Intraperitoneal activation of myeloid cells clears ascites and reveals IL27-dependent regression of metastatic ovarian cancer.
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PROVIDER: PRJNA1166902 | ENA |
REPOSITORIES: ENA
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Project description:Patients with metastatic ovarian cancer (OvCa) have a 5-year survival rate of less than 30% due to persisting dissemination of chemoresistant cells in the peritoneal fluid and the immunosuppressive microenvironment in the peritoneal cavity. Here, we report that intraperitoneal administration of β-glucan and IFNγ (BI) induced robust tumor regression in clinically relevant models of metastatic OvCa. BI induced tumor regression by controlling fluid tumor burden and activating localized antitumor immunity. β-glucan alone cleared ascites and eliminated fluid tumor cells by inducing intraperitoneal clotting in the fluid and Dectin-1-Syk-dependent NETosis in the omentum. In omentum tumors, BI expanded a novel subset of immunostimulatory IL27+ macrophages and neutralizing IL27 impaired BI efficacy in vivo. Moreover, BI directly induced IL27 secretion in macrophages where single agent treatment did not. Finally, BI extended mouse survival in a chemoresistant model and significantly improved chemotherapy response in a chemo-sensitive model. In summary, we propose a new therapeutic strategy for the treatment of metastatic OvCa.
2024-10-22 | GSE278380 | GEO
Project description:Ovarian cancer is a major cause of cancer mortality among women largely due to late diagnosis of advanced stage metastatic disease. More extensive molecular analysis of metastatic ovarian cancer is needed to identify post-translational modifications of proteins particularly associated with metastatic disease so that we can better understand the metastatic process and identify potential therapeutic targets. Proteins are the target of many recently developed cancer treatments, but an often neglected aspect of biomarker discovery is protein glycosylation, especially those involving tumor-associated carbohydrate antigens (TACAs) such as sialyl-Lewis(x) (SLe(x) and sialyl-Lewis(a) (SLe(a), which have been identified in various cancers. Although it is already known that considerable changes in protein glycosylation are major contributors to the initiation, progression and metastasis of tumors, specifics about glycosylation changes particularly important to the metastatic process are still lacking. In this report we describe the results of a combined glycomic and proteomic study of metastatic ovarian cancer (OC) ascites fluids. Glycoproteins in ascites fluid were enriched by affinity binding to lectins (ConA or WGA) and other affinity matrices. Separate glycomic and proteomic analyses were performed as well as glycopeptide analyses. Relative abundances of different N-glycan groups and proteins were identified from original ascites fluids and corresponding lectin bound samples. Levels of biomarkers CA125, MUC1 and fibronectin were also monitored in these samples by Western blot analysis. N-glycan analysis of ascites fluids showed the presence of large, highly fucosylated and sialylated, complex and hybrid glycans, some of which were not observed in normal serum. Proteins in OC ascites that were more abundant or not present in the serum control, were haptoglobin, fibronectin, lumican, fibulin, hemopexin, ceruloplasmin, alpha-1-antitrypsin and alpha-1-antichymotrypsin. Glycopeptide analysis identified N- and O-glycans in clusterin, hemopexin, and fibulin that were present in OC ascites.
2016-08-15 | PXD003794 | Pride
Project description:HGSOC, the most aggressive form of OC, is characterized by insidious onset, rapid intraperitoneal spread and development of massive ascites. Peritoneal adhesion was considered as the first step of abdominal metastasis, underscoring that only tumor cells gain access to peritoneal adherence contribute to metastasis. Studies on ovarian cancer progression were mainly focused on the primary and metastatic tumor cells, while understanding of the ascitic tumor cells is limited. We hypothesized that uncovering the gene expression profiles of ascitic tumor cells from high grade serous ovarian cancer patients will allow us to understand more specifically their unique phenotype which mediates the peritoneal adhesion. In this study, gene expression profiling was completed for 15 magnetic sorted tumor cells samples from matched primary tumors, ascites and metastases of 5 high grade serous ovarian cancer patients. By comparing the expression data from ascitic tumor cells with primary and metastasis tumor cells, we identified a set of differential expressed genes in ovarian ascitic tumor cells advantageous for peritoneal adhesion and metastasis. Further study revealed that ascites microenvironment modulated the ascitic tumor cells phenotype and contributed to ovarian cancer dissemination through facilitating CAFs in formation of compact spheroids with ascitic tumor cells. We used microarrays to profile the expression of 15 matched tumor cells samples in order to identify molecular alteration between primary tumor cells, ascitic tumor cells and metastatic tumor cells in high grade serous ovarian cancer.
