10.1002/jgm.3693 -
Technology in Cancer Research &... 2024Gastric cancer (GC) is one of the most prevalent malignancies worldwide, and early detection is crucial for improving patient survival rates. We aimed to identify immune...
OBJECTIVES
Gastric cancer (GC) is one of the most prevalent malignancies worldwide, and early detection is crucial for improving patient survival rates. We aimed to identify immune infiltrating cell-related biomarkers in early gastric cancer (EGC) progression.
METHODS
The GSE55696 and GSE130823 datasets with low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and EGC samples were downloaded from the Gene Expression Omnibus database to perform an observational study. Immune infiltration analysis was performed by single sample gene set enrichment analysis and Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data. Weighted gene co-expression network analysis was used to explore the co-expression modules and genes, and further enrichment analysis was performed on these genes. A protein-protein interaction (PPI) network of these genes was constructed to identify biomarkers associated with EGC progression. Screened hub genes were validated by the rank sum test and reverse transcription quantitative polymerase chain reaction.
RESULTS
Immune scores were significantly elevated in EGC samples compared to LGIN and HGIN samples. The green-yellow module exhibited the strongest correlation with both immune score and disease progression. The 87 genes within this module were associated with the chemokine signaling pathways, the PI3K-Akt signaling pathways, leukocyte transendothelial migration, and Ras signaling pathways. Through PPI network analysis, the hub genes identified were protein tyrosine phosphatase receptor-type C (PTPRC), pleckstrin, CD53, CD48, lymphocyte cytosolic protein 1 (LCP1), hematopoietic cell-specific Lyn substrate 1, IKAROS Family Zinc Finger 1, Bruton tyrosine kinase, and Vav guanine nucleotide exchange factor 1. Notably, CD48, LCP1, and PTPRC showed high expression levels in EGC samples, with the remaining hub genes demonstrating a similar expression trend.
CONCLUSION
This study identified 9 immune cell-related biomarkers that may be actively involved in the progression of EGC and serve as potential targets for GC diagnosis and treatment.
Topics: Humans; Stomach Neoplasms; Biomarkers, Tumor; Disease Progression; Protein Interaction Maps; Gene Regulatory Networks; Gene Expression Regulation, Neoplastic; Lymphocytes, Tumor-Infiltrating; Gene Expression Profiling; Computational Biology; Databases, Genetic; Prognosis; Tumor Microenvironment
PubMed: 38860335
DOI: 10.1177/15330338241262724 -
Biochemical Society Transactions Jun 2024The tumor microenvironment (TME) is a complex and dynamic ecosystem that adjoins the cancer cells within solid tumors and comprises distinct components such as... (Review)
Review
The tumor microenvironment (TME) is a complex and dynamic ecosystem that adjoins the cancer cells within solid tumors and comprises distinct components such as extracellular matrix, stromal and immune cells, blood vessels, and an abundance of signaling molecules. In recent years, the mechanical properties of the TME have emerged as critical determinants of tumor progression and therapeutic response. Aberrant mechanical cues, including altered tissue architecture and stiffness, contribute to tumor progression, metastasis, and resistance to treatment. Moreover, burgeoning immunotherapies hold great promise for harnessing the immune system to target and eliminate solid malignancies; however, their success is hindered by the hostile mechanical landscape of the TME, which can impede immune cell infiltration, function, and persistence. Consequently, understanding TME mechanoimmunology - the interplay between mechanical forces and immune cell behavior - is essential for developing effective solid cancer therapies. Here, we review the role of TME mechanics in tumor immunology, focusing on recent therapeutic interventions aimed at modulating the mechanical properties of the TME to potentiate T cell immunotherapies, and innovative assays tailored to evaluate their clinical efficacy.
Topics: Humans; Tumor Microenvironment; Neoplasms; Immunotherapy; Animals; Extracellular Matrix; T-Lymphocytes
PubMed: 38856041
DOI: 10.1042/BST20231427 -
Theranostics 2024The stem or progenitor antecedents confer developmental plasticity and unique cell identities to cancer cells via genetic and epigenetic programs. A comprehensive...
