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Cancers May 2024Bone marrow fibrosis in myeloproliferative neoplasm (MPN), myelodysplastic syndromes (MDS), MPN/MDS overlap syndromes and acute myeloid leukemia (AML) is associated with...
Bone marrow fibrosis in myeloproliferative neoplasm (MPN), myelodysplastic syndromes (MDS), MPN/MDS overlap syndromes and acute myeloid leukemia (AML) is associated with poor prognosis and early treatment failure. Myelofibrosis (MF) is accompanied by reprogramming of multipotent bone marrow mesenchymal stromal cells (MSC) into osteoid and fiber-producing stromal cells. We demonstrate NRP2 and osteolineage marker NCAM1 (neural cell adhesion molecule 1) expression within the endosteal niche in normal bone marrow and aberrantly in MPN, MDS MPN/MDS overlap syndromes and AML ( = 99), as assessed by immunohistochemistry. Increased and diffuse expression in mesenchymal stromal cells and osteoblasts correlates with high MF grade in MPN ( < 0.05 for NRP2 and NCAM1). Single cell RNA sequencing (scRNAseq) re-analysis demonstrated NRP2 expression in endothelial cells and partial co-expression of NRP2 and NCAM1 in normal MSC and osteoblasts. Potential ligands included transforming growth factor β1 (TGFB1) from osteoblasts and megakaryocytes. Murine ThPO and JAK2 myelofibrosis models showed co-expression of Nrp2 and Ncam1 in osteolineage cells, while fibrosis-promoting MSC only express Nrp2. In vitro experiments with MC3T3-E1 pre-osteoblasts and analysis of mouse femurs suggest that Nrp2 is functionally involved in osteogenesis. In summary, NRP2 represents a potential novel druggable target in patients with myelofibrosis.
PubMed: 38792002
DOI: 10.3390/cancers16101924 -
Biomedicines Apr 2024Androgen receptor (AR) is a transcription factor expressed in various normal tissues and is a therapeutic target for prostate and possibly other cancers. A TMA...
Androgen receptor (AR) is a transcription factor expressed in various normal tissues and is a therapeutic target for prostate and possibly other cancers. A TMA containing 18,234 samples from 141 different tumor types/subtypes and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. AR positivity was found in 116 tumor types including 66 tumor types (46.8%) with ≥1 strongly positive tumor. Moderate/strong AR positivity was detected in testicular sex cord-stromal tumors (93.3-100%) and neoplasms of the prostate (79.3-98.7%), breast (25.0-75.5%), other gynecological tumors (0.9-100%), kidney (5.0-44.1%), and urinary bladder (5.4-24.2%). Low AR staining was associated with advanced tumor stage (pTa versus pT2-4; < 0.0001) in urothelial carcinoma; advanced pT ( < 0.0001), high tumor grade ( < 0.0001), nodal metastasis ( < 0.0001), and reduced survival ( = 0.0024) in invasive breast carcinoma; high pT ( < 0.0001) and grade ( < 0.0001) in clear cell renal cell carcinoma (RCC); and high pT ( = 0.0055) as well as high grade ( < 0.05) in papillary RCC. AR staining was unrelated to histopathological/clinical features in 157 endometrial carcinomas and in 221 ovarian carcinomas. Our data suggest a limited role of AR immunohistochemistry for tumor distinction and a prognostic role in breast and clear cell RCC and highlight tumor entities that might benefit from AR-targeted therapy.
PubMed: 38790919
DOI: 10.3390/biomedicines12050957 -
Cells May 2024A heterogenous population of inflammatory elements, other immune and nonimmune cells and cancer-associated fibroblasts (CAFs) are evident in solid malignancies where... (Review)
Review
A heterogenous population of inflammatory elements, other immune and nonimmune cells and cancer-associated fibroblasts (CAFs) are evident in solid malignancies where they coexist with the growing tumor mass. In highly desmoplastic malignancies, CAFs are the prominent mesenchymal cell type in the tumor microenvironment (TME), where their presence and abundance signal a poor prognosis. CAFs play a major role in the progression of various cancers by remodeling the supporting stroma into a dense, fibrotic matrix while secreting factors that promote the maintenance of cancer stem-like characteristics, tumor cell survival, aggressive growth and metastasis and reduced sensitivity to chemotherapeutics. Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse. Identifying the molecular underpinnings for such multidirectional crosstalk among the various normal and neoplastic cell types in the TME may provide new targets and novel opportunities for therapeutic intervention. This review highlights recent concepts regarding the complexity of CAF biology in cholangiocarcinoma, a highly desmoplastic cancer. The discussion focuses on CAF heterogeneity, functionality in drug resistance, contributions to a progressively fibrotic tumor stroma, the involved signaling pathways and the participating genes.
