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Nature Medicine Aug 2020Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor...
Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor prognosis. To comprehensively characterize the HGSOC ascites ecosystem, we used single-cell RNA sequencing to profile ~11,000 cells from 22 ascites specimens from 11 patients with HGSOC. We found significant inter-patient variability in the composition and functional programs of ascites cells, including immunomodulatory fibroblast sub-populations and dichotomous macrophage populations. We found that the previously described immunoreactive and mesenchymal subtypes of HGSOC, which have prognostic implications, reflect the abundance of immune infiltrates and fibroblasts rather than distinct subsets of malignant cells. Malignant cell variability was partly explained by heterogeneous copy number alteration patterns or expression of a stemness program. Malignant cells shared expression of inflammatory programs that were largely recapitulated in single-cell RNA sequencing of ~35,000 cells from additionally collected samples, including three ascites, two primary HGSOC tumors and three patient ascites-derived xenograft models. Inhibition of the JAK/STAT pathway, which was expressed in both malignant cells and cancer-associated fibroblasts, had potent anti-tumor activity in primary short-term cultures and patient-derived xenograft models. Our work contributes to resolving the HSGOC landscape and provides a resource for the development of novel therapeutic approaches.
Topics: Ascites; Cell Line, Tumor; Cystadenoma, Serous; DNA Copy Number Variations; Drug Resistance, Neoplasm; Female; Fibroblasts; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Janus Kinase 1; Neoplasm Grading; Neoplasm Proteins; Ovarian Neoplasms; Prognosis; STAT Transcription Factors; Sequence Analysis, RNA; Signal Transduction; Single-Cell Analysis
PubMed: 32572264
DOI: 10.1038/s41591-020-0926-0 -
The American Journal of the Medical... Jan 2023Malignant peritoneal mesothelioma (MPM) is a rare, life-threatening malignant tumor. We present a report of a rare case of a 67-year-old male patient with MPM and severe... (Review)
Review
Malignant peritoneal mesothelioma (MPM) is a rare, life-threatening malignant tumor. We present a report of a rare case of a 67-year-old male patient with MPM and severe abdominal pain, bloating, and bloody ascites as manifestations. The diagnosis was confirmed by cytology of ascites aspiration fluid and further verified by laparoscopic exploratory biopsy. The characteristics of signs and clinical manifestations in this case are less common. As everyone knows, asbestos exposure is usually associated with pleural mesothelioma, but only 6%-10% of malignant mesothelioma cases originate from the peritoneum, which is far less than pleural mesothelioma. Generally, its non-specificity provides a huge challenge to medical professionals in its diagnosis, and this is also the main reason for delayed diagnosis. Patients should be vigilant, even though no clear risk factor is observed.
Topics: Male; Humans; Aged; Mesothelioma, Malignant; Ascites; Mesothelioma; Asbestos; Pleural Neoplasms; Peritoneal Neoplasms
PubMed: 35940275
DOI: 10.1016/j.amjms.2022.07.008 -
Nature Cancer Aug 2023Ovarian cancer (OC) is an aggressive gynecological tumor usually diagnosed with widespread metastases and ascites. Here, we depicted a single-cell landscape of the OC...
Ovarian cancer (OC) is an aggressive gynecological tumor usually diagnosed with widespread metastases and ascites. Here, we depicted a single-cell landscape of the OC ecosystem with five tumor-relevant sites, including omentum metastasis and malignant ascites. Our data reveal the potential roles of ascites-enriched memory T cells as a pool for tumor-infiltrating exhausted CD8 T cells and T helper 1-like cells. Moreover, tumor-enriched macrophages exhibited a preference for monocyte-derived ontogeny, whereas macrophages in ascites were more of embryonic origin. Furthermore, we characterized MAIT and dendritic cells in malignant ascites, as well as two endothelial subsets in primary tumors as predictive biomarkers for platinum-based chemotherapy response. Taken together, our study provides a global view of the female malignant ascites ecosystem and offers valuable insights for its connection with tumor tissues and paves the way for potential markers of efficacy evaluation and therapy resistance in OC.
Topics: Female; Humans; Ascites; CD8-Positive T-Lymphocytes; Ecosystem; Ovarian Neoplasms; Single-Cell Analysis
PubMed: 37488416
DOI: 10.1038/s43018-023-00599-8 -
Journal of Surgical Oncology Jul 2019Malignant ascites (MA) carries a poor prognosis. It can have a significant impact on quality of life (QOL), with increasing abdominal distention, pain, and dyspnea.... (Review)
Review
Malignant ascites (MA) carries a poor prognosis. It can have a significant impact on quality of life (QOL), with increasing abdominal distention, pain, and dyspnea. Diuretics typically do not work well for MA. Paracentesis is effective in providing temporary symptom relief but requires frequent repeat procedures. Options for durable symptom management include indwelling catheters, peritoneal ports, peritoneovenous shunts, intraperitoneal (i.p.) catumaxomab, and hyperthermic i.p. chemotherapy. These interventions do not necessarily improve overall survival but may improve QOL.
