Surface proteomic analysis of osteosarcoma identifies EPHA2 as receptor for targeted drug delivery

PosthumaDeBoer, Jantine; Piersma, Sander R.; Pham, Thang V.; Egmond, Pim W van; Knol, Jaco C.; Cleton-Jansen, A.M.; Geer, M A van; Beusechem, Victor W. van; Kaspers, Gertjan J. L.; Royen, Barend J. van; Jiménez, Connie R.; Helder, Marco N.

doi:10.1038/bjc.2013.578

Cited by 46 publications

(39 citation statements)

References 54 publications

(76 reference statements)

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“…10F,G). EPHA2 has been previously identified as a highly expressed surface protein in OS cells and tissue [41][42][43] . We found that LGALS1, a potent inducer of T-cell apoptosis 44,45 , was LGALS1 upregulation has been reported in human OS tissue samples 46 and is associated with metastatic and aggressive cancer cell phenotypes [47][48][49] .…”

Section: Figure 5 Prm-based Confirmation Of Hypoxia-induced Expressimentioning

confidence: 99%

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

Song

Pearce

Jiang

et al. 2020

Sci Rep

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osteosarcoma (oS) is the most common bone cancer in children and young adults. Solid tumors are characterized by intratumoral hypoxia, and hypoxic cells are associated with the transformation to aggressive phenotype and metastasis. the proteome needed to support an aggressive osteosarcoma cell phenotype remains largely undefined. To link metastatic propensity to a hypoxia-induced proteotype, we compared the protein profiles of two isogenic canine OS cell lines, POS (low metastatic) and HMpoS (highly metastatic), under normoxia and hypoxia. Label-free shotgun proteomics was applied to comprehensively characterize the hypoxia-responsive proteome profiles in the OS cell phenotypes. Hypothesis-driven parallel reaction monitoring was used to validate the differential proteins observed in the shotgun data and to monitor proteins of which we expected to exhibit hypoxia responsiveness, but which were absent in the label-free shotgun data. We established a "distance" score (|z HMPOS − z POS |), and "sensitivity" score (|z Hypoxia − z Normoxia ) to quantitatively evaluate the proteome shifts exhibited by oS cells in response to hypoxia. evaluation of the sensitivity scores for the proteome shifts observed and principal component analysis of the hypoxia-responsive proteins indicated that both cell types acquire a proteome that supports a Warburg phenotype with enhanced cell migration and proliferation characteristics. Cell migration and glucose uptake assays combined with protein function inhibitor studies provided further support that hypoxia-driven adaption of pathways associated with glycolytic metabolism, collagen biosynthesis and remodeling, redox regulation and immunomodulatory proteins typify a proteotype associated with an aggressive cancer cell phenotype. Our findings further suggest that proteins involved in collagen remodeling and immune editing may warrant further evaluation as potential targets for anti-metastatic treatment strategies in osteosarcoma.

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Section: Figure 5 Prm-based Confirmation Of Hypoxia-induced Expressimentioning

confidence: 99%

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

Song

Pearce

Jiang

et al. 2020

Sci Rep

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“…The toxicity of peppered carrier with combination of siRNA-DOX would be enhanced, leads to increase killing efficiency of endosomal cells and also increase in vivo side effects against normal cells. Though the pH and thermo sensitivity properties of purposed formula contribute in local targeting of osteosarcoma cells but the systemic targeting of osteosarcoma cells using peptide would be more effective that are being developed in our lab for DOX-siRNA delivery [21].…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

A comprehensive mathematical model of drug release kinetics from nano-liposomes, derived from optimization studies of cationic PEGylated liposomal doxorubicin formulations for drug-gene delivery