Topics: Humans; Tumor Microenvironment; Cholangiocarcinoma; Cancer-Associated Fibroblasts; Disease Progression; Bile Duct Neoplasms; Animals; Signal Transduction; Drug Resistance, Neoplasm
PubMed: 38786020
DOI: 10.3390/cells13100796 -
Oxford Medical Case Reports May 2024Gastrointestinal stromal tumors (GISTs) are the most common type of gastrointestinal mesenchymal tumors. The most common site for developing these neoplasms is the...
Gastrointestinal stromal tumors (GISTs) are the most common type of gastrointestinal mesenchymal tumors. The most common site for developing these neoplasms is the stomach and small intestine. In contrast, anorectal GISTs are very rare. Population-based studies have shown an increased risk of colorectal cancers (CRC) in patients with Crohn's disease (CD). As in sporadic CRC, adenocarcinomas are the most commonly observed tumor. Accordingly, it is expected that rectal mass in CD patients to be an adenocarcinoma. Some reports have presented CD cases with GISTs along the gastrointestinal tract; however, to the best of our knowledge, a rectal GIST has not been reported in CD. Herein, we report a 41-year-old woman with CD who presented with 8 weeks of constipation and was diagnosed with rectal GIST and briefly review existing reports regarding GIST in IBD.
PubMed: 38784781
DOI: 10.1093/omcr/omae039 -
Cureus Apr 2024Gastrointestinal stromal tumors (GISTs) are neoplasms arising from the bowel wall, most often in the jejunoileum of the small intestine, but rarely from...
Gastrointestinal stromal tumors (GISTs) are neoplasms arising from the bowel wall, most often in the jejunoileum of the small intestine, but rarely from extragastrointestinal locations. GISTs most often occur in patients older than 40 years of age and can present with a multitude of gastrointestinal symptoms. We present a rare case of an extragastrointestinal stromal tumor (EGIST) causing abdominal pain and melena in a 34-year-old Hispanic male. The patient presented with diffuse abdominal pain, melena, and severe anemia. Computed tomography of the abdomen revealed a large mass abutting the small bowel. The patient was taken to surgery where the mass, which appeared to be deriving from the omentum and invading the adjacent small bowel, was completely excised and found to be a spindle cell GIST. Excision margins were determined to be negative, and the patient was started on a tyrosine kinase inhibitor for maintenance therapy. The patient continues to follow up on an outpatient basis for surveillance. This case represents the rare disease entity EGIST presenting outside the typical demographics of the disease in a young patient with no identified previous genetic syndromes. Gross examination of the mass in this case was also atypical given the appearance that the mass was rooted in the omentum and invading the small bowel which would suggest the primary tumor site was extragastrointestinal. This case demonstrates the need to build a differential diagnosis that includes GIST and the ability to successfully treat this disease if it is identified early in the clinical course.
PubMed: 38784342
DOI: 10.7759/cureus.58824 -
BMC Women's Health May 2024Cervical mullerian adenosarcoma is a rare uterine sarcoma, especially in young women. Its pathological features are low-grade malignant tumors with bidirectional...
BACKGROUND
Cervical mullerian adenosarcoma is a rare uterine sarcoma, especially in young women. Its pathological features are low-grade malignant tumors with bidirectional differentiation, and the degree of malignancy is similar to that of low-grade endometrial stromal sarcoma. This paper reports the case of a young asexual patient who has been closely followed up after tumor resection and has not had any recurrences.
CASE PRESENTATION
A 20-year-old, young asexual woman was diagnosed with cervical mullerian adenosarcoma with sarcomatous overgrowth (MASO). Cervical tumor resection was performed after admission, and the resection margin was negative. After the operation, she refused to undergo secondary surgery due to fertility requirements and did not receive adjuvant treatment. The patient was closely followed up after the operation and has not yet relapsed.
CONCLUSION
A young woman with cervical MASO did not receive adjuvant treatment after cervical tumor resection. For women with fertility requirements, close follow-ups should be conducted after the operation to guard against tumor recurrence and radical tumor resection should be performed as early as possible after the patient no longer requires their fertility.
Topics: Humans; Female; Adenosarcoma; Young Adult; Uterine Cervical Neoplasms; Uterine Neoplasms; Sexual Behavior
PubMed: 38783282
DOI: 10.1186/s12905-024-03140-w -
Scientific Reports May 2024Killer cell lectin-like receptor B1 (KLRB1) is implicated in cancer progression and immunity. In this study, we aimed to evaluate the expression levels of KLRB1 in lung...
