α2,3-Sialyltransferase ST3Gal III Modulates Pancreatic Cancer Cell Motility and Adhesion In Vitro and Enhances Its Metastatic Potential In Vivo

Pérez-Garay, Marta; Arteta, Beatriz; Pagès, Lluís; Llorens, Rafael de; Bolós, Carme de; Vidal‐Vanaclocha, Fernando; Peracaula, Rosa

doi:10.1371/journal.pone.0012524

Cited by 76 publications

(88 citation statements)

References 69 publications

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“…Although all PDA cell lines expressed both types of SA receptors on their surfaces, differences in expression levels were noted. Such heterogeneity in levels of SA expression in different cell lines was not surprising, as altered levels of expression of sialyltransferases and fucosyltransferases have been demonstrated in different types of tumors, including pancreatic, breast, colon, gastric, cervical, and renal cancers (47,48). Similar results have also been observed in the case of melanoma cell lines, with heterogeneous distribution of surface receptors when different lines were compared (49).…”

Section: Discussionsupporting

confidence: 56%

Oncolytic Activity of Avian Influenza Virus in Human Pancreatic Ductal Adenocarcinoma Cell Lines

Kasloff

Pizzuto

Silic-Benussi

et al. 2014

J Virol

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Pancreatic ductal adenocarcinoma (PDA) is the most lethal form of human cancer, with dismal survival rates due to late-stage diagnoses and a lack of efficacious therapies. Building on the observation that avian influenza A viruses (IAVs) have a tropism for the pancreas in vivo, the present study was aimed at testing the efficacy of IAVs as oncolytic agents for killing human PDA cell lines. Receptor characterization confirmed that human PDA cell lines express the alpha-2,3-and the alpha-2,6-linked glycan receptor for avian and human IAVs, respectively. PDA cell lines were sensitive to infection by human and avian IAV isolates, which is consistent with this finding. Growth kinetic experiments showed preferential virus replication in PDA cells over that in a nontransformed pancreatic ductal cell line. Finally, at early time points posttreatment, infection with IAVs caused higher levels of apoptosis in PDA cells than gemcitabine and cisplatin, which are the cornerstone of current therapies for PDA. In the BxPC-3 PDA cell line, apoptosis resulted from the engagement of the intrinsic mitochondrial pathway. Importantly, IAVs did not induce apoptosis in nontransformed pancreatic ductal HPDE6 cells. Using a model based on the growth of a PDA cell line as a xenograft in SCID mice, we also show that a slightly pathogenic avian IAV significantly inhibited tumor growth following intratumoral injection. Taken together, these results are the first to suggest that IAVs may hold promise as future agents of oncolytic virotherapy against pancreatic ductal adenocarcinomas. IMPORTANCEDespite intensive studies aimed at designing new therapeutic approaches, PDA still retains the most dismal prognosis among human cancers. In the present study, we provide the first evidence indicating that avian IAVs of low pathogenicity display a tropism for human PDA cells, resulting in viral RNA replication and a potent induction of apoptosis in vitro and antitumor effects in vivo. These results suggest that slightly pathogenic IAVs may prove to be effective for oncolytic virotherapy of PDA and provide grounds for further studies to develop specific and targeted viruses, with the aim of testing their efficacy in clinical contexts.

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Section: Discussionsupporting

confidence: 56%

Oncolytic Activity of Avian Influenza Virus in Human Pancreatic Ductal Adenocarcinoma Cell Lines

Kasloff

Pizzuto

Silic-Benussi

et al. 2014

J Virol

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“…Some authors reported the higher immunoreactivity of the enzyme a-2,6-sialyltransferase in well differentiated tumors (e.g. in hepatic cell carcinoma [21]), but others found the a-2,6-GalST immunoexpression to be more prevalent in tumors of higher histological grade (colorectal cancer [11], pancreatic cancer cell line [12]). The same concerns the influence of on cellular motility and invasive capabilities.…”

Section: Discussionmentioning

confidence: 99%

“…Various studies have found a-2,6-GalSA to be associated with cell differentiation and proliferation [7], intercellular and cell-matrix interactions [8] and immunity [9]. Their role in cancer has not yet been fully established, although available studies tend to demonstrate it as an indicator of poor prognosis [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

The presence and clinical implications of α-2,6-galactose-linked sialic acids in non-small-cell lung cancer brain metastases — preliminary study

Pelak

Jarosz

Strączyńska-Niemiec

et al. 2014

Folia Histochem Cytobiol.