Haghiralsadat

Amoabediny

Helder

et al. 2017

Artificial Cells, Nanomedicine, and Biotechnology

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This study focuses on the development of a universal mathematical model for drug release kinetics from liposomes to allow in silico prediction of optimal conditions for fine-tuned controlled drug release. As a prelude for combined siRNA-drug delivery, nanoliposome formulations were optimized using various mole percentages of a cationic lipid (1,2-dioleoyl-3-trimethylammonium-propane, DOTAP) in the presence or absence of 3 mol% distearoyl phosphoethanolamine, polyethylene glycol (PEG-2000mDSPE). Outcome parameters were particle size, zeta potential, entrapment efficiency, in vitro drug release, and tumor cell kill efficiency. The optimized formula (containing 20% DOTAP with 3% DSPE-mPEG(2000) was found to be stable for six months, with round-shaped particles without aggregate formation, an average diameter of 71 nm, a suitable positive charge, and 89% drug encapsulation efficiency (EE). The 41% drug release during 6 h confirmed controlled release. Furthermore, the release profiles as functions of pH and temperature were investigated and the kinetics of the drug release could adequately be fitted to Korsmeyer-Peppas' model by multiple regression analysis. The statistical parameters confirmed good conformity of final models. Functionality of the novel cationic liposome formulations (± DOX) was tested on osteosarcoma (OS) cell lines. Increased OS cell toxicity (1.3-fold) was observed by the DOX-loaded vs. the free DOX. A feasibility pilot showed that siRNA could be loaded efficiently as well. In conclusion, we have established a predictive mathematical model for the fine-tuning of controlled drug release from liposomal formulations, while creating functional drug-delivery liposomes with potential for siRNA co-delivery to increase specificity and efficacy.

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“…For example, a recent study has shown that EphA2 is the most abundant cell surface protein in osteosarcoma cells while being expressed at low levels in healthy bone tissue, and is therefore an excellent candidate for targeted drug delivery in this type of cancer [98]. In addition, EphA2 expression in the absence of ephrin-induced activation has been associated with cancer stem cells and with epithelial-mesenchymal transition [99-102], suggesting that agonistic peptides that bind to EphA2 may not only enable targeting of the most malignant and therapy-resistant cancer cells but also in parallel trigger the tumor suppressing effects of EphA2 signaling.…”

Section: Peptide Conjugates Targeting Eph Receptorsmentioning

confidence: 99%

“…The YSA peptide, which can be encoded by the adenovirus genome because it contains only natural amino acids and which can also promote adenovirus internalization through EphA2 activation [51], shows particular promise for adenoviral transduction of EphA2-positive cancer cells. Several studies with YSA-redirected adenoviruses have demonstrated efficient EphA2-dependent transduction of endothelial, osteosarcoma and pancreatic cancer cells in culture as well as of ex vivo slices from patient-derived pancreatic tumors and melanoma metastases [98, 113, 116, 117]. Successful in vivo transduction of pancreatic cancer and melanoma xenografts in the mouse was also observed after intratumor adenovirus injection but not yet through systemic adenovirus administration, which represents the next goal.…”

Section: Peptide Conjugates Targeting Eph Receptorsmentioning

confidence: 99%

Targeting the Eph System with Peptides and Peptide Conjugates

Riedl¹,

Pasquale

2015

CDT

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Eph receptor tyrosine kinases and ephrin ligands constitute an important cell communication system that controls development, tissue homeostasis and many pathological processes. Various Eph receptors/ephrins are present in essentially all cell types and their expression is often dysregulated by injury and disease. Thus, the 14 Eph receptors are attracting increasing attention as a major class of potential drug targets. In particular, agents that bind to the extracellular ephrin-binding pocket of these receptors show promise for medical applications. This pocket comprises a broad and shallow groove surrounded by several flexible loops, which makes peptides particularly suitable to target it with high affinity and selectivity. Accordingly, a number of peptides that bind to Eph receptors with micromolar affinity have been identified using phage display and other approaches. These peptides are generally antagonists that inhibit ephrin binding and Eph receptor/ephrin signaling, but some are agonists mimicking ephrin-induced Eph receptor activation. Importantly, some of the peptides are exquisitely selective for single Eph receptors. Most identified peptides are linear, but recently the considerable advantages of cyclic scaffolds have been recognized, particularly in light of potential optimization towards drug leads. To date, peptide improvements have yielded derivatives with low nanomolar Eph receptor binding affinity, high resistance to plasma proteases and/or long in vivo half-life, exemplifying the merits of peptides for Eph receptor targeting. Besides their modulation of Eph receptor/ephrin function, peptides can also serve to deliver conjugated imaging and therapeutic agents or various types of nanoparticles to tumors and other diseased tissues presenting target Eph receptors.

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Surface proteomic analysis of osteosarcoma identifies EPHA2 as receptor for targeted drug delivery

Cited by 46 publications

References 54 publications

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

A comprehensive mathematical model of drug release kinetics from nano-liposomes, derived from optimization studies of cationic PEGylated liposomal doxorubicin formulations for drug-gene delivery

Targeting the Eph System with Peptides and Peptide Conjugates

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