Killer cell lectin-like receptor B1 (KLRB1) is implicated in cancer progression and immunity. In this study, we aimed to evaluate the expression levels of KLRB1 in lung adenocarcinoma (LUAD) and analyze the relationship between KLRB1 expression levels, LUAD progression, and the tumor immune microenvironment. KLRB1 levels in LUAD were analyzed using data from the TCGA and XENA databases. Additionally, the diagnostic values of KLRB1 were analyzed in patients with LUAD. Survival and meta-analyses were employed to investigate the relationship between KLRB1 levels and other prognostic factors in patients with LUAD. Bioinformatics and cellular experiments were used to understand the functions and mechanisms of KLRB1. In addition, correlation analysis was used to investigate the relationship between KLRB1 levels and the immune microenvironment in LUAD. Reduced KLRB1 expression in LUAD was found to positively correlate with tumor size, distant metastasis, pathological stage, age, overall survival, diagnostic value, and disease-specific survival in patients with LUAD (P < 0.05). Conversely, increased KLRB1 expression was found to positively correlate with the overall survival and disease-specific survival in patients with LUAD (P < 0.05). We also found that the overexpression of KLRB1 can inhibit the proliferation, migration, and invasion of LUAD cells and promote apoptosis. KLRB1 was involved in immune cell differentiation, NF-kB, PD-L1, and PD-1 checkpoint pathways and others. Additionally, KLRB1 expression was linked to tumor purity, stromal, immune, and estimate scores, the levels of immune cells including B cells, CD8 T cells, and CD4 T cells, and immune cell markers in LUAD. Reduced KLRB1 expression has a significant positive correlation with diagnosis, poor prognosis, and immunity to cancer in patients with LUAD. KLRB1 inhibited cell proliferation and migration in patients with LUAD. These results suggest that KLRB1 may serve as a potential therapeutic target in patients with LUAD.
Topics: Female; Humans; Male; Middle Aged; Adenocarcinoma of Lung; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Gene Expression Regulation, Neoplastic; Lung Neoplasms; Neoplasm Metastasis; Prognosis; Tumor Microenvironment
PubMed: 38782996
DOI: 10.1038/s41598-024-60414-x -
International Journal of Surgery Case... Jun 2024Gastrointestinal stromal tumors (GISTs) represent a unique subset of neoplasms within the digestive tract. They can manifest in various organs throughout the digestive...
INTRODUCTION
Gastrointestinal stromal tumors (GISTs) represent a unique subset of neoplasms within the digestive tract. They can manifest in various organs throughout the digestive tract, ranging from the oral cavity to the anus, with a predilection for the stomach and small intestine. A distinct subtype of GISTs, known as Extra-gastrointestinal stromal tumors (EGISTs), originate outside the typical GIST organs such as the mesentery, retroperitoneum, and occasionally the omentum. EGISTs are relatively rare, accounting for <5 % of all GIST cases.
PRESENTATION OF CASE
We present the case of a 30-year-old female patient who presented with an upper abdominal mass associated with anorexia, fever, and weakness. Radiographic imaging revealed a cystic mass beneath the left hypochondrium. Exploratory laparoscopy confirmed the presence of an isolated mass adherent to the gastrocolic ligament and greater omentum. Histopathological examination confirmed GIST, characterized by spindle-shaped cells with DOG1 and CD117/C-kit expression. The patient underwent successful tumor resection and was discharged home with postoperative imatinib therapy. Follow-up at 14 months showed no recurrence.
DISCUSSION
The rarity of Gastrointestinal Stromal Tumors (GISTs) in the Greater Omentum highlights diagnostic challenges and underscores the need for further research. Immunohistochemical analysis aids in diagnosis, with Ki-67 staining indicating a high-risk classification. Surgery remains the primary treatment, with potential adjuvant therapy utilizing Imatinib mesylate.
CONCLUSION
Our case underscores the rare occurrence of GIST in the Greater Omentum. Despite their infrequency, EGISTs should be considered in intra-abdominal masses, emphasizing accurate diagnosis for appropriate management and the need for further research.
PubMed: 38781841
DOI: 10.1016/j.ijscr.2024.109793 -
Clinical and Translational Medicine May 2024Mucinous colorectal adenocarcinoma (MCA) is a distinct subtype of colorectal cancer (CRC) with the most aggressive pattern, but effective treatment of MCA remains a...
BACKGROUND
Mucinous colorectal adenocarcinoma (MCA) is a distinct subtype of colorectal cancer (CRC) with the most aggressive pattern, but effective treatment of MCA remains a challenge due to its vague pathological characteristics. An in-depth understanding of transcriptional dynamics at the cellular level is critical for developing specialised MCA treatment strategies.