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Brain metastases (BM) in non-small-cell lung cancer (NSCLC) patients present an increasing clinical challenge. Identifying biomarkers which specifically identify patients at high risk of BM may improve their early diagnosis, which is crucial for surgical and radiotherapeutic treatment outcome. Alpha-2,6-sialyltransferase (a-2,6-ST) and the primary product of its activity, alpha-2,6-galactose-linked sialic acids (a-2,6-GalSA) have been found responsible for the adhesion of tumor cells to the brain vessels' endothelium and enabling their transmigration through the blood-brain barrier in brain metastatic tumors. The aim of the study was to investigate by histochemical method the presence and possible role of a-2,6-GalSA in the formation of brain metastasis in NSCLC. In the screening phase 76 metastatic brain tumors were stained for a-2,6-GalSA and the second phase involved an identical staining of 20 primary tumors of patients who had their primary tumors treated with surgery or definite radiochemotherapy yet who later developed BM. The results were compared to a control group of 22 patients treated with surgery for NSCLC and who survived 5 years without the recurrence of disease. Alpha-2,6-GalSA presence was found to be down-regulated in poorly differentiated tumor types, whereas majority of differentiated tumors overexpressed it. This was statistically significant for both BM and the primary tumors. The expression of a-2,6-GalSA remained stable in primary and metastatic tumor pairs, however, no statistically significant differences were observed between study and control groups. Within the study group, a higher a-2,6-GalSA expression was associated with better overall survival, but not all statistical models found this result significant. Further studies are recommended to validate these findings.

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“…Aberrant sialylation is correlated with increased motility of cancer cells and promotes metastasis (6,18,21). This prompted us to evaluate the potential of P-3F ax -Neu5Ac to alter the migratory capacity of B16F10 cells.…”

Section: P-3f Ax -Neu5ac Treatment Impairs Binding To Ecm Components mentioning

confidence: 99%

“…Hypersialylation (a2,6) of a1b1 integrin enhances binding to collagen type I and favors cancer cell migration (20). P erez-Garay and colleagues reported that ST3Gal-III-overexpressing pancreatic adenocarcinoma cells formed metastatic lesions and drastically decreased survival in mice (21).…”

Section: Introductionmentioning

confidence: 99%

Targeting Aberrant Sialylation in Cancer Cells Using a Fluorinated Sialic Acid Analog Impairs Adhesion, Migration, and In Vivo Tumor Growth

Büll

Boltje

Wassink

et al. 2013

Molecular Cancer Therapeutics

157

133

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Cancer cells decorate their surface with a dense layer of sialylated glycans by upregulating the expression of sialyltransferases and other glycogenes. Although sialic acids play a vital role in many biologic processes, hypersialylation in particular has been shown to contribute to cancer cell progression and metastasis. Accordingly, selective strategies to interfere with sialic acid synthesis might offer a powerful approach in cancer therapy. In the present study, we assessed the potential of a recently developed fluorinated sialic acid analogue (P-3F ax -Neu5Ac) to block the synthesis of sialoglycans in murine melanoma cells and the consequences on cell adhesion, migration, and in vivo growth. The results showed that P-3F ax -Neu5Ac readily caused depletion of a2,3-/a2,6-linked sialic acids in B16F10 cells for several days. Long-term inhibition of sialylation for 28 days was feasible without affecting cell viability or proliferation. Moreover, P-3F ax -Neu5Ac proved to be a highly potent inhibitor of sialylation even at high concentrations of competing sialyltransferase substrates. P-3F ax -Neu5Ac-treated cancer cells exhibited impaired binding to poly-L-lysine, type I collagen, and fibronectin and diminished migratory capacity. Finally, blocking sialylation of B16F10 tumor cells with this novel sialic acid analogue reduced their growth in vivo. These results indicate that P-3F ax -Neu5Ac is a powerful glycomimetic capable of inhibiting aberrant sialylation that can potentially be used for anticancer therapy. Mol Cancer Ther; 12(10); 1935-46. Ó2013 AACR.

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α2,3-Sialyltransferase ST3Gal III Modulates Pancreatic Cancer Cell Motility and Adhesion In Vitro and Enhances Its Metastatic Potential In Vivo

Cited by 76 publications

References 69 publications

Oncolytic Activity of Avian Influenza Virus in Human Pancreatic Ductal Adenocarcinoma Cell Lines

Oncolytic Activity of Avian Influenza Virus in Human Pancreatic Ductal Adenocarcinoma Cell Lines

The presence and clinical implications of α-2,6-galactose-linked sialic acids in non-small-cell lung cancer brain metastases — preliminary study

Targeting Aberrant Sialylation in Cancer Cells Using a Fluorinated Sialic Acid Analog Impairs Adhesion, Migration, and In Vivo Tumor Growth

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