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Stanniocalcin 1 in tumor microenvironment promotes metastasis of ovarian cancer.

ABSTRACT: Background: Tumor metastasis is the major challenge for ovarian cancer treatment. Cancer-associated fibroblasts (CAFs), a major component existing in tumor microenvironment, can secrete several cytokines to interact with cancer epithelial cells, and promote cancer metastasis. Stanniocalcin 1 (STC1), a secretory glycoprotein hormone, has been proven to be an important factor in ovarian tumorigenesis. Methods: In this study, we focused on the functional role of STC1 in ovarian cancer microenvironment, investigated STC1's effects on the proliferation and metastasis of ovarian cancer cells, and explored the molecular mechanism underlying STC1-mediated cancer metastasis. Results: By analyzing the GEO dataset and examined STC1 expression in CAFs isolated from ovarian cancer patients, we found that expression of STC1 was higher in ovarian cancer stroma and CAFs than in the normal ovarian stroma and normal fibroblasts (NFs). Addition of recombinant human STC1 (rhSTC1) promoted cell proliferation and metastasis in ovarian cancer, while adoption of STC1 neutralizing antibody (STC1 Ab) abolished the effects. Furthermore, our results revealed that STC1 promoted the phosphorylation of Akt (Ser473), and upregulated several epithelial-mesenchymal transition (EMT) markers including fibronectin?vimentin and slug. In addition, we demonstrated that STC1 in tumor microenvironment could mediate the conversion of NFs to CAFs. Conclusion: Taken together, the study results suggested the crucial role of STC1 in tumor environment on the metastasis of ovarian cancer.

SUBMITTER: Yang Y

PROVIDER: S-EPMC6489642 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Stanniocalcin 1 in tumor microenvironment promotes metastasis of ovarian cancer.

Yang Yuqi Y Yin Sheng S Li Shuqing S Chen Yaping Y Yang Lina L

OncoTargets and therapy 20190411

<b>Background:</b> Tumor metastasis is the major challenge for ovarian cancer treatment. Cancer-associated fibroblasts (CAFs), a major component existing in tumor microenvironment, can secrete several cytokines to interact with cancer epithelial cells, and promote cancer metastasis. Stanniocalcin 1 (STC1), a secretory glycoprotein hormone, has been proven to be an important factor in ovarian tumorigenesis. <b>Methods:</b> In this study, we focused on the functional role of STC1 in ovarian cancer ...[more]

PMID: 31114228

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Project description:IntroductionOvarian and other peritoneal cancers have a strong tendency to metastasize into the surrounding adipose tissue. This study describes an effect of the adipose microenvironment on upregulation of sialic acid-containing glycans in ovarian cancer (OC). Heterogeneous populations of glycosylated OC tumors converged to a highly sialylated cell state that regulates tumorigenesis in an immune-dependent manner.MethodsWe modeled the adipose microenvironment by conditioning growth media with human patient-derived adipose tissue. OC cell lines grown in the presence vs. absence of adipose conditioned media (ACM) were characterized by transcriptomics, western blotting, and chemical biology glycan labeling methods. Fluorescence-activated cell sorting was used to separate adipose-driven upregulation of hypersialylated ("SNA-high") vs. hyposialylated ("SNA-low") OC subpopulations. The two subpopulations were characterized by further transcriptomic and quantitative polymerase chain reaction analyses, then injected into a syngeneic mouse model. Immune system involvement was implicated using wild type and athymic nude mice with a primary endpoint of overall survival.ResultsAdipose conditioning resulted in upregulation of sialyltransferases ST3GAL1, ST6GAL1, ST6GALNAC3, and ST8Sia1. In culture, OC cells displayed two distinct sialylated subpopulations that were stable for up to 9 passages, suggesting inherent heterogeneity in sialylation that is maintained throughout cell division and media changes. OC tumors that implanted in the omental adipose tissue exclusively reprogrammed to the highly sialylated subpopulation. In wild type C57BL/6 mice, only the hypersialylated SNA-high subpopulation implanted in the adipose, whereas the hyposialylated SNA-low subpopulation failed to be tumorigenic (p=0.023, n=5). In the single case where SNA-low established a tumor, post-mortem analysis revealed reprogramming of the tumor to the SNA-high state in vivo. In athymic nude mice, both subpopulations rapidly formed tumors, implicating a role of the adaptive immune system.ConclusionsThese findings suggest a model of glycan-dependent tumor evolution wherein the adipose microenvironment reprograms OC to a tumorigenic state that resists the adaptive immune system. Mechanistically, adipose factors upregulate sialyltransferases. To our knowledge, this is the first demonstration of the effect of adipose microenvironment on OC tumor sialylation. Our results set the stage for translational applications targeting sialic acid pathways in OC and other peritoneal cancer tumorigenesis and metastasis.

Project description:BackgroundThe tumor microenvironment (TME) is not only a key factor in the malignant progression of cancer but also plays an indispensable role in tumor immunotherapy. As an important regulatory factor in the TME, long non-coding RNAs (incRNA) are important for the development of bladder cancer. The purpose of this study was to explore the molecular mechanism of malignant progression of bladder cancer (BCa) from the perspective of immunology, establish a reliable signature, and evaluate its effect on prognosis, metastasis, and the effectiveness of immunotherapy.MethodsThe TME was assessed by single-sample gene set enrichment analysis (ssGSEA) in 373 patients with muscle invasive bladder cancer (MIBC) in The Cancer Genome Atlas (TCGA). Combining RNA sequence data from 49 BCa patients in our center, we established TME-related prognostic signatures (TMERPS) based on TME-related immune prognosis genes using weighted gene correlation network analysis, selection operator Cox analysis, minimum absolute shrinkage, and survival analysis. Real-Time Quantitative PCR was used for expression level analysis of related genes. Functional enrichment analysis and nomograms were used to explore the potential impact of TMERPS on the immune system, prognosis, and metastasis.ResultsThe ssGSEA proved to be an accurate assessment of immune levels in BCa samples. TMERPS was established based on six TME-associated prognostic lncRNAs and was shown to be closely associated with prognosis, metastasis, and immune levels, and to have a significant stratifying effect on the therapeutic efficacy of immune checkpoint inhibitors. Finally, three TMERPS-based nomograms were shown to be effective in predicting prognosis, lymph node metastasis, and distant metastasis in BCa patients.ConclusionsTMERPS can stratify BCa patients into different risk groups with different prognoses, immunotherapy sensitivity, and risk of metastasis. TMERPS-based nomograms can effectively predict prognosis and metastasis in BCa patients.

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Stanniocalcin 1 in tumor microenvironment promotes metastasis of ovarian cancer.

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Stanniocalcin 1 in tumor microenvironment promotes metastasis of ovarian cancer.

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