Topics: Ascites; Humans; Neoplasms; Palliative Care; Prognosis; Quality of Life
PubMed: 30903617
DOI: 10.1002/jso.25453 -
Nature Communications Feb 2023Peritoneal metastasis is the leading cause of death for gastrointestinal cancers. The native and therapy-induced ascites ecosystems are not fully understood. Here, we...
Peritoneal metastasis is the leading cause of death for gastrointestinal cancers. The native and therapy-induced ascites ecosystems are not fully understood. Here, we characterize single-cell transcriptomes of 191,987 ascites cancer/immune cells from 35 patients with/without gastric cancer peritoneal metastasis (GCPM). During GCPM progression, an increase is seen of monocyte-like dendritic cells (DCs) that are pro-angiogenic with reduced antigen-presenting capacity and correlate with poor gastric cancer (GC) prognosis. We also describe the evolution of monocyte-like DCs and regulatory and proliferative T cells following therapy. Moreover, we track GC evolution, identifying high-plasticity GC clusters that exhibit a propensity to shift to a high-proliferative phenotype. Transitions occur via the recently described, autophagy-dependent plasticity program, paligenosis. Two autophagy-related genes (MARCKS and TXNIP) mark high-plasticity GC with poorer prognosis, and autophagy inhibitors induce apoptosis in patient-derived organoids. Our findings provide insights into the developmental trajectories of cancer/immune cells underlying GCPM progression and therapy resistance.
Topics: Humans; Ascites; Peritoneal Neoplasms; Peritoneum; Stomach Neoplasms
PubMed: 36788228
DOI: 10.1038/s41467-023-36310-9 -
Surgical Oncology Clinics of North... Jul 2021In addition to severe, life-limiting complications such as malignant bowel obstruction, fistulae, and malignant ascites, peritoneal carcinomatosis frequently causes... (Review)
Review
In addition to severe, life-limiting complications such as malignant bowel obstruction, fistulae, and malignant ascites, peritoneal carcinomatosis frequently causes life-impacting symptoms such as pain, nausea, anorexia, cachexia, and fatigue. A variety of medical, interventional, and surgical therapies are now available for management of both complications and symptoms. Although surgery in this population is often associated with a relatively high risk of morbidity and mortality, operative intervention can offer effective palliative treatment in appropriately selected patients. Early involvement of palliative care specialists as part of a multidisciplinary team is essential to providing optimal, holistic care of patients with peritoneal carcinomatosis.
Topics: Ascites; Humans; Intestinal Obstruction; Palliative Care; Peritoneal Neoplasms; Treatment Outcome
PubMed: 34053663
DOI: 10.1016/j.soc.2021.02.004 -
British Journal of Cancer Jul 2020The build-up of fluid in the peritoneal cavity-ascites-is a hallmark of ovarian cancer, the most lethal of all gynaecological malignancies. This remarkable fluid, which... (Review)
Review
The build-up of fluid in the peritoneal cavity-ascites-is a hallmark of ovarian cancer, the most lethal of all gynaecological malignancies. This remarkable fluid, which contains a variety of cellular and acellular components, is known to contribute to patient morbidity and mortality by facilitating metastasis and contributing to chemoresistance, but remains largely under-researched. In this review, we will critically analyse the evidence associating ascites with metastasis and chemoresistance in ovarian cancer and provide an update on research in the field. We will argue the case for ascites as a unique and accessible substrate for tracking tumour progression and for translational research that will enhance our understanding of this cancer and lead to improvements in patient outcomes.
Topics: Ascites; Biomarkers, Tumor; Female; Humans; Ovarian Neoplasms; Ovary; Proteomics
PubMed: 32382112
DOI: 10.1038/s41416-020-0875-x -
Experimental & Molecular Medicine Dec 2020Gastric cancer (GC) patients develop malignant ascites as the disease progresses owing to peritoneal metastasis. GC patients with malignant ascites have a rapidly...
Gastric cancer (GC) patients develop malignant ascites as the disease progresses owing to peritoneal metastasis. GC patients with malignant ascites have a rapidly deteriorating clinical course with short survival following the onset of malignant ascites. Better optimized treatment strategies for this subset of patients are needed. To define the cellular characteristics of malignant ascites of GC, we used single-cell RNA sequencing to characterize tumor cells and tumor-associated macrophages (TAMs) from four samples of malignant ascites and one sample of cerebrospinal fluid. Reference transcriptomes for M1 and M2 macrophages were generated by in vitro differentiation of healthy blood-derived monocytes and applied to assess the inflammatory properties of TAMs. We analyzed 180 cells, including tumor cells, macrophages, and mesothelial cells. Dynamic exchange of tumor-promoting signals, including the CCL3-CCR1 or IL1B-IL1R2 interactions, suggests macrophage recruitment and anti-inflammatory tuning by tumor cells. By comparing these data with reference transcriptomes for M1-type and M2-type macrophages, we found noninflammatory characteristics in macrophages recovered from the malignant ascites of GC. Using public datasets, we demonstrated that the single-cell transcriptome-driven M2-specific signature was associated with poor prognosis in GC. Our data indicate that the anti-inflammatory characteristics of TAMs are controlled by tumor cells and present implications for treatment strategies for GC patients in which combination treatment targeting cancer cells and macrophages may have a reciprocal synergistic effect.
