The Genomic and Proteomic Content of Cancer Cell-Derived Exosomes

Henderson, Meredith C.; Azorsa, David O.

doi:10.3389/fonc.2012.00038

Cited by 151 publications

(131 citation statements)

References 97 publications

Supporting

Mentioning

130

Contrasting

Order By: Relevance

“…Thus, our study documents for the first time the scope of proteomic changes that are induced in EVs of epithelial cancer cells in the course of mesenchymal changes imposed in a manner dependent on the activity of EGFR and E-cadherin. We believe that these results add new perspective to the previous proteomic studies performed on EV fractions [63][64][65], by demonstrating the molecular plasticity of the vesiculation process and its links to cellular differentiation and transformation. What remains to be determined is the functional consequence of the emission, retention and/or intercellular transfer of proteins we identified in the cargo of EVs.…”

Section: Discussionmentioning

confidence: 62%

Qualitative changes in the proteome of extracellular vesicles accompanying cancer cell transition to mesenchymal state

Garnier

Magnus

Meehan

et al. 2013

Experimental Cell Research

View full text Add to dashboard Cite

Transitions of the cancer cell phenotype between epithelial and mesenchymal states is likely to alter the patterns of intercellular communication. In this regard we have previously documented that EMT-like changes trigger quantitative changes in exosomal vesicle emission in A431 cancer cells driven by oncogenic epidermal growth factor receptor (EGFR). Here we report that extracellular vesicles (EVs) produced by these cancer cells in their epithelial and mesenchymal states exhibit profound qualitative differences in their proteome. Thus, induction of the EMT-like state through blockade of E-cadherin and EGFR stimulation resulted in mesenchymal shift in cellular morphology and enrichment in the CD44-high/CD24-low immunophenotype, often linked to cellular stemness. This change also resulted in reprogramming of the EV-related proteome (distinct from that of corresponding cells), which contained 30 unique protein signals, and revealed enrichment in pathways related to cellular growth, cell-to-cell signalling, and cell movement. Some of the most prominent EV-related proteins were validated, including integrin "2 and tetraspanin CD9. We propose that changes in cellular differentiation status translate into unique qualitative rearrangements in the cargo of EVs, a process that may have implications for intercellular communication and could serve as source of new biomarkers of EMT-like changes in cancer.3

show abstract

Section: Discussionmentioning

confidence: 62%

Qualitative changes in the proteome of extracellular vesicles accompanying cancer cell transition to mesenchymal state

Garnier

Magnus

Meehan

et al. 2013

Experimental Cell Research

View full text Add to dashboard Cite

show abstract

“…Additionally, it is known that several members of the Rab GTPase family affect exosome secretion via the trans-Golgi network or by inducible vesicular trafficking [35,41]. Exosomes released from cancer cells can be taken up by neighboring cells and are capable of inducing pathways involved in cancer initiation and progression [42,43]. Therefore, it is thought that DENND2D plays an important role in carcinogenesis and cancer progression via regulation of Rab GTPases.…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of expression and methylation status of DENN/MADD domain-containing protein 2D in gastric cancer

et al. 2014

View full text Add to dashboard Cite

Background Patients with advanced gastric cancer (GC) have an adverse prognosis even after curative resection. Development of novel diagnostic and therapeutic approaches for GC is urgently required. Methods The expression and methylation status of DENN/MADD domain-containing protein 2D (DEN-ND2D), a member of the membrane trafficking proteins, were evaluated in 12 GC cell lines and 112 pairs of surgical specimens. Subgroup analysis based on tumor differentiation, location, and morphology was also performed. Expression and distribution of DENND2D protein were determined by immunohistochemistry. Results The majority of GC cell lines (75 %) and tissues (79 %) showed reduced expression of DENND2D mRNA compared with noncancerous gastric tissues. GC tissues showed a significantly lower mean expression level of mRNA and a higher frequency of promoter hypermethylation of DENND2D than corresponding noncancerous tissues. No significant differences in DENND2D mRNA expression and methylation status were found between GC subtypes categorized by tumor differentiation, location, and morphology. The expression patterns of DENND2D protein were confirmed to be consistent with those of DENND2D mRNA. Downregulation of DENND2D mRNA in GC tissues was significantly associated with factors related to more advanced GC and subsequent adverse prognosis. Among 72 patients who underwent R0 resection, downregulation of DENND2D mRNA in GC tissues was an independent prognostic factor and associated with early recurrence. Conclusions Our results suggested that DENND2D is a putative tumor suppressor gene regulated by promoter hypermethylation in GC. Downregulation of DENND2D can serve as a novel tumor biomarker to predict progression and early recurrence of all types of GC.

