Inhibition of cell surface mediated plasminogen activation by a monoclonal antibody against α‐Enolase

López-Alemany, Roser; Longstaff, Colin; Hawley, Stephen B.; Mirshahi, Massoud; Fàbregas, Pere; Jardı́, Mercè; Merton, Elizabeth; Miles, Lindsey A.; Félez, Jordi

doi:10.1002/ajh.10299

Cited by 104 publications

(99 citation statements)

References 38 publications

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“…Its surface expression has been reported in myeloid and mammary tumor cell lines. 23,28 Interestingly, microarray data indicated that a-enolase is not increased in pancreatic tissues from CP, but only in PDAC. This strengthens the hypothesis that upregulation of aenolase is associated with pancreatic tumorigenesis rather than general inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…23,[34][35][36][37][38][39] It is known that a-enolase expressed at cell surface acts as a plasminogen receptor. 28,40 The bound plasminogen is more efficiently activated to plasmin and thus contributes to pathological processes such as tumor cell invasion, metastases and inflammatory responses. 41 The role of these antibody responses remains to be defined in the clinical follow-up.…”

Section: Discussionmentioning

confidence: 99%

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An integrated humoral and cellular response is elicited in pancreatic cancer by α‐enolase, a novel pancreatic ductal adenocarcinoma‐associated antigen

Cappello¹,

Tomaino²,

Chiarle³

et al. 2009

Intl Journal of Cancer

107

125

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Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a very poor 5-year survival rate. a-Enolase is a glycolytic enzyme that also acts as a surface plasminogen receptor. We find that it is overexpressed in PDAC and present on the cell surface of PDAC cell lines. The clinical correlation of its expression with tumor status has been reported for lung and hepatocellular carcinoma. We have previously demonstrated that sera from PDAC patients contain IgG autoantibodies to a-enolase. The present work was intended to assess the ability of a-enolase to induce antigen-specific T cell responses. We show that a-enolase-pulsed dendritic cells (DC) specifically stimulate healthy autologous T cells to proliferate, secrete IFN-c and lyse PDAC cells but not normal cells. In vivo, a-enolase-specific T cells inhibited the growth of PDAC cells in immunodeficient mice. In 8 out of 12 PDAC patients with circulating IgG to a-enolase, the existence of a-enolase-specific T cells was also demonstrated. Taken as a whole, these results indicate that a-enolase elicits a PDAC-specific, integrated humoral and cellular response. It is thus a promising and clinically relevant molecular target candidate for immunotherapeutic approaches as new adjuvants to conventional treatments in pancreatic cancer. ' 2009 UICC

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

An integrated humoral and cellular response is elicited in pancreatic cancer by α‐enolase, a novel pancreatic ductal adenocarcinoma‐associated antigen

Cappello¹,

Tomaino²,

Chiarle³

et al. 2009

Intl Journal of Cancer

107

125

View full text Add to dashboard Cite

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“…21 Another possible role is the inhibition of migration of pancreatic tumor cells or MDSCs into the tumor through the ENO1-plasminogen pathway blockade. 22,23 An additional important effect of ENO1 vaccination is the significant decrease of MDSCs and Treg cells. The massive secretion of IL-6 in the pancreas of ENO1-vaccinated mice (data not shown) may explain the increase of Th17 rather than FoxP3 ϩ cells.…”

Section: Pancreasmentioning

confidence: 99%

Vaccination With ENO1 DNA Prolongs Survival of Genetically Engineered Mice With Pancreatic Cancer

et al. 2013

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See Covering the Cover synopsis on page 862. BACKGROUND & AIMS:Pancreatic ductal adenocarcinoma (PDA) is an aggressive tumor, and patients typically present with late-stage disease; rates of 5-year survival after pancreaticoduodenectomy are low. Antibodies against ␣-enolase (ENO1), a glycolytic enzyme, are detected in more than 60% of patients with PDA, and ENO1-specific T cells inhibit the growth of human pancreatic xenograft tumors in mice. We investigated whether an ENO1 DNA vaccine elicits antitumor immune responses and prolongs survival of mice that spontaneously develop autochthonous, lethal pancreatic carcinomas. METHODS:We injected and electroporated a plasmid encoding ENO1 (or a control plasmid) into Kras G12D /Cre (KC) mice and Kras G12D /Trp53 R172H /Cre (KPC) mice at 4 weeks of age (when pancreatic intraepithelial lesions are histologically evident). Antitumor humoral and cellular responses were analyzed by histology, immunohistochemistry, enzyme-linked immunosorbent assays, flow cytometry, and enzyme-linked immunosorbent spot and cytotoxicity assays. Survival was analyzed by Kaplan-Meier analysis. RESULTS: The ENO1 vaccine induced antibody and a cellular response and increased survival times by a median of 138 days in KC mice and 42 days in KPC mice compared with mice given the control vector. On histologic analysis, the vaccine appeared to slow tumor progression. The vaccinated mice had increased serum levels of anti-ENO1 immunoglobulin G, which bound the surface of carcinoma cells and induced complement-dependent cytotoxicity. ENO1 vaccination reduced numbers of myeloid-derived suppressor cells and T-regulatory cells and increased T-helper 1 and 17 responses. CONCLU-SIONS: In a genetic model of pancreatic carcinoma, vaccination with ENO1 DNA elicits humoral and cellular immune responses against tumors, delays tumor progression, and significantly extends survival. This vaccination strategy might be developed as a neoadjuvant therapy for patients with PDA.