2017-12-19 | GSE73064 | GEO
Project description:Ovarian cancer is the leading cause of gynecological cancer related death. The overall 5 year survival rate is only 29%. Over 85% of ovarian cancer patients present with advanced stage III or IV disease characterized by intraperitoneal metastasis when diagnosed. However, the process and mechanism of ovarian tumor metastasis remain poorly understood partially because of the lack of a mouse model which could recapitulate the development of metastatic lesion in an appropriate timeframe. In order to generate a convenient ovarian cancer model with accelerated peritoneal metastasis, we performed an in vivo selection study using ID8 ovarian cancer cells to establish a rapid metastasizing mouse ovarian cancer cell line, designated ID8-M. Syngeneic mice with intraperitoneal inoculation of ID8-M cells showed measurable ascites average 35 days after the inoculation and survived only an average of 52 days, while those inoculated with parental ID8 cells showed measurable ascites after 67 days and survived over 81 days. Further analysis showed that, compared with ID8 tumors, ID8-M tumors resulted in more macrophages in the ascites; and compared to ID8 cells, ID8-M cells were more potent to promote macrophages to acquire a M2 phenotype. A microarray analysis provided information to explain the accelerated metastatic phenotype of ID8-M cells.
2015-03-16 | GSE66934 | GEO
Project description:Ovarian cancer patients are generally diagnosed at stage III/IV, when ascites is common. The volume of ascites positively correlates with the extent of metastasis and negatively with prognosis. Membrane GRP78, a stress-inducible endoplasmic reticulum chaperone which also appears on the plasma membrane (memGRP78) of aggressive cancers, plays a crucial role in the maintenance of embryonic stem cells. Our present study demonstrates that tumor cells isolated from ascites generated by epithelial ovarian cancer (ID8 cells) bearing mice have increased memGRP78 expression compared to ID8 cells in normal culture. We hypothesize that these ascites associated memGRP78+ cells are cancer stem-like cells (CSC) and memGRP78 is functionally important in CSCs. Supporting this hypothesis, we show that memGRP78+ cells isolated from ascites have increased sphere forming and tumor initiating abilities compared to memGRP78- cells. When the tumor microenvironment is recapitulated by adding ascites fluid to cell culture, ID8 cells express more memGRP78 and increased self-renewing ability compared to those cultured in medium alone. Moreover, compared to their counterparts cultured in normal medium, ID8 cells cultured in ascites, or isolated from ascites, show an increased expression of stem cell markers Sca-1, Snail and SOX9. Importantly, antibodies directed against the carboxy (COOH)-terminal domain of GRP78 significantly reduce the self-renewing ability of murine and human ovarian cancer cells pre-incubated with ascites, associated with a decreased phosphorylation of Akt and GSK3α, and reduced level of the transcriptional factor Snail. Based on this data, we suggest that memGRP78 is a logical therapeutic target for late stage ovarian cancer. Two types of ovarian cancer cells from different organ sites are profiled by gene expression. Parental cells (ID8) and ID8 cells which have metastasized to Ascites (AS).
