Did you mean: splenic neoplasms
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Nature Communications Nov 2022Triple-Negative Breast Cancer (TNBC) has a poor prognosis and adverse clinical outcomes among all breast cancer subtypes as there is no available targeted therapy....
Triple-Negative Breast Cancer (TNBC) has a poor prognosis and adverse clinical outcomes among all breast cancer subtypes as there is no available targeted therapy. Overexpression of Enhancer of zeste homolog 2 (EZH2) has been shown to correlate with TNBC's poor prognosis, but the contribution of EZH2 catalytic (H3K27me3) versus non-catalytic EZH2 (NC-EZH2) function in TNBC progression remains elusive. We reveal that selective hyper-activation of functional EZH2 (H3K27me3) over NC-EZH2 alters TNBC metastatic landscape and fosters its peritoneal metastasis, particularly splenic. Instead of H3K27me3-mediated repression of gene expression; here, it promotes KRT14 transcription by attenuating binding of repressor SP1 to its promoter. Further, KRT14 loss significantly reduces TNBC migration, invasion, and peritoneal metastasis. Consistently, human TNBC metastasis displays positive correlation between H3K27me3 and KRT14 levels. Finally, EZH2 knockdown or H3K27me3 inhibition by EPZ6438 reduces TNBC peritoneal metastasis. Altogether, our preclinical findings suggest a rationale for targeting TNBC with EZH2 inhibitors.
Topics: Humans; Enhancer of Zeste Homolog 2 Protein; Histones; Keratin-14; Peritoneal Neoplasms; Triple Negative Breast Neoplasms; Up-Regulation
PubMed: 36446780
DOI: 10.1038/s41467-022-35059-x -
Cancers Mar 2023Hemangiosarcoma is a mesenchymal neoplasm originating in the endothelial cells of blood vessels; they can be classified as non-visceral and visceral types. Non-visceral... (Review)
Review
Hemangiosarcoma is a mesenchymal neoplasm originating in the endothelial cells of blood vessels; they can be classified as non-visceral and visceral types. Non-visceral hemangiosarcomas can affect the skin, subcutaneous tissues, and muscle tissues; visceral hemangiosarcomas can affect the spleen, liver, heart, lungs, kidneys, oral cavity, bones, bladder, uterus, tongue, and retroperitoneum. Among domestic species, dogs are most affected by cutaneous HSA. Cutaneous HSA represents approximately 14% of all HSA diagnosed in this species and less than 5% of dermal tumors, according to North American studies. However, Brazilian epidemiological data demonstrate a higher prevalence, which may represent 27 to 80% of all canine HSAs and 13.9% of all skin neoplasms diagnosed in this species. Cutaneous HSA most commonly affects middle-aged to elderly dogs (between 8 and 15 years old), with no gender predisposition for either the actinic or non-actinic forms. The higher prevalence of cutaneous HSA in some canine breeds is related to lower protection from solar radiation, as low skin pigmentation and hair coverage lead to greater sun exposure. Actinic changes, such as solar dermatosis, are frequent in these patients, confirming the influence of solar radiation on the development of this neoplasm. There are multiple clinical manifestations of hemangiosarcoma in canines. The diagnostic approach and staging classification of cutaneous HSAs are similar between the different subtypes. The definitive diagnosis is obtained through histopathological analysis of incisional or excisional biopsies. Cytology can be used as a presurgical screening test; however, it has little diagnostic utility in cases of HSA because there is a high risk of blood contamination and sample hemodilution. Surgery is generally the treatment of choice for dogs with localized non-visceral HSA without evidence of metastatic disease. Recently, electrochemotherapy (ECT) has emerged as an alternative therapy for the local ablative treatment of different neoplastic types; the use of radiotherapy for the treatment of dogs with cutaneous HSA is uncommon. There is greater consensus in the literature regarding the indications for adjuvant chemotherapy in subcutaneous and muscular HSA; doxorubicin is the most frequently used antineoplastic agent for subcutaneous and muscular subtypes and can be administered alone or in combination with other drugs. Other therapies include antiangiogenic therapy, photodynamic therapy, the association of chemotherapy with the metronomic dose, targeted therapies, and natural products. The benefits of these therapies are presented and discussed. In general, the prognosis of splenic and cardiac HSA is unfavorable. As a challenging neoplasm, studies of new protocols and treatment modalities are necessary to control this aggressive disease.