Topics: Ascites; Case-Control Studies; Cell Communication; Cell Plasticity; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; High-Throughput Nucleotide Sequencing; Humans; Macrophages; Peritoneal Neoplasms; Prognosis; Signal Transduction; Single-Cell Analysis; Stomach Neoplasms; Transcriptome; Tumor Microenvironment
PubMed: 33277616
DOI: 10.1038/s12276-020-00538-y -
Klinicka Onkologie : Casopis Ceske a... 2022Meigs syndrome is defined by the presence of a benign ovarian tumor, ascites, and pleural effusion (predominantly on the right side). A characteristic sign of Meigs...
BACKGROUND
Meigs syndrome is defined by the presence of a benign ovarian tumor, ascites, and pleural effusion (predominantly on the right side). A characteristic sign of Meigs syndrome is the complete disappearance of exudate after surgical resection of the ovarian tumor.
CASE REPORT
We present a case report of a 58-year-old patient admitted for an advanced ovarian tumor with pleural effusion, ascites, and tumor marker elevation typical for ovarian cancer. Cytological examination of ascites and pleural effusion was repeatedly negative for malignancy. Histopathological examination of the bio-psied tissue was concluded as low-grade mesenchymal neoplasia. The second opinion of histopathological examination was concluded as low grade fibroblastic pelvic tumor without the possibility of exact specification. Dia-gnoses of desmoid fibromatosis and low-grade fibromyxiod sarcoma (less likely) were considered. Surgical resection was indicated, and a large tumor with numerous adhesions to the uterus, bladder, and thin loops with a noticeably thickened peritoneum were perioperatively described. Histologically, left ovarian fibroma with productive peritonitis and sanguine-induced ascites was dia-gnosed. Due to the clinical findings and the result of the histopathological examination, the case was classified as Meigs syndrome. Two months after the surgery, the ascites and pleural effusion disappeared, and the tumor marker levels normalized.
CONCLUSION
The present case report documents that it is always necessary to consider diseases other than those most likely at the outset, as the treatment algorithm and prognosis of these rare diseases may differ significantly.
Topics: Ascites; Biomarkers, Tumor; Female; Fibroma; Humans; Meigs Syndrome; Middle Aged; Ovarian Neoplasms; Pleural Effusion
PubMed: 35760576
DOI: 10.48095/ccko2022232 -
The Journal of Clinical Investigation Feb 2021The development of ascites correlates with advanced stage disease and poor prognosis in ovarian cancer. Vascular permeability is the key pathophysiological change...
The development of ascites correlates with advanced stage disease and poor prognosis in ovarian cancer. Vascular permeability is the key pathophysiological change involved in ascites development. Previously, we provided evidence that perivascular M2-like macrophages protect the vascular barrier through direct contact with endothelial cells (ECs). Here, we investigated the molecular mechanism and its clinical significance in the ovarian cancer setting. We found that upon direct coculture with the endothelium, M2 macrophages tuned down their VLA4 and reduced the levels of VCAM1 in ECs. On the other hand, ectopically overexpressing VLA4 in macrophages or VCAM1 in ECs induced hyperpermeability. Mechanistically, downregulation of VLA4 or VCAM1 led to reduced levels of RAC1 and ROS, which resulted in decreased phosphorylation of PYK2 (p-PYK2) and VE-cadherin (p-VE-cad), hence enhancing cell adhesion. Furthermore, targeting the VLA4/VCAM1 axis augmented vascular integrity and abrogated ascites formation in vivo. Finally, VLA4 expression on the macrophages isolated from ascites dictated permeability ex vivo. Importantly, VLA4 antibody acted synergistically with bevacizumab to further enhance the vascular barrier. Taking these data together, we reveal here that M2 macrophages regulate the vascular barrier though the VCAM1/RAC1/ROS/p-PYK2/p-VE-cad cascade, which provides specific therapeutic targets for the treatment of malignant ascites.
Topics: Animals; Ascites; Capillary Permeability; Female; Human Umbilical Vein Endothelial Cells; Humans; Integrin alpha4beta1; Macrophages; Mice; Neoplasm Proteins; Ovarian Neoplasms; RAW 264.7 Cells; Signal Transduction; THP-1 Cells; Vascular Cell Adhesion Molecule-1
PubMed: 33295887
DOI: 10.1172/JCI140315