Primary Ovarian Carcinomas and Abdominal Metastasis Contain 4,6-Disulfated Chondroitin Sulfate Rich Regions, Which Provide Adhesive Properties to Tumour Cells

Vallen, Myrtille J.E.; Schmidt, Samuel; Oosterhof, Arie; Bulten, Johan; Massuger, Leon F.A.G.; Kuppevelt, Toin H. Van

doi:10.1371/journal.pone.0111806

Cited by 32 publications

(28 citation statements)

References 46 publications

(58 reference statements)

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“…Here, CHST11-mediated regulation of CSPG4, which serves as P-selectin ligand through its CS chain, was observed. Similarly, the impact of 4,6-disulfated chondroitin sulfate-rich regions (CS-E) on the adhesive properties of ovarian tumor cells has been recently described [30]. CS-E also regulates cellular signaling, such as the Wnt/beta-catenin-pathway [12,32] which exerts critical pro-tumorigenic and pro-metastatic functions in many human cancers, including ovarian cancer [1].…”

Section: Discussionmentioning

confidence: 99%

“…In ovarian cancer, there are recent evidences that chondroitin sulfate as well as diverse enzymes involved in the sulfation process of these structures plays an important role for metastatic spread of tumor cells, to some extent via modulation of their adhesive properties [24,30]. CS is composed of repeating disaccharides of N-acetylgalactosamine (GalNAc) and Dglucuronic acid (GlcA) with different sulfation patterns, mediated by various specific CHSTs: [6,9,15,18,21,23].…”

Section: Introductionmentioning

confidence: 99%

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Prognostic impact of chondroitin-4-sulfotransferase CHST11 in ovarian cancer

et al. 2015

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Ovarian cancer (OvCa) accounts for the highest tumor-related mortality among gynecological malignancies, but the underlying mechanisms are poorly understood. Glycosaminoglycans are abundantly present in ovarian tumors, and there is rising evidence that chondroitin sulfate (CS) as well as diverse carbohydrate sulfotransferases (CHSTs), the enzymes involved in the sulfation process of these structures, plays an important role in metastatic spread of tumor cells. mRNA expression levels of CHST3/7/11/12/13/15 were compared between malignant (86 OvCas) and non-malignant tumors (6 borderline tumors and 3 cystadenomas). CHST11 and CHST15 were further chosen for Western blot analysis in a cohort of 216 OvCas. Protein expression levels were correlated with clinicopathologic prognostic parameters and survival data. A significantly higher mRNA expression of CHST11, CHST12, and CHST15 was measured in ovarian cancer samples in comparison to non-malignant ones, and the same trend was observed for CHST13. For CHST3 and CHST7, no significant differences were found between the two groups. At protein level, high CHST11 expression was independently associated with unfavorable progression-free survival (PFS; p = 0.027). A similar trend was observed for CHST15, showing a nearly significant correlation between high expression levels and shorter recurrence-free survival in patients without macroscopic residual tumor after surgery (p = 0.053). We conclude that CHSTs involved in the synthesis of CS-A and CS-E might influence ovarian cancer progression, and we suggest CHST11 as independent unfavorable prognostic factor in this entity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prognostic impact of chondroitin-4-sulfotransferase CHST11 in ovarian cancer

et al. 2015

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“…These malignant characteristics are observed in other advanced tumors like ovarian cancer. In ovarian cancer, CS-E is detected in both tumor and stromal cells and is involved in the peerless aggressiveness of the cancer and correlates with poor prognosis [ 21 ]. Based on their similar distribution patterns, it is thought that both tumor cell-derived as well as stromal cell-derived CS-E play vital roles in the various steps of tumor progression in advanced tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Highly sulfated disaccharide units like E-unit, GlcAβ1-3GalNAc (4S, 6S), where 4S and 6S stand for 4- O - and 6- O -sulfate, respectively, and E-unit-rich CS (CS-E) preparations are synthesized by a specific enzyme, carbohydrate sulfotransferase 15 (CHST15), and show remarkable biological activities [ 6 – 12 ]. Accumulating evidence has revealed the involvement of CS-E in tumor cell invasion and metastasis in the lung [ 6 , 13 ], ovary [ 7 , 14 ], breast [ 15 ] and skin [ 16 ]. The role of CS-E in initiating tumor cell invasion was demonstrated, suggesting the potential of CS-E as a key molecule in establishing novel therapeutics against various solid tumors including PDAC [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Cell Proliferation and Growth of Pancreatic Cancer by Silencing of Carbohydrate Sulfotransferase 15 In Vitro and in a Xenograft Model

