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Radiology. Imaging Cancer Jul 2024Purpose To determine whether metrics from mean apparent propagator (MAP) MRI perform better than apparent diffusion coefficient (ADC) value in assessing the tumor-stroma...
Purpose To determine whether metrics from mean apparent propagator (MAP) MRI perform better than apparent diffusion coefficient (ADC) value in assessing the tumor-stroma ratio (TSR) status in breast carcinoma. Materials and Methods From August 2021 to October 2022, 271 participants were prospectively enrolled (ClinicalTrials.gov identifier: NCT05159323) and underwent breast diffusion spectral imaging and diffusion-weighted imaging. MAP MRI metrics and ADC were derived from the diffusion MRI data. All participants were divided into high-TSR (stromal component < 50%) and low-TSR (stromal component ≥ 50%) groups based on pathologic examination. Clinicopathologic characteristics were collected, and MRI findings were assessed. Logistic regression was used to determine the independent variables for distinguishing TSR status. The area under the receiver operating characteristic curve (AUC) and sensitivity, specificity, and accuracy were compared between the MAP MRI metrics, either alone or combined with clinicopathologic characteristics, and ADC, using the DeLong and McNemar test. Results A total of 181 female participants (mean age, 49 years ± 10 [SD]) were included. All diffusion MRI metrics differed between the high-TSR and low-TSR groups ( < .001 to = .01). Radial non-Gaussianity from MAP MRI and lymphovascular invasion were significant independent variables for discriminating the two groups, with a higher AUC (0.81 [95% CI: 0.74, 0.87] vs 0.61 [95% CI: 0.53, 0.68], < .001) and accuracy (138 of 181 [76%] vs 106 of 181 [59%], < .001) than that of the ADC. Conclusion MAP MRI may serve as a better approach than conventional diffusion-weighted imaging in evaluating the TSR of breast carcinoma. MR Diffusion-weighted Imaging, MR Imaging, Breast, Oncology ClinicalTrials.gov Identifier: NCT05159323 © RSNA, 2024.
Topics: Humans; Female; Breast Neoplasms; Middle Aged; Prospective Studies; Carcinoma, Ductal, Breast; Diffusion Magnetic Resonance Imaging; Sensitivity and Specificity; Adult; Breast; Aged; Magnetic Resonance Imaging
PubMed: 38874529
DOI: 10.1148/rycan.230165 -
Revue Medicale Suisse Jun 2024Gastrointestinal Stromal Tumors (GISTs) account for 1 to 2% of gastrointestinal malignant tumors. They are characterized by overexpression of the tyrosine kinase (KIT)....
Gastrointestinal Stromal Tumors (GISTs) account for 1 to 2% of gastrointestinal malignant tumors. They are characterized by overexpression of the tyrosine kinase (KIT). 60% of GISTs originate in the stomach. Managing them remains complex and varies depending on several factors such as location, size, molecular biology, type of clinical presentation, and the risks/benefits of surgical treatment. Surgery remains the only curative treatment, while tyrosine kinase inhibitors have demonstrated their efficacy as systemic treatment in the perioperative context. Risk stratification for recurrence guides the choice of adjuvant treatment, with a recommended duration of 3 years for high-risk patients.
Topics: Gastrointestinal Stromal Tumors; Humans; Stomach Neoplasms; Neoplasm Recurrence, Local
PubMed: 38867560
DOI: 10.53738/REVMED.2024.20.878.1158 -
BMC Urology Jun 2024To predict outcomes and identify potential therapeutic targets for cancers, it is critical to find novel specific biomarkers. The objective of this study was to search...
BACKGROUND
To predict outcomes and identify potential therapeutic targets for cancers, it is critical to find novel specific biomarkers. The objective of this study was to search for and explore novel bladder cancer-associated protein biomarkers.
METHODS
A library of monoclonal antibodies (mAbs) against the JAM-ICR cell line was first generated, and clones with high affinity were selected. Hybridomas were screened using bladder cancer (BLCA) cell lines and normal cells. The target of the selected mAb was then characterized through immunoaffinity purification, western blotting, and mass spectrometry analysis. Expression of the target antigen was assessed by flow cytometry and IHC methods. Several databases were also used to evaluate the target antigen in BLCA and other types of cancers.
RESULTS
Based on screenings, a 6D6 clone was selected that recognized an isoform of beta-actin (ACTB). Our data showed that ACTB expression on different cell lines was heterogeneous and varied significantly from low to high intensity. 6D6 bound strongly to epithelial cells while showing weak to no reactivity to stromal, endothelial, and smooth muscle cells. There was no association between ACTB intensity and related prognostic factors in BLCA. In silico evaluations revealed a significant correlation between ACTB and overexpressed genes and biomarkers in BLCA. Additionally, the differential expression of ACTB in tumor and healthy tissue as well as its correlation with survival time in a number of cancers were shown.
CONCLUSIONS
The heterogeneous expression of ACTB may suggest the potential value of this marker in the diagnosis or prognosis of cancer.
Topics: Urinary Bladder Neoplasms; Humans; Antibodies, Monoclonal; Actins; Biomarkers, Tumor; Cell Line, Tumor
PubMed: 38867273
DOI: 10.1186/s12894-024-01489-6 -
Cell Reports. Medicine Jun 2024Leptomeningeal disease (LMD) remains a rapidly lethal complication for late-stage melanoma patients. Here, we characterize the tumor microenvironment of LMD and...
