A Novel Model of Cancer Drug Resistance: Oncosomal Release of Cytotoxic and Antibody-Based Drugs

Eguchi, Takanori; Taha, Eman A.; Calderwood, Stuart K.; Ono, Koji

doi:10.3390/biology9030047

Cited by 27 publications

(31 citation statements)

References 196 publications

(238 reference statements)

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“…CDC37 could positively regulate EMT and the release of EVs through permitting the function of these protein kinases. Consistently, recent studies have shown that EMT in cancer cells was often coupled with the release of EVs and drug resistance [22,98,99].…”

Section: Discussionsupporting

confidence: 60%

Cell Stress Induced Stressome Release Including Damaged Membrane Vesicles and Extracellular HSP90 by Prostate Cancer Cells

Eguchi

Sogawa

Ono

et al. 2020

Cells

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Tumor cells exhibit therapeutic stress resistance-associated secretory phenotype involving extracellular vesicles (EVs) such as oncosomes and heat shock proteins (HSPs). Such a secretory phenotype occurs in response to cell stress and cancer therapeutics. HSPs are stress-responsive molecular chaperones promoting proper protein folding, while also being released from cells with EVs as well as a soluble form known as alarmins. We have here investigated the secretory phenotype of castration-resistant prostate cancer (CRPC) cells using proteome analysis. We have also examined the roles of the key co-chaperone CDC37 in the release of EV proteins including CD9 and epithelial-to-mesenchymal transition (EMT), a key event in tumor progression. EVs derived from CRPC cells promoted EMT in normal prostate epithelial cells. Some HSP family members and their potential receptor CD91/LRP1 were enriched at high levels in CRPC cell-derived EVs among over 700 other protein types found by mass spectrometry. The small EVs (30–200 nm in size) were released even in a non-heated condition from the prostate cancer cells, whereas the EMT-coupled release of EVs (200–500 nm) and damaged membrane vesicles with associated HSP90α was increased after heat shock stress (HSS). GAPDH and lactate dehydrogenase, a marker of membrane leakage/damage, were also found in conditioned media upon HSS. During this stress response, the intracellular chaperone CDC37 was transcriptionally induced by heat shock factor 1 (HSF1), which activated the CDC37 core promoter, containing an interspecies conserved heat shock element. In contrast, knockdown of CDC37 decreased EMT-coupled release of CD9-containing vesicles. Triple siRNA targeting CDC37, HSP90α, and HSP90β was required for efficient reduction of this chaperone trio and to reduce tumorigenicity of the CRPC cells in vivo. Taken together, we define “stressome” as cellular stress-induced all secretion products, including EVs (200–500 nm), membrane-damaged vesicles and remnants, and extracellular HSP90 and GAPDH. Our data also indicated that CDC37 is crucial for the release of vesicular proteins and tumor progression in prostate cancer.

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Section: Discussionsupporting

confidence: 60%

Cell Stress Induced Stressome Release Including Damaged Membrane Vesicles and Extracellular HSP90 by Prostate Cancer Cells

Eguchi

Sogawa

Ono

et al. 2020

Cells

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“…Exosome-mediated enhanced EMT and stemness in the drug resistance of BC Recent studies have shown that the release characteristics of EVs are usually coupled with cellular phenotypic transformation, including EMT 81,82 and CSC 83,84 . EMT and stemness promote the EV-releasing phenotype of cells, and tumor-derived EVs could in turn initiate EMT and stemness in tumor cells 85 . Thus it is conceivable that the EMT and CSC phenotypes are involved in promoting tumor progression and the acquisition of therapeutic resistance mediated by exosomes.…”

Section: Exosomes Regulate Emt Cancer Stem Cell (Csc) and Tme In Thmentioning

confidence: 99%

Exosomes and breast cancer drug resistance

et al. 2020

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Drug resistance is a daunting challenge in the treatment of breast cancer (BC). Exosomes, as intercellular communicative vectors in the tumor microenvironment, play an important role in BC progression. With the in-depth understanding of tumor heterogeneity, an emerging role of exosomes in drug resistance has attracted extensive attention. The functional proteins or non-coding RNAs contained in exosomes secreted from tumor and stromal cells mediate drug resistance by regulating drug efflux and metabolism, pro-survival signaling, epithelial–mesenchymal transition, stem-like property, and tumor microenvironmental remodeling. In this review, we summarize the underlying associations between exosomes and drug resistance of BC and discuss the unique biogenesis of exosomes, the change of exosome cargo, and the pattern of release by BC cells in response to drug treatment. Moreover, we propose exosome as a candidate biomarker in predicting and monitoring the therapeutic drug response of BC and as a potential target or carrier to reverse the drug resistance of BC.