PubMed: 37046686
DOI: 10.3390/cancers15072025 -
Blood Oct 2020Hepatosplenic T-cell lymphoma (HSTCL) is a rare T-cell neoplasm that most commonly arises from a small subset of γ/δ T-cell receptor-expressing lymphocytes. HSTCL is... (Review)
Review
Hepatosplenic T-cell lymphoma (HSTCL) is a rare T-cell neoplasm that most commonly arises from a small subset of γ/δ T-cell receptor-expressing lymphocytes. HSTCL is more common in adolescent and young adults and has a rapidly progressive clinical course and poor outcome due to its refractoriness to conventional chemotherapy regimens. Approximately 20% of the cases arise in the background of chronic immunosuppression or immune dysregulation. Patients commonly present with constitutional symptoms, hepatic and liver enlargement, and cytopenias; hematophagocytic syndrome can also occur. The most frequent chromosomal aberrations associated with HSTCL are isochromosome 7q and trisomy 8, and most cases harbor mutations in genes involved in chromatin modification or the JAK/STAT pathway. The rarity of this disease, along with lack of nodal involvement and presenting symptoms that mimic different entities including infectious etiologies, makes this lymphoma a significant diagnostic challenge. In this review, we highlight the clinical and pathologic features of HSTCL. Moreover, we summarize the results of recent molecular studies suggesting potential targets for novel therapeutics strategies.
Topics: Animals; Humans; Liver Neoplasms; Lymphoma, T-Cell; Splenic Neoplasms
PubMed: 32756940
DOI: 10.1182/blood.2019004118 -
Blood Feb 2022Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying... (Observational Study)
Observational Study
Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and in genetically modified mouse models, and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.
Topics: Aged; Animals; Female; Humans; Male; Mice; Middle Aged; Chromosome Aberrations; Immunophenotyping; Lymphoma, B-Cell, Marginal Zone; Multigene Family; Mutation; Spleen; Splenic Neoplasms; Transcriptome; Tumor Microenvironment
PubMed: 34653238
DOI: 10.1182/blood.2021012386 -
American Journal of Hematology Dec 2019Hairy cell leukemia (HCL) and HCL-like disorders, including HCL variant (HCL-V) and splenic diffuse red pulp lymphoma (SDRPL), are a very heterogeneous group of mature... (Review)
Review
DISEASE OVERVIEW
Hairy cell leukemia (HCL) and HCL-like disorders, including HCL variant (HCL-V) and splenic diffuse red pulp lymphoma (SDRPL), are a very heterogeneous group of mature lymphoid B-cell disorders. They are characterized by the identification of hairy cells, a specific genetic profile, a different clinical course and the need for appropriate treatment.
DIAGNOSIS
Diagnosis of HCL is based on morphological evidence of hairy cells, an HCL immunologic score of three or four based on the CD11C, CD103, CD123, and CD25 expression. Also, the trephine biopsy which makes it possible to specify the degree of tumoral medullary infiltration and the presence of BRAF V600E somatic mutation.
RISK STRATIFICATION
Progression of patients with HCL is based on a large splenomegaly, leukocytosis, a high number of hairy cells in the peripheral blood and the immunoglobulin heavy chain variable region gene mutational status. The VH4-34 positive HCL cases are associated with poor prognosis.
TREATMENT
Risk adapted therapy with purine nucleoside analogs (PNA) are indicated in symptomatic first line HCL patients. The use of PNA followed by rituximab represents an alternative option. Management of progressive or refractory disease is based on the use of BRAF inhibitors associated or not with MEK inhibitors, recombinant immunoconjugates targeting CD22 or BCR inhibitors.