The stem or progenitor antecedents confer developmental plasticity and unique cell identities to cancer cells via genetic and epigenetic programs. A comprehensive characterization and mapping of the cell-of-origin of breast cancer using novel technologies to unveil novel subtype-specific therapeutic targets is still absent. We integrated 195,144 high-quality cells from normal breast tissues and 406,501 high-quality cells from primary breast cancer samples to create a large-scale single-cell atlas of human normal and cancerous breasts. Potential heterogeneous origin of malignant cells was explored by contrasting cancer cells against reference normal epithelial cells. Multi-omics analyses and both and experiments were performed to screen and validate potential subtype-specific treatment targets. Novel biomarkers of identified immune and stromal cell subpopulations were validated by immunohistochemistry in our cohort. Tumor stratification based on cancer cell-of-origin patterns correlated with clinical outcomes, genomic aberrations and diverse microenvironment constitutions. We found that the luminal progenitor (LP) subtype was robustly associated with poor prognosis, genomic instability and dysfunctional immune microenvironment. However, the LP subtype patients were sensitive to neoadjuvant chemotherapy (NAC), PARP inhibitors (PARPi) and immunotherapy. The LP subtype-specific target PLK1 was investigated by both and experiments. Besides, large-scale single-cell profiling of breast cancer inspired us to identify a range of clinically relevant immune and stromal cell subpopulations, including subsets of innate lymphoid cells (ILCs), macrophages and endothelial cells. The present single-cell study revealed the cellular repertoire and cell-of-origin patterns of breast cancer. Combining single-cell and bulk transcriptome data, we elucidated the evolution mimicry from normal to malignant subtypes and expounded the LP subtype with vital clinical implications. Novel immune and stromal cell subpopulations of breast cancer identified in our study could be potential therapeutic targets. Taken together, Our findings lay the foundation for the precise prognostic and therapeutic stratification of breast cancer.
Topics: Humans; Single-Cell Analysis; Female; Breast Neoplasms; Tumor Microenvironment; Animals; Mice; Biomarkers, Tumor; Cell Line, Tumor; Prognosis
PubMed: 38855191
DOI: 10.7150/thno.96163 -
World Journal of Gastroenterology May 2024In this editorial we comment on the review by Wang published in the recent issue of the W in 2023. Small extracellular vesicles (exosomes) play important roles in the... (Review)
Review
In this editorial we comment on the review by Wang published in the recent issue of the W in 2023. Small extracellular vesicles (exosomes) play important roles in the tumor microenvironment. In this review, the authors introduce the following points: (1) The composition and function of exosomal microRNAs (miRNAs) of different cell origins in hepatocellular carcinoma (HCC); (2) the crosstalk between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC; and (3) the potential applicability of exosomal miRNAs derived from mesen-chymal stem cells in the treatment of HCC. In addition, the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC was introduced. In this review, the authors give us an overview of the exosomal RNA and summarize the function of exosomal RNA in HCC, which provides a deeper understanding of exosomal miRNAs to the readers.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Exosomes; MicroRNAs; Tumor Microenvironment; Gene Expression Regulation, Neoplastic; Mesenchymal Stem Cells; Disease Progression; Animals; Biomarkers, Tumor
PubMed: 38855155
DOI: 10.3748/wjg.v30.i20.2618 -
Veterinary Medicine and Science Jul 2024A 7-year-old castrated male Golden Retriever weighing 36.8 kg presented to the Veterinary Teaching Hospital with vomiting, anorexia and depression. After blood tests,...
A 7-year-old castrated male Golden Retriever weighing 36.8 kg presented to the Veterinary Teaching Hospital with vomiting, anorexia and depression. After blood tests, radiographic, ultrasound and computed tomography examinations, a 7.85 × 5.90 × 8.75 cm mass was identified in the caecum. To visualise the tumour margin and improve the accuracy of tumour resection, intraoperative short-wave infrared imaging using indocyanine green was performed during surgery. An indocyanine green solution was injected intravenously as a bolus of 5 mg/kg 24 h before surgery. Tumour resection was performed with a 0.5 cm margin from the fluorescent-marked tissues. Histopathological examination revealed a diagnosis of a gastrointestinal stromal tumour (GIST) and the absence of neoplastic cells in the surgical margin, indicating a successful surgery. To our knowledge, this is the first case of a GIST resection in a dog using intraoperative short-wave infrared imaging.
