Autoantibody Signatures Involving Glycolysis and Splicesome Proteins Precede a Diagnosis of Breast Cancer among Postmenopausal Women

Ladd, Jon J.; Chao, Timothy; Johnson, Melissa M.; Qiu, Ji; Chin, Alice; Israel, Rebecca; Pitteri, Sharon J.; Mao, Jianning; Wu, Menghuai; Amon, Lynn M.; McIntosh, Martin W.; Li, Christopher I.; Prentice, Ross L.; Disis, Nora; Hanash, Samir M.

doi:10.1158/0008-5472.can-12-2560

Cited by 59 publications

(63 citation statements)

References 53 publications

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“…Possibly, the splicing U12 snRNA was transported to the extracellular medium in complex with splicing proteins, similar to the export of miRNA in complexes with Ago2, HDL, or NPM1 from cells. This hypothesis is in good agreement with the recently published data on the analysis of autoantibodies, which are present in the blood of breast cancer patients (43). Ladd et al convincingly demonstrated that most autoantibodies in the blood of cancer patients and tumor-bearing mice are produced against spliceosomal proteins.…”

Section: Discussionsupporting

confidence: 90%

Proteome–Metabolome Profiling of Ovarian Cancer Ascites Reveals Novel Components Involved in Intercellular Communication

Shender

Pavlyukov

Ziganshin

et al. 2014

Molecular & Cellular Proteomics

107

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aOvarian cancer ascites is a native medium for cancer cells that allows investigation of their secretome in a natural environment. This medium is of interest as a promising source of potential biomarkers, and also as a medium for cell-cell communication. The aim of this study was to elucidate specific features of the malignant ascites metabolome and proteome. In order to omit components of the systemic response to ascites formation, we compared malignant ascites with cirrhosis ascites. Metabolome analysis revealed 41 components that differed significantly between malignant and cirrhosis ascites. Most of the identified cancer-specific metabolites are known to be important signaling molecules. Proteomic analysis identified 2096 and 1855 proteins in the ovarian cancer and cirrhosis ascites, respectively; 424 proteins were specific for the malignant ascites. Functional analysis of the proteome demonstrated that the major differences between cirrhosis and malignant ascites were observed for the cluster of spliceosomal proteins. Additionally, we demonstrate that several splicing RNAs were exclusively detected in malignant ascites, where they probably existed within protein complexes. This result was confirmed in vitro using an ovarian cancer cell line. Identification of spliceosomal proteins and RNAs in an extracellular medium is of particular interest; the finding suggests that they might play a role in the communication between cancer cells. In addition, malignant ascites contains a high number of exosomes that are known to play an important role in signal transduction. Thus our study reveals the specific features of malignant ascites that are associated with its function as a medium of intercellular communication. Molecular & Cellular

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Section: Discussionsupporting

confidence: 90%

Proteome–Metabolome Profiling of Ovarian Cancer Ascites Reveals Novel Components Involved in Intercellular Communication

Shender

Pavlyukov

Ziganshin

et al. 2014

Molecular & Cellular Proteomics

107

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“…HLA binding of EPLSQESEV and EPLSQESQV was predicted to be HLA-B*51:01 and restricted, and HLA binding of QESEVEEPL and QESQVEEPL was predicted to be HLA-B*40:01 restricted (Supplementary Table S5). Thus, these repeating amino acid sequences may amplify the immune response against VCX in patients with HLA-B*51:01 or HLA-B*40:01.As part of prior studies that were aimed at identifying tumor antigens associated with autoantibodies in epithelial tumors types, we conducted discovery studies using recombinant and natural protein microarrays (19, 20). Given our discovery of novel CT antigens we examined their association with an autoantibody response using protein microarrays.…”

Section: Resultsmentioning

confidence: 99%

“…One control was matched to colon adenocarcinoma cases and two to five controls were matched to individual lung adenocarcinoma cases. The array study was performed as part of discovery studies of biomarker candidates for the early detection of epithelial tumor types (19, 20). Plasma samples were randomly allocated to the arrays within batches to eliminate potential bias, and were each hybridized with an individual protein microarray at a dilution of 1/500 in probe buffer (Synthetic Block in 150 mM PBS, 0.1% Tween-20) (PB) for 1.5 hours at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

