Specific Mesothelial Signature Marks the Heterogeneity of Mesenchymal Stem Cells From High-Grade Serous Ovarian Cancer

Verardo, Roberto; Piazza, Silvano; Klaric, Enio; Ciani, Yari; Bussadori, Giulio; Marzinotto, Stefania; Mariuzzi, Laura; Cesselli, Daniela; Beltrami, Antonio Paolo; Mano, Miguel; Itoh, Masayoshi; Kawaji, Hideya; Lassmann, Timo; Carninci, Piero; Hayashizaki, Yoshihide; Forrest, Alistair R.R.; Beltrami, Carlo Alberto; Schneider, Claudio

doi:10.1002/stem.1791

Cited by 16 publications

(11 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…C). The expression of CD44, CD29, CD73, CD90, and CD105 in cultured cells from malignant fluids of lung cancer patients was not as high as those from breast or ovarian cancer patients, these data were consistent with previous reports . CD73, CD90, and CD105 were also found to be expressed in freshly isolated CD45 − cells from patients' malignant fluids (Fig.…”

Section: Resultssupporting

confidence: 92%

Brief Report: Human Mesenchymal Stem-Like Cells Facilitate Floating Tumorigenic Cell Growth via Glutamine-Ammonium Cycle

Tang

et al. 2015

Stem Cells

View full text Add to dashboard Cite

How mesenchymal stem cells (MSCs) promote tumor growth remains incompletely understood. Here, we show that mesenchymal stem-like cells (MSLCs) are commonly present in malignant pleural effusion or ascites of cancer patients, where they directly interact with tumor cells. Chemokines and chemokine receptors, especially the CCL2/CCR2 pathway, are involved in this interaction. SIGNIFICANCE STATEMENTPatients with solid primary tumors may develop malignant pleural effusion or ascites, posing a formidable challenge in treatment. Mesenchymal stem-like cells (MSLC) are found commonly present in malignant pleural effusion or ascites of patients, where they profoundly influence floating malignant cells through an intercellular metabolic pathway. MSLCs release glutamine that tumor cells take up. In turn, tumor cells secrete ammonium, the product of glutamine metabolism, and MSLCs take ammonium up. Thus, the glutamine-ammonium cycle is formed between MSLCs and tumorigenic cells. These findings not only provide insights into the new facet of MSLCs in malignant fluids but also implicate the potential clinical applications.

show abstract

Section: Resultssupporting

confidence: 92%

Brief Report: Human Mesenchymal Stem-Like Cells Facilitate Floating Tumorigenic Cell Growth via Glutamine-Ammonium Cycle

Tang

et al. 2015

Stem Cells

View full text Add to dashboard Cite

show abstract

“…As a multi-potent stem cell population, CA-MSCs (unlike cancer associated fibroblasts) will passage for many months in culture. CA-MSCs have a normal genome and do not form tumors [ 16 ]. However, CA-MSCs are strongly pro-tumorigenic, increasing both tumor growth and “stemness” [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistanceviaa BMP4/HH signaling loop

et al. 2016

View full text Add to dashboard Cite

The tumor microenvironment is critical to cancer growth and therapy resistance. We previously characterized human ovarian carcinoma-associated mesenchymal stem cells (CA-MSCs). CA-MSCs are multi-potent cells that can differentiate into tumor microenvironment components including fibroblasts, myofibroblasts and adipocytes. We previously reported CA-MSCs, compared to normal MSCs, express high levels of BMP proteins and promote tumor growth by increasing numbers of cancer stem-like cells (CSCs). We demonstrate here that ovarian tumor cell-secreted Hedgehog (HH) induces CA-MSC BMP4 expression. CA-MSC-derived BMP4 reciprocally increases ovarian tumor cell HH expression indicating a positive feedback loop. Interruption of this loop with a HH pathway inhibitor or BMP4 blocking antibody decreases CA-MSC-derived BMP4 and tumor-derived HH preventing enrichment of CSCs and reversing chemotherapy resistance. The impact of HH inhibition was only seen in CA-MSC-containing tumors, indicating the importance of a humanized stroma. These results are reciprocal to findings in pancreatic and bladder cancer, suggesting HH signaling effects are tumor tissue specific warranting careful investigation in each tumor type. Collectively, we define a critical positive feedback loop between CA-MSC-derived BMP4 and ovarian tumor cell-secreted HH and present evidence for the further investigation of HH as a clinical target in ovarian cancer.

show abstract

“…CAGE was used to annotate functional elements within the human genome in the ENCODE project [ 8 ], and it was used to monitor global transcriptome states characterizing diverse cell types across the human body in the FANTOM5 project [ 8 – 10 ]. Obtaining an accurate map of transcriptome in a wide range of primary cells, organs, and cell lines enabled us to understand a series of observations, such as structural relationships between cancer cell lines [ 11 ], mesothelial signatures in high-grade serous ovarian cancer [ 12 ], and regulatory regions of the three genes involved in Rett Syndrome [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Novel biomarkers that assist in accurate discrimination of squamous cell carcinoma from adenocarcinoma of the lung

et al. 2016

Self Cite

View full text Add to dashboard Cite

BackgroundTargeted therapies based on the molecular and histological features of cancer types are becoming standard practice. The most effective regimen in lung cancers is different between squamous cell carcinoma (SCC) and adenocarcinoma (AD). Therefore a precise diagnosis is crucial, but this has been difficult, particularly for poorly differentiated SCC (PDSCC) and AD without a lepidic growth component (non-lepidic AD). Biomarkers enabling a precise diagnosis are therefore urgently needed.MethodsCap Analysis of Gene Expression (CAGE) is a method used to quantify promoter activities across the whole genome by determining the 5’ ends of capped RNA molecules with next-generation sequencing. We performed CAGE on 97 frozen tissues from surgically resected lung cancers (22 SCC and 75 AD), and confirmed the findings by immunohistochemical analysis (IHC) in an independent group (29 SCC and 45 AD).ResultsUsing the genome-wide promoter activity profiles, we confirmed that the expression of known molecular markers used in IHC for SCC (CK5, CK6, p40 and desmoglein-3) and AD (TTF-1 and napsin A) were different between SCC and AD. We identified two novel marker candidates, SPATS2 for SCC and ST6GALNAC1 for AD, as showing comparable performance and complementary utility to the known markers in discriminating PDSCC and non-lepidic AD. We subsequently confirmed their utility at the protein level by IHC in an independent group.ConclusionsWe identified two genes, SPATS2 and ST6GALNAC1, as novel complemental biomarkers discriminating SCC and AD. These findings will contribute to a more accurate diagnosis of NSCLC, which is crucial for precision medicine for lung cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2792-1) contains supplementary material, which is available to authorized users.

show abstract

Specific Mesothelial Signature Marks the Heterogeneity of Mesenchymal Stem Cells From High-Grade Serous Ovarian Cancer

Cited by 16 publications

References 77 publications

Brief Report: Human Mesenchymal Stem-Like Cells Facilitate Floating Tumorigenic Cell Growth via Glutamine-Ammonium Cycle

Brief Report: Human Mesenchymal Stem-Like Cells Facilitate Floating Tumorigenic Cell Growth via Glutamine-Ammonium Cycle

Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistanceviaa BMP4/HH signaling loop

Novel biomarkers that assist in accurate discrimination of squamous cell carcinoma from adenocarcinoma of the lung

Contact Info

Product

Resources

About