Topics: Animals; Indocyanine Green; Dogs; Male; Gastrointestinal Stromal Tumors; Dog Diseases; Optical Imaging
PubMed: 38853600
DOI: 10.1002/vms3.1506 -
The Journal of Pathology. Clinical... Jul 2024Colorectal cancer remains a leading cause of mortality worldwide. Significant variation in response to treatment and survival is evident among patients with similar... (Review)
Review
Colorectal cancer remains a leading cause of mortality worldwide. Significant variation in response to treatment and survival is evident among patients with similar stage disease. Molecular profiling has highlighted the heterogeneity of colorectal cancer but has had limited impact in daily clinical practice. Biomarkers with robust prognostic and therapeutic relevance are urgently required. Ideally, biomarkers would be derived from H&E sections used for routine pathological staging, have reliable sensitivity and specificity, and require minimal additional training. The biomarker targets would capture key pathological features with proven additive prognostic and clinical utility, such as the local inflammatory response and tumour microenvironment. The Glasgow Microenvironment Score (GMS), first described in 2014, combines assessment of peritumoural inflammation at the invasive margin with quantification of tumour stromal content. Using H&E sections, the Klintrup-Mäkinen (KM) grade is determined by qualitative morphological assessment of the peritumoural lymphocytic infiltrate at the invasive margin and tumour stroma percentage (TSP) calculated in a semi-quantitative manner as a percentage of stroma within the visible field. The resulting three prognostic categories have direct clinical relevance: GMS 0 denotes a tumour with a dense inflammatory infiltrate/high KM grade at the invasive margin and improved survival; GMS 1 represents weak inflammatory response and low TSP associated with intermediate survival; and GMS 2 tumours are typified by a weak inflammatory response, high TSP, and inferior survival. The prognostic capacity of the GMS has been widely validated while its potential to guide chemotherapy has been demonstrated in a large phase 3 trial cohort. Here, we detail its journey from conception through validation to clinical translation and outline the future for this promising and practical biomarker.
Topics: Humans; Colorectal Neoplasms; Tumor Microenvironment; Biomarkers, Tumor; Prognosis; Neoplasm Grading
PubMed: 38853386
DOI: 10.1002/2056-4538.12385 -
BMC Medicine Jun 2024Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive ages. Our previous study has implicated a possible link between RNA...
BACKGROUND
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive ages. Our previous study has implicated a possible link between RNA editing and PCOS, yet the actual role of RNA editing, its association with clinical features, and the underlying mechanisms remain unclear.
METHODS
Ten RNA-Seq datasets containing 269 samples of multiple tissue types, including granulosa cells, T helper cells, placenta, oocyte, endometrial stromal cells, endometrium, and adipose tissues, were retrieved from public databases. Peripheral blood samples were collected from twelve PCOS and ten controls and subjected to RNA-Seq. Transcriptome-wide RNA-Seq data analysis was conducted to identify differential RNA editing (DRE) between PCOS and controls. The functional significance of DRE was evaluated by luciferase reporter assays and overexpression in human HEK293T cells. Dehydroepiandrosterone and lipopolysaccharide were used to stimulate human KGN granulosa cells to evaluate gene expression.
RESULTS
RNA editing dysregulations across multiple tissues were found to be associated with PCOS in public datasets. Peripheral blood transcriptome analysis revealed 798 DRE events associated with PCOS. Through weighted gene co-expression network analysis, our results revealed a set of hub DRE events in PCOS blood. A DRE event in the eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2:chr2:37,100,559) was associated with PCOS clinical features such as luteinizing hormone (LH) and the ratio of LH over follicle-stimulating hormone. Luciferase assays, overexpression, and knockout of RNA editing enzyme adenosine deaminase RNA specific (ADAR) showed that the ADAR-mediated editing cis-regulated EIF2AK2 expression. EIAF2AK2 showed a higher expression after dehydroepiandrosterone and lipopolysaccharide stimulation, triggering changes in the downstrean MAPK pathway.
CONCLUSIONS
Our study presented the first evidence of cross-tissue RNA editing dysregulation in PCOS and its clinical associations. The dysregulation of RNA editing mediated by ADAR and the disrupted target EIF2AK2 may contribute to PCOS development via the MPAK pathway, underlining such epigenetic mechanisms in the disease.
Topics: Humans; Polycystic Ovary Syndrome; Female; RNA Editing; eIF-2 Kinase; Adult; HEK293 Cells; Gene Expression Profiling; Clinical Relevance
PubMed: 38853264
DOI: 10.1186/s12916-024-03434-8 -
Experimental Oncology May 2024To study the prognostic value of the density of tumor-infiltrating lymphocytes (TILs) and its association with other clinical-morphological parameters in colon...
