Targeted proteomics in urinary extracellular vesicles identifies biomarkers for diagnosis and prognosis of prostate cancer

Sequeiros, Tamara; Rigau, Marina; Chiva, Cristina; Montes, Melania; García-Grau, Iolanda; García, Marta; Díaz, Sherley; Celma, A.; Bijnsdorp, Irene V.; Campos, Alex; Mauro, Primiano Pio Di; Borrós, Salvador; Reventós, Jaume; Doll, Andreas; Paciucci, Rosanna; Pegtel, D. Michiel; Torres, Inés de; Sabidó, Eduard; Moróte, Juan; Oliván, Mireia

doi:10.18632/oncotarget.13634

Cited by 83 publications

(71 citation statements)

References 50 publications

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“…This notion of multiplexing biomarkers was also explored in a study by Sequeiros and co‐workers, which aimed to develop a multiprotein panel for diagnosis and stratification of PC patients using urinary EVs . The authors employed selected reaction monitoring (SRM) to evaluate the abundance of 64 proteins previously identified as being upregulated in EVs from PC patients.…”

Section: Urinementioning

confidence: 99%

Tumor‐Derived Extracellular Vesicles as a Novel Source of Protein Biomarkers for Cancer Diagnosis and Monitoring

Ruhen

Meehan

2019

Proteomics

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“Liquid biopsies” have received attention as a complementary tool for traditional tissue biopsies that may enhance the spectrum of analysis for tumor‐derived factors. One such factor gaining prominence in the liquid biopsy field is extracellular vesicles (EVs), membrane‐bound nanovesicles which are secreted by cells into biofluids such as blood, urine, and saliva. EVs are released in both physiological and pathological conditions and can transport a variety of molecules, including proteins, metabolites, RNA, microRNAs, and DNA, to distant sites throughout the body. As such, they are emerging as a promising source of tumor biomarkers for the noninvasive diagnosis, prognosis, and monitoring of cancer patients. In particular, the wealth of tumor‐related information that can be gleaned from the EV proteomic cargo has become apparent through mass spectrometric analysis, which has provided new benchmarks for clinically focused biomarker research. In this review, the current achievements in the use of MS for identifying potential EV‐derived protein biomarkers of cancer are explored, and the techniques and challenges involved in this pursuit are summarized.

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Section: Urinementioning

confidence: 99%

Tumor‐Derived Extracellular Vesicles as a Novel Source of Protein Biomarkers for Cancer Diagnosis and Monitoring

Ruhen

Meehan

2019

Proteomics

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“…TGM4 was found down-regulated 1.7-fold in urinary extracellular vesicles of PCa and had AUC 0.58 to diagnose PCa on biopsy 66 . Immunohistochemistry with tissue microarrays revealed under-expression of TGM4 in prostate tissues (P <0.001) and AUC of 0.81 to detect PCa versus benign disease 66 . TGM4 in the urinary extracellular vesicles also differentiated between low-and high-grade PCa with high sensitivity and specificity (P <0.001; AUC 0.82).…”

Section: Cc-by-nc-mentioning

confidence: 97%

“…TGM4 was previously suggested as a prostate cancer biomarker, but results were inconsistent and revealed either significant over-expression 65 or under-expression [66][67][68][69] of TGM4 in PCa versus benign disease, or inconclusive results with the opposite directions based on different assays 70 . TGM4 was found down-regulated 1.7-fold in urinary extracellular vesicles of PCa and had AUC 0.58 to diagnose PCa on biopsy 66 . Immunohistochemistry with tissue microarrays revealed under-expression of TGM4 in prostate tissues (P <0.001) and AUC of 0.81 to detect PCa versus benign disease 66 .…”

Section: Cc-by-nc-mentioning

confidence: 99%

Multi-omics biomarker pipeline reveals elevated levels of protein-glutamine gamma-glutamyltransferase 4 in seminal plasma of prostate cancer patients