Topics: Algorithms; Antimetabolites, Antineoplastic; B-Lymphocytes; Biopsy; Bone Marrow Examination; Cladribine; Humans; Immunophenotyping; Immunotoxins; Leukemia, Hairy Cell; Middle Aged; Mutation, Missense; Neoplasm Proteins; Neoplasms, Second Primary; Neoplastic Stem Cells; Point Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Risk Assessment; Rituximab; Salvage Therapy
PubMed: 31591741
DOI: 10.1002/ajh.25653 -
Science Immunology Feb 2020Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses during cancer. It remains elusive how...
Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses during cancer. It remains elusive how MDSCs differ from their normal myeloid counterparts, which limits our ability to specifically detect and therapeutically target MDSCs during cancer. Here, we sought to determine the molecular features of breast cancer-associated MDSCs using the widely studied mouse model based on the mouse mammary tumor virus (MMTV) promoter-driven expression of the polyomavirus middle T oncoprotein (MMTV-PyMT). To identify MDSCs in an unbiased manner, we used single-cell RNA sequencing to compare MDSC-containing splenic myeloid cells from breast tumor-bearing mice with wild-type controls. Our computational analysis of 14,646 single-cell transcriptomes revealed that MDSCs emerge through an aberrant neutrophil maturation trajectory in the spleen that confers them an immunosuppressive cell state. We establish the MDSC-specific gene signature and identify CD84 as a surface marker for improved detection and enrichment of MDSCs in breast cancers.
Topics: Animals; Biomarkers, Tumor; Breast Neoplasms; Cell Differentiation; Female; Humans; Mice; Mice, Inbred Strains; Mice, Transgenic; Myeloid-Derived Suppressor Cells; RNA, Neoplasm; Signaling Lymphocytic Activation Molecule Family; Single-Cell Analysis; Transcriptome
PubMed: 32086381
DOI: 10.1126/sciimmunol.aay6017 -
Theranostics 2021Metastasis, the development of secondary malignant growth at a distance from a primary tumor, is the main cause of cancer-associated death. However, little is known...
Metastasis, the development of secondary malignant growth at a distance from a primary tumor, is the main cause of cancer-associated death. However, little is known about how metastatic cancer cells adapt to and colonize in the new organ environment. Here we sought to investigate the functional mechanism of cholesterol metabolic aberration in colorectal carcinoma (CRC) liver metastasis. The expression of cholesterol metabolism-related genes in primary colorectal tumors (PT) and paired liver metastases (LM) were examined by RT-PCR. The role of SREBP2-dependent cholesterol biosynthesis pathway in cell growth and CRC liver metastasis were determined by SREBP2 silencing in CRC cell lines and experimental metastasis models including, intra-splenic injection models and liver orthotropic injection model. Growth factors treatment and co-culture experiment were performed to reveal the mechanism underlying the up-regulation of SREBP2 in CRC liver metastases. The efficacy of inhibition of cholesterol biosynthesis pathway by betulin or simvastatin were evaluated in experimental metastasis models. In the present study, we identify a colorectal cancer (CRC) liver metastasis-specific cholesterol metabolic pathway involving the activation of SREBP2-dependent cholesterol biosynthesis, which is required for the colonization and growth of metastatic CRC cells in the liver. Inhibiting this cholesterol biosynthesis pathway suppresses CRC liver metastasis. Mechanically, hepatocyte growth factor (HGF) from liver environment activates SREBP2-dependent cholesterol biosynthesis pathway by activating c-Met/PI3K/AKT/mTOR axis in CRC cells. Our findings support the notion that CRC liver metastases show a specific cholesterol metabolic aberration. Targeting this cholesterol biosynthesis pathway could be a promising treatment for CRC liver metastasis.
Topics: Adenocarcinoma; Animals; Cholesterol; Coculture Techniques; Colorectal Neoplasms; Genetic Vectors; Hepatocyte Growth Factor; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Proteins; Organ Specificity; Proto-Oncogene Proteins c-met; RNA Interference; RNA, Small Interfering; Random Allocation; Signal Transduction; Simvastatin; Sterol Regulatory Element Binding Protein 2; TOR Serine-Threonine Kinases; Tumor Stem Cell Assay
PubMed: 33995676
DOI: 10.7150/thno.55609 -
Molecular Cancer Jan 2022Cancer-associated fibroblasts (CAFs) are critically involved in gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC). However, the underlying...