2015-03-09 | E-GEOD-61285 | biostudies-arrayexpress
Project description:RNAseq of ovarian cancer ascites cells
| PRJEB19616 | ENA
Project description:Ovarian cancer patients are generally diagnosed at stage III/IV, when ascites is common. The volume of ascites positively correlates with the extent of metastasis and negatively with prognosis. Membrane GRP78, a stress-inducible endoplasmic reticulum chaperone which also appears on the plasma membrane (memGRP78) of aggressive cancers, plays a crucial role in the maintenance of embryonic stem cells. Our present study demonstrates that tumor cells isolated from ascites generated by epithelial ovarian cancer (ID8 cells) bearing mice have increased memGRP78 expression compared to ID8 cells in normal culture. We hypothesize that these ascites associated memGRP78+ cells are cancer stem-like cells (CSC) and memGRP78 is functionally important in CSCs. Supporting this hypothesis, we show that memGRP78+ cells isolated from ascites have increased sphere forming and tumor initiating abilities compared to memGRP78- cells. When the tumor microenvironment is recapitulated by adding ascites fluid to cell culture, ID8 cells express more memGRP78 and increased self-renewing ability compared to those cultured in medium alone. Moreover, compared to their counterparts cultured in normal medium, ID8 cells cultured in ascites, or isolated from ascites, show an increased expression of stem cell markers Sca-1, Snail and SOX9. Importantly, antibodies directed against the carboxy (COOH)-terminal domain of GRP78 significantly reduce the self-renewing ability of murine and human ovarian cancer cells pre-incubated with ascites, associated with a decreased phosphorylation of Akt and GSK3α, and reduced level of the transcriptional factor Snail. Based on this data, we suggest that memGRP78 is a logical therapeutic target for late stage ovarian cancer.
2015-03-09 | GSE61285 | GEO
Project description:Microarrays were used to examine gene expression changes in the surgical resections of high-grade serous ovarian cancer patients exhibiting clinically distinct levels of ascites volume. The present studies primary aim was to determine if there is a molecular gene expression difference between the patients presenting at time of surgery when high volumes ascites cases were compared to those with low volume ascites. The secondary aim was to determine what relevance this difference, if found, has to previously discovered molecular sub-types of high grade serous ovarian cancer. Total RNA obtained from snap-frozen stage III-IV high-grade serous ovarian cancer patients presenting with low volume (<=200 cc) or high volume (>=1000 cc) ascites volume.
2014-10-01 | E-GEOD-51831 | biostudies-arrayexpress
Project description:Macrophages form a primary immune cells population in tumor tissues and malignant ascites microenvironment (MAM). They can be activated and polarized into tumor-associated macrophages (TAM) by the embedded environment and promote tumor progression and metastasis However, the molecular mechanisms of MAM in macrophage polarization and the effects on epithelial ovarian cancer (EOC) metastatic progression remain elusive. Here, we found that that MAM modulates RhoA-GTPase-F-actin-Hippo signaling cascade in facilitating M2-like macrophage polarization that, in turn, promotes tumor dissemination. PUFA enriched magligant ascites microenvironment promote macrophage lipid oxidative phosphorylation and supression RhoA-GTPase-Yap1 axis. Genetic ablation Yap1 in macrophage exhibited M2-like polarization and enhanced ovrian tumor dissemination. Pharmacology inhibit Mst1/2 could rescue M2-like TAM polarization in MAM and alter the lipid oxidation of macrophages in MAM, more importantly, inhibit ovarian metastatic properties. Through comparasion primary TAM (P-TAM) and metastasis TAM (M-TAM), we proved that Hippo-Yap1 siganl results M-TAM with high M2/M1 ratio. These findings implicate critical functions of PUFA modulate RhoA-Hippo axis in facility TAM polarization and also suggest manipulation of PUFA metabolism or RhoA-Hippo siganl as a therapeutic strategy aganist EOC metastasis.
2024-05-01 | GSE175552 | GEO
Project description:Ovarian cancer is characterized by transcoelomic metastasis into the peritoneal cavity. The peritoneal malignant ascites is enriched with ovarian cancer cells and a small amount of tumor-associated immune cells which create a unique microenvironment actively contributing to progression of the disease. However, it is remain unclear how cancer cells communicate to its local environment under the influence of chemotherapy. To address this issue, we performed LC-MS/MS analyses of ovarian cancer ascites from the same patients before and after chemotherapy. We found that neoadjuvant chemotherapy causes a significant changes in the composition of ascites, and these changes are similar in samples obtained from all patients (n=10). Functional annotation of upregulated proteins with the use of KEGG and GO databases revealed that malignant ascites after chemotherapy were enriched with the cluster of spliceosomal proteins. These splicing factors were linked to induction of epithelial-to-mesenchymal transition leading to a more aggressive phenotype of cancer cells.
2024-05-29 | PXD019327 | Pride