Drabovich

Saraon

Drabovich³

et al. 2017

Preprint

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Prostate-specific antigen, a widely used biomarker of prostate cancer, lacks specificity and prognostic significance, which often results in over-diagnosis and over-treatment of prostate cancer. In this study, we investigated if seminal plasma proteins could increase specificity of detecting primary prostate cancer and discriminate between low-and high-grade cancers. To select 148 most promising biomarker candidates, we combined transcripts or proteins identified through five independent data mining or experimental approaches: tissue transcriptomics, seminal plasma proteomics, cell secretomics, tissue specificity and androgen regulation. To follow up these candidates, we designed a rigorous biomarker verification and validation pipeline based on multiplex quantitative selected reaction monitoring assays. We verified 77 and validated 19 most promising proteins in seminal plasma of 67 negative biopsy and 152 prostate cancer patients. Validation revealed a prostate-specific, secreted and androgen-regulated protein-glutamine gamma-glutamyltransferase 4 (TGM4), which could predict prostate cancer on biopsy and outperformed age and serum PSA. In the independent validation set re-measured by an in-house ELISA, TGM4 was significantly up-regulated (3.7-fold, P=0.005) and revealed AUC 0.66 for differentiating between negative biopsy and prostate cancer in patients with age ≥50 and blood serum PSA ≥4 ng/mL. Interestingly, none of validated biomarkers could differentiate between low-and high-grade cancers. Very low levels of TGM4 (120 pg/mL) were detected by ELISA in blood serum, but could not differentiate between negative biopsy, prostate cancer or prostate inflammation. Significantly higher levels of TGM4 in blood serum (3.5-fold, P = 0.0004) were found for younger men (<40 y.o.) relative to older men (≥70 y.o.). Our work may represent one of the most comprehensive studies on prostate cancer biomarkers in seminal plasma. Even though moderate performance of TGM4 as a single biomarker will unlikely result in its immediate use in the clinic, TGM4 may be further investigated in the distinct subtypes of prostate cancer and included into emerging multibiomarker panels.

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“…It is also noteworthy that EVs and their content can serve as biomarkers for cancer . Given that there are changes in EV content that could mediate their ability to induce drug resistance when transferred between cells, it is logical that these changes could also serve as a biomarker for the presence of tumors that are either resistant to specific drugs or harbor the capacity to transfer resistance .…”

Section: Perspective and Future Directionsmentioning

confidence: 99%

Mechanisms of Drug Resistance in Cancer: The Role of Extracellular Vesicles

2017

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Drug resistance remains a major barrier to the successful treatment of cancer. The mechanisms by which therapeutic resistance arises are multifactorial. Recent evidence has shown that extracellular vesicles (EVs) play a role in mediating drug resistance. EVs are small vesicles carrying a variety of macromolecular cargo released by cells into the extracellular space and can be taken up into recipient cells, resulting in transfer of cellular material. EVs can mediate drug resistance by several mechanisms. They can serve as a pathway for sequestration of cytotoxic drugs, reducing the effective concentration at target sites. They can act as decoys carrying membrane proteins and capturing monoclonal antibodies intended to target receptors at the cell surface. EVs from resistant tumor cells can deliver mRNA, miRNA, long noncoding RNA, and protein inducing resistance in sensitive cells. This provides a new model for how resistance that arises can then spread through a heterogeneous tumor. EVs also mediate cross-talk between cancer cells and stromal cells in the tumor microenvironment, leading to tumor progression and acquisition of therapeutic resistance. In this review, we will describe what is known about how EVs can induce drug resistance, and discuss the ways in which EVs could be used as therapeutic targets or diagnostic markers for managing cancer treatment. While further characterization of the vesiculome and the mechanisms of EV function are still required, EVs offer an exciting opportunity in the fight against cancer.

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Targeted proteomics in urinary extracellular vesicles identifies biomarkers for diagnosis and prognosis of prostate cancer

Cited by 83 publications

References 50 publications

Tumor‐Derived Extracellular Vesicles as a Novel Source of Protein Biomarkers for Cancer Diagnosis and Monitoring

Tumor‐Derived Extracellular Vesicles as a Novel Source of Protein Biomarkers for Cancer Diagnosis and Monitoring

Multi-omics biomarker pipeline reveals elevated levels of protein-glutamine gamma-glutamyltransferase 4 in seminal plasma of prostate cancer patients

Mechanisms of Drug Resistance in Cancer: The Role of Extracellular Vesicles

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