BACKGROUND
Cancer-associated fibroblasts (CAFs) are critically involved in gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanism by which CAFs promote chemotherapy resistance remains unexplored. Here, we explored the role of circRNAs in CAF-induced GEM resistance in PDAC.
METHODS
circRNA sequencing and quantitative real-time PCR (qRT-PCR) were utilized to screen CAF-specific circRNAs. The effects of CAF circFARP1 expression on GEM resistance in tumor cells were assessed in vitro and in vivo. RNA-seq, RNA pulldown, RNA immunoprecipitation, and luciferase reporter assays were used to screen the downstream target and underlying mechanism of circFARP1.
RESULTS
circFARP1 (hsa_circ_0002557), a CAF-specific circRNA, was positively correlated with GEM chemoresistance and poor survival in an advanced PDAC cohort. Silencing or overexpressing circFARP1 in CAFs altered the ability of CAFs to induce tumor cell stemness and GEM resistance via leukemia inhibitory factor (LIF). Mechanistically, we found that circFARP1 directly binds with caveolin 1 (CAV1) and blocks the interaction of CAV1 and the E3 ubiquitin-protein ligase zinc and ring finger 1 (ZNRF1) to inhibit CAV1 degradation, which enhances LIF secretion. In addition, circFARP1 upregulated LIF expression by sponging miR-660-3p. Moreover, high circFARP1 levels were positively correlated with elevated serum LIF levels in PDAC and poor patient survival. Decreasing circFARP1 levels and neutralizing LIF significantly suppressed PDAC growth and GEM resistance in patient-derived xenograft models.
CONCLUSIONS
The circFARP1/CAV1/miR-660-3p/LIF axis is critical for CAF-induced GEM resistance in PDAC. Hence, circFARP1 may be a potential therapeutic target for PDAC.
Topics: Animals; Cancer-Associated Fibroblasts; Caveolin 1; Cell Line, Tumor; Deoxycytidine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Leukemia Inhibitory Factor; Mice; MicroRNAs; Models, Biological; Pancreatic Neoplasms; RNA Interference; RNA, Circular; Rho Guanine Nucleotide Exchange Factors; STAT3 Transcription Factor; Signal Transduction; Xenograft Model Antitumor Assays; Gemcitabine
PubMed: 35045883
DOI: 10.1186/s12943-022-01501-3 -
American Journal of Medical Genetics.... Dec 2022RASopathies are a set of clinical syndromes that have molecular and clinical overlap. Genetically, these syndromes are defined by germline pathogenic variants in... (Review)
Review
RASopathies are a set of clinical syndromes that have molecular and clinical overlap. Genetically, these syndromes are defined by germline pathogenic variants in RAS/MAPK pathway genes resulting in activation of this pathway. Clinically, their common molecular signature leads to comparable phenotypes, including cardiac anomalies, neurologic disorders and notably, elevated cancer risk. Cancer risk in individuals with RASopathies has been estimated from retrospective reviews and cohort studies. For example, in Costello syndrome, cancer incidence is significantly elevated over the general population, largely due to solid tumors. In some forms of Noonan syndrome, cancer risk is also elevated over the general population and is enriched for hematologic malignancies. Thus, cancer surveillance guidelines have been developed to monitor for the occurrence of such cancers in individuals with some RASopathies. These include abdominal ultrasound and urinalyses for individuals with Costello syndrome, while complete blood counts and splenic examination are recommended in Noonan syndrome. Improved cancer risk estimates and refinement of surveillance recommendations will improve the care of individuals with RASopathies.
Topics: Humans; Noonan Syndrome; Costello Syndrome; Incidence; Retrospective Studies; ras Proteins; Neoplasms
PubMed: 36533693
DOI: 10.1002/ajmg.c.32018