A Search for Novel Cancer/Testis Antigens in Lung Cancer Identifies VCX/Y Genes, Expanding the Repertoire of Potential Immunotherapeutic Targets

et al. 2014

Self Cite

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Cancer/testis (CT) antigens are potential immunotherapeutic targets in cancer. However, the expression of particular antigens is limited to a subset of tumors of a given type. Thus, there is a need to identify antigens with complementary expression patterns for effective therapeutic intervention. In this study, we searched for genes that were distinctly expressed at a higher level in lung tumor tissue and the testes compared to other non-tumor tissues and identified members of the VCX/Y gene family as novel CT antigens. VCX3A, a member of the VCX/Y gene family, was expressed at the protein level in approximately 20% of lung adenocarcinomas and 35% of squamous cell carcinomas, but not expressed in normal lung tissues. Among CT antigens with concordant mRNA and protein expression levels, four CT antigens, XAGE1, VCX, IL13RA2, and SYCE1, were expressed, alone or in combination, in about 80% of lung adenocarcinoma tumors. The CT antigen VCX/Y gene family broadens the spectrum of CT antigens expressed in lung adenocarcinomas for clinical applications.

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“…Most breast cancers, however, have low to no CD8 TIL. This is most likely due to the Th2 bias that occurs early in oncogenesis resulting in significant antibody generation but low Type I T-cell expansion (39–41). We show that Th1/Th17 secreting T-cells generated with IL-2/IL-21 drive significantly more CD8 T-cells into the tumor after infusion than cells cultured with more standard cytokine combinations.…”

Section: Discussionmentioning

confidence: 99%

The Antitumor Efficacy of IL2/IL21-Cultured Polyfunctional Neu-Specific T Cells Is TNFα/IL17 Dependent

Phan-Lai

Dang

Gad

et al. 2016

Clinical Cancer Research

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Purpose Infusion of HER2 specific T-cells, derived from vaccine-primed patients and expanded with IL-2/IL-12, has induced tumor regression in a minority of patients with metastatic treatment-refractory HER2+ breast cancer. We questioned whether alteration of cytokine growth factors used to culture vaccine-primed T-cells could improve anti-tumor activity. Experimental Design Using the TgMMTV-neu murine mammary tumor model we cultured T-cells derived from mice immunized with a previously defined neu class II peptide, p98–114 (neu p98), and evaluated different cytokine combinations for expansion. Results Infusion of neu p98 specific T-cell lines derived from all cytokine conditions evaluated resulted in significant anti-tumor activity compared to infused naïve splenocytes (p<0.05). T-cells cultured with IL-2/IL-21 could uniquely mediate complete regression of spontaneous mammary tumors. IL-2/IL-21 cultured neu specific T-cells demonstrated a different cytokine secretion pattern as compared to other cultured T-cells; secreting high levels of TNF-alpha and IL-17 (p<0.05). Moreover, tumor infiltrating CD8+ cells were significantly increased after the infusion of IL-2/IL-21 cultured T-cells as compared to tumors treated with T-cells expanded under other cytokine conditions (p<0.001). The anti-tumor effect of the infusion of IL-2/IL-21 cultured cells was mediated by CD8 T-cells. Depletion of TNF-alpha or IL-17, but not IFN-gamma, abrogated the tumor growth inhibition induced by the IL-2/IL-21 T-cells and markedly decreased the influx of CD8 into tumors. Finally, IL-2/IL-21 cultured human antigen specific T-cells also displayed a similar polyfunctional Th1/Th17 phenotype. Conclusion Expansion of HER2 vaccine-primed T-cells with IL-2/IL-21 may have the potential to effectively mediate tumor regression when used in adoptive transfer.

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Autoantibody Signatures Involving Glycolysis and Splicesome Proteins Precede a Diagnosis of Breast Cancer among Postmenopausal Women

Cited by 59 publications

References 53 publications

Proteome–Metabolome Profiling of Ovarian Cancer Ascites Reveals Novel Components Involved in Intercellular Communication

Proteome–Metabolome Profiling of Ovarian Cancer Ascites Reveals Novel Components Involved in Intercellular Communication

A Search for Novel Cancer/Testis Antigens in Lung Cancer Identifies VCX/Y Genes, Expanding the Repertoire of Potential Immunotherapeutic Targets

The Antitumor Efficacy of IL2/IL21-Cultured Polyfunctional Neu-Specific T Cells Is TNFα/IL17 Dependent

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