AIM
To study the prognostic value of the density of tumor-infiltrating lymphocytes (TILs) and its association with other clinical-morphological parameters in colon adenocarcinomas (CAC).
MATERIALS AND METHODS
236 CAC samples were examined. TILs density was estimated as the percentage of tumor stromal area occupied by TILs. By the index of TILs density, the patients were divided into 3 groups: TILs 0-9% (n = 88); TILs 10-39% (n = 106); TILs > 40% (n = 42). Dependent on this index, their overall survival (OS) was analyzed.
RESULTS
Kaplan - Meier curves revealed a significant (p < 0.001) difference in the OS for patients with different TILs infiltration intensities. Multivariate Cox's proportional hazard regression model analysis has confirmed that patients with moderate TILs density (HR 0.57, 95% CI 0.34-0.96, p = 0.035) had better OS rates compared to low TILs density. TILs were associated with the stage (p < 0.001), lymph node metastasis pN (p < 0.001), distant metastasis M (p < 0.001), and the patient's outcome (p < 0.001).
CONCLUSION
TILs can be considered an additional prognostic tool during regular histological examination and are strongly associated with the most significant clinical-morphological features of CAC.
Topics: Humans; Lymphocytes, Tumor-Infiltrating; Colonic Neoplasms; Prognosis; Adenocarcinoma; Male; Female; Middle Aged; Aged; Adult; Neoplasm Staging; Aged, 80 and over; Kaplan-Meier Estimate; Proportional Hazards Models; Lymphatic Metastasis
PubMed: 38852053
DOI: 10.15407/exp-oncology.2024.01.045 -
International Journal of Surgery Case... Jul 2024Cutaneous leiomyomas, benign tumors from smooth muscle fibers, constitute about 5 % of all leiomyomas. They exhibit diverse inheritance patterns and can be linked to...
INTRODUCTION AND IMPORTANCE
Cutaneous leiomyomas, benign tumors from smooth muscle fibers, constitute about 5 % of all leiomyomas. They exhibit diverse inheritance patterns and can be linked to systemic malignancies. Gastrointestinal stromal tumors (GISTs), arising from the interstitial cells of Cajal, are the most common mesenchymal tumors in the gastrointestinal tract. Despite their prevalence, simultaneous occurrences of cutaneous leiomyomas and GISTs are rare, necessitating exploration of their potential relationship.
CASE PRESENTATION
A 25-year-old male with no significant medical history presented with multiple painful erythematous nodules on his chest, upper back, and arms. Histopathological analysis diagnosed these as multiple cutaneous piloleiomyomatosis. Despite recommendations for surgical intervention, the patient chose medical management and experienced significant pain relief with nifedipine. Later, the development of abdominal symptoms led to the discovery of multiple gastric lesions, diagnosed as benign spindle cell neoplasms, necessitating partial gastrectomy.
CLINICAL DISCUSSION
The differential diagnosis of cutaneous leiomyomas includes various soft tissue tumors, requiring histopathological confirmation. Genetic mutations affecting proteins critical to cellular energy production and tumor suppression underlie these conditions. Treatment options include pharmacological management and surgical excision. The discovery of GISTs in this patient aligns with rare literature reports, emphasizing the need for vigilant evaluation of systemic malignancies in patients with leiomyomatosis.
CONCLUSION
This case highlights the potential of cutaneous leiomyomas to indicate deeper malignancies like GISTs, stressing the importance of interdisciplinary collaboration in diagnosis and treatment. It underscores the interconnectedness of benign dermatological conditions and internal malignancies, advocating for comprehensive evaluation in patients with leiomyomatosis.
METHODS
This case report meticulously follows the SCARE 2023 guidelines: updating consensus Surgical Case Report guidelines (Sohrabi et al., 2023 [1]). These guidelines ensure high-quality reporting in surgical case reports. The report details the evaluation, diagnosis, and a comprehensive review of the literature pertaining to a patient with multiple leiomyoma cutis associated with gastrointestinal stromal tumors. By employing a multidisciplinary approach, this report achieves a thorough and standardized presentation of the case, serving as an additional tool for raising awareness regarding such rare conditions.
PubMed: 38851074
DOI: 10.1016/j.ijscr.2024.109870