METHODS
We integrated single-cell RNA sequencing and spatial transcriptomics data to systematically profile the MCA tumor microenvironment (TME), particularly the interactome of stromal and immune cells. In addition, a three-dimensional bioprinting technique, canonical ex vivo co-culture system, and immunofluorescence staining were further applied to validate the cellular communication networks within the TME.
RESULTS
This study identified the crucial intercellular interactions that engaged in MCA pathogenesis. We found the increased infiltration of FGF7/THBS1 myofibroblasts in MCA tissues with decreased expression of genes associated with leukocyte-mediated immunity and T cell activation, suggesting a crucial role of these cells in regulating the immunosuppressive TME. In addition, MS4A4A macrophages that exhibit M2-phenotype were enriched in the tumoral niche and high expression of MS4A4A was associated with poor prognosis in the cohort data. The ligand-receptor-based intercellular communication analysis revealed the tight interaction of MUC1 malignant cells and ZEB1 endothelial cells, providing mechanistic information for MCA angiogenesis and molecular targets for subsequent translational applications.
CONCLUSIONS
Our study provides novel insights into communications among tumour cells with stromal and immune cells that are significantly enriched in the TME during MCA progression, presenting potential prognostic biomarkers and therapeutic strategies for MCA.
KEY POINTS
Tumour microenvironment profiling of MCA is developed. MUC1 tumour cells interplay with FGF7/THBS1 myofibroblasts to promote MCA development. MS4A4A macrophages exhibit M2 phenotype in MCA. ZEB1 endotheliocytes engage in EndMT process in MCA.
Topics: Humans; Colorectal Neoplasms; Tumor Microenvironment; Single-Cell Analysis; Adenocarcinoma, Mucinous; Mucin-1; Cell Communication
PubMed: 38778448
DOI: 10.1002/ctm2.1701 -
Clinical and Experimental Medicine May 2024Acute myeloid leukemia represents a group of malignant blood disorders that originate from clonal over-proliferation and the differentiation failure of hematopoietic...
Acute myeloid leukemia represents a group of malignant blood disorders that originate from clonal over-proliferation and the differentiation failure of hematopoietic precursors, resulting in the accumulation of blasts in the bone marrow. Mesenchymal stromal cells (MSCs) have been shown to exert diverse effects on tumor cells through direct and indirect interaction. Exosomes, as one of the means of indirect intercellular communication, are released from different types of cells, including MSCs, and their various contents, such as lncRNAs, enable them to exert significant impacts on target cells. Our study aims to investigate the effects of BM-MSC exosomes on the cellular and molecular characterization of HL-60 AML cells, particularly detecting the alterations in the expression of lncRNAs involved in AML leukemogenesis, cell growth, drug resistance, and poor prognosis. BM-MSCs were cultured with serum-free culture media to isolate exosomes from their supernatants. The validation of exosomes was performed in three stages: morphological analysis using TEM, size evaluation using DLS, and CD marker identification using flow cytometry. Subsequently, the HL-60 AML cells were treated with isolated BM-MSC exosomes to determine the impact of their contents on leukemic cells. Cell metabolic activity was evaluated by the MTT assay, while cell cycle progression, apoptosis, ROS levels, and proliferation were assessed by flow cytometry. Furthermore, RT-qPCR was conducted to determine the expression levels of lncRNAs and apoptosis-, ROS-, and cell cycle-related genes. MTT assay and flow cytometry analysis revealed that BM-MSC exosomes considerably suppressed cell metabolic activity, proliferation, and cell cycle progression. Also, these exosomes could effectively increase apoptosis and ROS levels in HL-60 cells. The expression levels of p53, p21, BAX, and FOXO4 were increased, while the BCL2 and c-Myc levels decreased. MALAT1, HOTAIR, and H19 expression levels were also significantly decreased in treated HL-60 cells compared to their untreated counterparts. BM-MSC exosomes suppress cell cycle progression, proliferation, and metabolic activity while simultaneously elevating the ROS index and apoptosis ratio in HL-60 cells, likely by reducing the expression levels of MALAT1, HOTAIR, and H19. These findings suggest that BM-MSC exosomes might serve as potential supportive therapies for leukemia.
Topics: Humans; Exosomes; Mesenchymal Stem Cells; RNA, Long Noncoding; Leukemia, Myeloid, Acute; HL-60 Cells; Cell Proliferation; Apoptosis; Cell Cycle
PubMed: 38777995
DOI: 10.1007/s10238-024-01364-6