Leptomeningeal disease (LMD) remains a rapidly lethal complication for late-stage melanoma patients. Here, we characterize the tumor microenvironment of LMD and patient-matched extra-cranial metastases using spatial transcriptomics in a small number of clinical specimens (nine tissues from two patients) with extensive in vitro and in vivo validation. The spatial landscape of melanoma LMD is characterized by a lack of immune infiltration and instead exhibits a higher level of stromal involvement. The tumor-stroma interactions at the leptomeninges activate tumor-promoting signaling, mediated through upregulation of SERPINA3. The meningeal stroma is required for melanoma cells to survive in the cerebrospinal fluid (CSF) and promotes MAPK inhibitor resistance. Knocking down SERPINA3 or inhibiting the downstream IGR1R/PI3K/AKT axis results in tumor cell death and re-sensitization to MAPK-targeting therapy. Our data provide a spatial atlas of melanoma LMD, identify the tumor-promoting role of meningeal stroma, and demonstrate a mechanism for overcoming microenvironment-mediated drug resistance in LMD.
Topics: Melanoma; Humans; Tumor Microenvironment; Meningeal Neoplasms; Stromal Cells; Animals; Cell Line, Tumor; Mice; Gene Expression Regulation, Neoplastic; Transcriptome; Gene Expression Profiling; Meninges; Drug Resistance, Neoplasm; Signal Transduction; Female
PubMed: 38866016
DOI: 10.1016/j.xcrm.2024.101606 -
Drug Development Research Jun 2024Gastric cancer (GC) is one of the most common malignancies worldwide. Hypoxia-inducible domain (HIGD) family members (e.g., HIGD1A) have been linked to tumor...
Gastric cancer (GC) is one of the most common malignancies worldwide. Hypoxia-inducible domain (HIGD) family members (e.g., HIGD1A) have been linked to tumor progression. However, the role of HIGD1B (another HIGD family member) in GC has yet to be fully understood. Based on data from TCGA_GC, GSE65801, and GSE65801 data sets, HIGD1B levels were evaluated in normal and GC tissues. Next, HIGD1B levels were validated by reverse transcription-quantitative PCR and western blot analysis analyses. Meanwhile, patients with GC in the TCGA_GC cohort were grouped into high- and low-HIGD1B level groups, and overall survival, functional enrichment, and immune infiltration were analyzed. Additionally, gain- and loss-of-function experiments were performed to determine the function of HIGD1B in GC cells. Compared to normal controls, HIGD1B mRNA levels were significantly elevated in GC tissues. Moreover, high HIGD1B levels may be an independent indicator of poor prognosis in patients with GC. Additionally, high HIGD1B levels were correlated with high stromal and ESTIMATE scores and elevated expression of immune checkpoints in patients with GC. Functional analyses showed that HIGD1B deficiency notably suppressed GC cell proliferation, migration, and invasion. Moreover, HIGD1B deficiency significantly induced mitochondria-mediated apoptosis in GC cells by inactivating Akt and ERK pathways. Collectively, HIGD1B may predict the prognosis of patients with GC and may function as an oncogene in GC. These findings suggest that HIGD1B may serve as a prognostic biomarker and potential therapeutic target in GC.
Topics: Humans; Stomach Neoplasms; Apoptosis; Proto-Oncogene Proteins c-akt; Mitochondria; Cell Line, Tumor; MAP Kinase Signaling System; Down-Regulation; Cell Proliferation; Male; Female; Gene Expression Regulation, Neoplastic
PubMed: 38863387
DOI: 10.1002/ddr.22221 -
Techniques in Coloproctology Jun 2024Retrorectal tumors are uncommon lesions developed in the retrorectal space. Data on their minimally invasive resection are scarce and the optimal surgical approach for...
BACKGROUND
Retrorectal tumors are uncommon lesions developed in the retrorectal space. Data on their minimally invasive resection are scarce and the optimal surgical approach for tumors below S3 remains debated.
METHODS
We performed a retrospective review of consecutive patients who underwent minimally invasive resection of retrorectal tumors between 2005 and 2022 at two tertiary university hospital centers, by comparing the results obtained for lesions located above or below S3.
RESULTS
Of over 41 patients identified with retrorectal tumors, surgical approach was minimally invasive for 23 patients, with laparoscopy alone in 19, with transanal excision in 2, and with combined approach in 2. Retrorectal tumor was above S3 in 11 patients (> S3 group) and below S3 in 12 patients (< S3 group). Patient characteristics and median tumor size were not significantly different between the two groups (60 vs 67 mm; p = 0.975). Overall median operative time was 131.5 min and conversion rate was 13% without significant difference between the two groups (126 vs 197 min and 18% vs 8%, respectively; p > 0.05). Final pathology was tailgut cyst (48%), schwannoma (22%), neural origin tumor (17%), gastrointestinal stromal tumor (4%), and other (19%). The 90-day complication rates were 27% and 58% in the > S3 and < S3 groups, respectively, without severe morbidity or mortality. After a median follow-up of 3.3 years, no recurrence was observed in both groups. Three patients presented chronic pain, three anal dysfunction, and three urinary dysfunction. All were successfully managed without reintervention.
CONCLUSIONS
Minimally invasive surgery for retrorectal tumors can be performed safely and effectively with low morbidity and no mortality. Laparoscopic and transanal techniques alone or in combination may be recommended as the treatment of choice of benign retrorectal tumors, even for lesions below S3, in centers experienced with minimally invasive surgery.
Topics: Humans; Retrospective Studies; Male; Female; Middle Aged; Laparoscopy; Aged; Rectal Neoplasms; Tertiary Care Centers; Adult; Operative Time; Treatment Outcome; Transanal Endoscopic Surgery; Aged, 80 and over; Rectum
PubMed: 38860990
DOI: 10.1007/s10151-024-02938-y -
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