et al. 2015

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Chondroitin sulfate E (CS-E), a highly sulfated glycosaminoglycan, is known to promote tumor invasion and metastasis. Because the presence of CS-E is detected in both tumor and stromal cells in pancreatic ductal adenocarcinoma (PDAC), multistage involvement of CS-E in the development of PDAC has been considered. However, its involvement in the early stage of PDAC progression is still not fully understood. In this study, to clarify the direct role of CS-E in tumor, but not stromal, cells of PDAC, we focused on carbohydrate sulfotransferase 15 (CHST15), a specific enzyme that biosynthesizes CS-E, and investigated the effects of the CHST15 siRNA on tumor cell proliferation in vitro and growth in vivo. CHST15 mRNA is highly expressed in the human pancreatic cancer cell lines PANC-1, MIA PaCa-2, Capan-1 and Capan-2. CHST15 siRNA significantly inhibited the expression of CHST15 mRNA in these four cells in vitro. Silencing of the CHST15 gene in the cells was associated with significant reduction of proliferation and up-regulation of the cell cycle inhibitor-related gene p21CIP1/WAF1. In a subcutaneous xenograft tumor model of PANC-1 in nude mice, a single intratumoral injection of CHST15 siRNA almost completely suppressed tumor growth. Reduced CHST15 protein signals associated with tumor necrosis were observed with the treatment with CHST15 siRNA. These results provide evidence of the direct action of CHST15 on the proliferation of pancreatic tumor cells partly through the p21CIP1/WAF1 pathway. Thus, CHST15-CS-E axis-mediated tumor cell proliferation could be a novel therapeutic target in the early stage of PDAC progression.

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“…By contrast, the metastatic potential of Lewis lung carcinoma cells or murine osteosarcoma cells positively correlates with the proportion of the E units in the CS that are localized on the cell surface [87,88,186]. Likewise, the overexpression of CS-E in ovarian cancer cells correlates with a poor prognosis [187] most probably due to an increase in the cell-ECM and cell-cell adhesiveness [188] that can facilitate the tissue colonization. It seems that the mechanisms that underlie the prometastatic activity of CS-E may involve effects on the cell motility stimulators such as VEGF and HGF [189,190], the promotion of circulating cancer cell survival and extravasation via the interaction with P selectin [191], support of tissue colonization by binding to local receptors such as RAGE [46], and the stimulation of activation and/or activity of enzymes responsible for ECM degradation such as MMP-7 [192], which is implicated in the disruption of cell-ECM contacts [193].…”

Section: The Effect Of C-6-s On the Invasive Properties Of Cancer Cellsmentioning

confidence: 99%

The dual role of the glycosaminoglycan chondroitin‐6‐sulfate in the development, progression and metastasis of cancer

et al. 2019

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The remarkable structural heterogeneity of chondroitin sulfate (CS) and dermatan sulfate (DS) generates biological information that can be unique to each of these glycosaminoglycans (GAGs), and changes in their composition are translated into alterations in the binding profiles of these molecules. CS/DS can bind to various cytokines and growth factors, cell surface receptors, adhesion molecules, enzymes and fibrillar glycoproteins of the extracellular matrix, thereby influencing both cell behavior and the biomechanical and biochemical properties of the matrix. In this review, we summarize the current knowledge concerning CS/DS metabolism in the human cancer stroma. The remodeling of the GAG profile in the tumor niche is manifested as a substantial increase in the CS content and a gradual decrease in the proportion between DS and CS. Furthermore, the composition of CS and DS is also affected, which results in a substantial increase in the 6‐O‐sulfated and/or unsulfated disaccharide content, which is concomitant with a decrease in the 4‐O‐sulfation level. Here, we discuss the possible impact of alterations in the CS/DS sulfation pattern on the binding capacity and specificity of these GAGs. Moreover, we propose potential consequences of the stromal accumulation of chondroitin‐6‐sulfate for the progression and metastasis of cancer.

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Primary Ovarian Carcinomas and Abdominal Metastasis Contain 4,6-Disulfated Chondroitin Sulfate Rich Regions, Which Provide Adhesive Properties to Tumour Cells

Cited by 32 publications

References 46 publications

Prognostic impact of chondroitin-4-sulfotransferase CHST11 in ovarian cancer

Prognostic impact of chondroitin-4-sulfotransferase CHST11 in ovarian cancer

Inhibition of Cell Proliferation and Growth of Pancreatic Cancer by Silencing of Carbohydrate Sulfotransferase 15 In Vitro and in a Xenograft Model

The dual role of the glycosaminoglycan chondroitin‐6‐sulfate in the development, progression and metastasis of cancer

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