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“…Epithelial-mesenchymal transition (EMT) is a key biological event potentially regulated by extracellular HSP90 [19,20]. EMT involves phenotypic changes in cells from epithelial to mesenchymal properties and promotes motility [21], migration, invasion, stemness [22], and drug resistance [23][24][25] in various types of cancer cells [26]. Numerous EMT-promoting factors have been identified, although recent studies, including ours, have revealed that cancer cell-derived EVs often initiate EMT in epithelial cells [8,10] and promote EMT in tumour cells [27].…”

Section: Introductionmentioning

confidence: 99%

Triple knockdown of CDC37, HSP90‐alpha and HSP90‐beta diminishes extracellular vesicles‐driven malignancy events and macrophage M2 polarization in oral cancer

Ono

Sogawa

Kawai

et al. 2020

J of Extracellular Vesicle

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Evidence has been accumulating to indicate that extracellular vesicles (EVs), including exosomes, released by cancer cells can foster tumour progression. The molecular chaperones – CDC37, HSP90α and HSP90β play key roles in cancer progression including epithelial-mesenchymal transition (EMT), although their contribution to EVs-mediated cell–cell communication in tumour microenvironment has not been thoroughly examined. Here we show that triple depletion of the chaperone trio attenuates numerous cancer malignancy events exerted through EV release. Metastatic oral cancer-derived EVs (MEV) were enriched with HSP90α HSP90β and cancer-initiating cell marker CD326/EpCAM. Depletion of these chaperones individually induced compensatory increases in the other chaperones, whereas triple siRNA targeting of these molecules markedly diminished the levels of the chaperone trio and attenuated EMT. MEV were potent agents in initiating EMT in normal epithelial cells, a process that was attenuated by the triple chaperone depletion. The migration, invasion, and in vitro tumour initiation of oral cancer cells were significantly promoted by MEV, while triple depletion of CDC37/HSP90α/β reversed these MEV-driven malignancy events. In metastatic oral cancer patient-derived tumours, HSP90β was significantly accumulated in infiltrating tumour-associated macrophages (TAM) as compared to lower grade oral cancer cases. HSP90-enriched MEV-induced TAM polarization to an M2 phenotype, a transition known to support cancer progression, whereas the triple chaperone depletion attenuated this effect. Mechanistically, the triple chaperone depletion in metastatic oral cancer cells effectively reduced MEV transmission into macrophages. Hence, siRNA-mediated knockdown of the chaperone trio (CDC37/HSP90α/HSP90β) could potentially be a novel therapeutic strategy to attenuate several EV-driven malignancy events in the tumour microenvironment. Abbreviations CDC37: cell division control 37; EMT: epithelial-mesenchymal transmission; EV: extracellular vesicles; HNSCC: head and neck squamous cell carcinoma; HSP90: heat shock protein 90; TAM: tumour-associated macrophage

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A Novel Model of Cancer Drug Resistance: Oncosomal Release of Cytotoxic and Antibody-Based Drugs

Cited by 27 publications

References 196 publications

Cell Stress Induced Stressome Release Including Damaged Membrane Vesicles and Extracellular HSP90 by Prostate Cancer Cells

Cell Stress Induced Stressome Release Including Damaged Membrane Vesicles and Extracellular HSP90 by Prostate Cancer Cells

Exosomes and breast cancer drug resistance

Triple knockdown of CDC37, HSP90‐alpha and HSP90‐beta diminishes extracellular vesicles‐driven malignancy events and macrophage M2 polarization in oral cancer

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