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“…It is a multifunctional enzyme that also plays a role in various processes such as growth control, tolerance to hypoxia, and allergic responses [73]. α-enolase is a plasminogen-binding protein and also appears to play a major role in the promotion of plasminogen activation by leukocytic cells [74]. Peptidylprolyl isomerase (cyclophilin A) has been associated with a number of cancer histiotypes including breast [75] and pancrease [76,77], and has been implicated in cellular resistance to hypoxia-and Cisplatininduced cell death [78] and resistance to aplidin [79].…”

Section: Non-classical Secretionmentioning

confidence: 99%

Identification of Differentially Secreted Biomarkers Using LC-MS/MS in Isogenic Cell Lines Representing a Progression of Breast Cancer

et al. 2007

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Proteins secreted (the secretome) from cancer cells are potentially useful as biomarkers of the disease. Using LC-MS/MS, the secreted proteomes from a series of isogenic breast cancer cell lines varying in aggressiveness were analyzed by mass spectrometry: non-tumorigenic MCF10A, premalignant/ tumorigenic MCF10AT, tumorigenic/locally invasive MCF10 DCIS.com and tumorigenic/ metastatic MCF 10CA cl. D. Proteomes were obtained from conditioned serum-free media, partially fractionated using a small reverse phase C2 column and digested with trypsin for analysis by LC-MS/MS, using a method previously shown to give highly enriched secreted proteomes (Mbeunkui, et. al., J. Prot. Res. 5, 899-906 2006). The search files produced from 5 analyses (3 separate preparations) were combined for database searching (Mascot) which produced a list of over 250 proteins from each cell line. The aim was to discover highly secreted proteins which changed significantly in abundance corresponding with aggressiveness. The most apparent changes were observed for alpha-1-antichymotrypsin and galectin-3-binding protein which were highly secreted proteins from MCF10 DCIS.com and MCF10CA cl. D, yet undetected in the MCF10A and MCF10AT cell lines. Other proteins showing increasing abundance in the more aggressive cell lines included alpha-1-antitrypsin, cathepsin D and lysyl oxidase. The S100 proteins, often associated with metastasis, showed variable changes in abundance. While the cytosolic proteins were low (e.g. actin and tubulin), there was significant secretion of proteins often associated with the cytoplasm. These proteins were all predicted as products of non-classical secretion (SecretomeIP, Center for Biological Sequence Analysis). The LC-MS/MS results were verified for five selected proteins by western blot analysis, and the relevance of other significant proteins is discussed. Comparisons with two other aggressive breast cancer cell lines are included and the protein with consistent association with aggressiveness in all lines, and in unrelated cancer cells, was the galectin-3-binding protein which has been associated with breast, prostate and colon cancer earlier, supporting the approach and findings. This analysis of an isogenic series of cell lines suggests the potential usefulness of the secretome for identifying prospective markers for the early detection and aggressiveness/progression of cancer.

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Inhibition of cell surface mediated plasminogen activation by a monoclonal antibody against α‐Enolase

Cited by 104 publications

References 38 publications

An integrated humoral and cellular response is elicited in pancreatic cancer by α‐enolase, a novel pancreatic ductal adenocarcinoma‐associated antigen

An integrated humoral and cellular response is elicited in pancreatic cancer by α‐enolase, a novel pancreatic ductal adenocarcinoma‐associated antigen

Vaccination With ENO1 DNA Prolongs Survival of Genetically Engineered Mice With Pancreatic Cancer

Identification of Differentially Secreted Biomarkers Using LC-MS/MS in Isogenic Cell Lines Representing a Progression of Breast Cancer

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