show abstract

“…13,46,54 For example, exosomes in the serum of glioblastoma patients contained specific mutant RNAs and miRNAs, which are characteristic for glioblastoma cells. 11 The finding that the HPV oncogenes can substantially affect exosome contents, as shown here for the model molecule Survivin, provides first evidence for the existence of HPV-linked molecular signatures in exosomes that could be used for diagnostic purposes.…”

Section: Infectious Causes Of Cancermentioning

confidence: 99%

Silencing of human papillomavirus (HPV) E6/E7 oncogene expression affects both the contents and the amounts of extracellular microvesicles released from HPV‐positive cancer cells

Honegger

Leitz

Bulkescher

et al. 2013

Intl Journal of Cancer

View full text Add to dashboard Cite

The human papillomavirus (HPV) E6/E7 oncogenes play a crucial role in the HPV-induced carcinogenesis. In this study, the authors investigated whether silencing of endogenous HPV E6/E7 expression may influence the contents or amounts of extracellular microvesicles (eMVs) released from HPV-positive cancer cells. It was found that eMVs secreted from HeLa cells are enriched for Survivin protein. RNA interference studies revealed that maintenance of both intracellular and microvesicular Survivin amounts was strongly dependent on continuous E6/E7 expression. This indicates that intracellular HPV activities are translated into visible alterations of protein contents in eMVs. Besides Survivin, eMVs from HeLa cells contain additional members of the inhibitor of apoptosis protein (IAP) family (XIAP, c-IAP1 and Livin). In contrast, no evidence for the presence of the HPV E6 and E7 oncoproteins in eMVs was obtained. Moreover, it was found that silencing of HPV E6/E7 expression led to a significant increase of exosomes-representing eMVs of endocytic origin-released from HeLa cells. This effect was associated with the reinduction of p53, stimulation of the p53 target genes TSAP6 and CHMP4C that can enhance exosome production and induction of senescence. Taken together, these results show that silencing of HPV E6/E7 oncogene expression profoundly affects both the composition and amounts of eMVs secreted by HPV-positive cancer cells. This indicates that HPVs can induce molecular signatures in eMVs that may affect intercellular communication and could be explored for diagnostic purposes.Specific types of human papillomaviruses (HPVs), such as HPV16 and HPV18, cause cervical cancer and are closely linked to the development of additional human malignancies in the oropharyngeal and anogenital regions. 1 The viral E6 and E7 oncoproteins are crucial both for the HPV-associated induction of transformation and for the maintenance of the tumorigenic phenotype of HPV-positive cervical cancer cells. 2,3 E6 and E7 dysregulate intracellular pathways involved in the control of cellular proliferation, apoptosis and genetic stability. For example, E6 induces the proteolytic degradation of the p53 tumor suppressor protein 4 and stimulates telomerase activity, 5 whereas E7 interferes with the activity of the retinoblastoma tumor suppressor protein, pRb, and other pocket proteins. 6 In contrast to the increasing understanding of the intracellular activities of the viral E6/E7 oncogenes, surprisingly little is known about possible effects on the intercellular communication of HPV-positive cancer cells.Extracellular microvesicles (eMVs) include exosomes that are small vesicles (50-100 nm in diameter) of endosomal origin secreted by a variety of cells, including tumor cells. 7 Exosomes have recently gained much interest in oncology, particularly due to three properties: (i) exosomes secreted from tumor cells can suppress the immune response toward the tumor, 8,9 (ii) tumor cell-derived exosomes can accelerate tumor growth and invasiveness by horizon...

show abstract

The Genomic and Proteomic Content of Cancer Cell-Derived Exosomes

Cited by 151 publications

References 97 publications

Qualitative changes in the proteome of extracellular vesicles accompanying cancer cell transition to mesenchymal state

Qualitative changes in the proteome of extracellular vesicles accompanying cancer cell transition to mesenchymal state

Prognostic impact of expression and methylation status of DENN/MADD domain-containing protein 2D in gastric cancer

Silencing of human papillomavirus (HPV) E6/E7 oncogene expression affects both the contents and the amounts of extracellular microvesicles released from HPV‐positive cancer cells

Contact Info

Product

Resources

About