Extracellular Vesicle Transmission of Chemoresistance to Ovarian Cancer Cells Is Associated with Hypoxia-Induced Expression of Glycolytic Pathway Proteins, and Prediction of Epithelial Ovarian Cancer Disease Recurrence.
Extracellular Vesicle Transmission of Chemoresistance to Ovarian Cancer Cells Is Associated with Hypoxia-Induced Expression of Glycolytic Pathway Proteins, and Prediction of Epithelial Ovarian Cancer Disease Recurrence.
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卵巢癌细胞化疗耐药的细胞外囊泡传递与缺氧诱导的糖酵解途径蛋白表达相关，并预测上皮性卵巢癌疾病复发。
DOI：
10.3390/cancers13143388
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发表时间：
2021-07-06
期刊：
影响因子：
5.2
通讯作者：
Salomon C
中科院分区：
文献类型：
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作者：
Alharbi M;Lai A;Sharma S;Kalita-de Croft P;Godbole N;Campos A;Guanzon D;Salas-Burgos A;Carrion F;Zuñiga FA;Perrin L;He Y;Pejovic T;Winters C;Morgan T;Hooper JD;Rice GE;Salomon C
卵巢癌是影响全球女性的最致命的癌症之一。它的高死亡率通常被归因于疾病早期症状的非特异性。为了降低卵巢癌的死亡率，更好地了解疾病的进展和确定有助于临床治疗的临床有用的生物标志物是必不可少的。氧分压降低(即低氧)不仅是实体瘤的特征，而且可能通过诱导肿瘤生长促进因子的释放来增强肿瘤的转移能力。最近，有人提出小肿瘤来源的细胞外小泡(SEV)促进肿瘤的进展。在这项研究中，我们建立了在低氧压下产生的SEV诱导卵巢癌细胞的代谢转换，这与糖酵解途径蛋白的变化有关，该变化促进了对卡铂的耐药性。值得注意的是，我们确定了一套与SEV相关的糖酵解途径蛋白，这些蛋白存在于卵巢癌患者中，可以预测疾病复发的准确率超过90%。缺氧是癌症进展和化疗耐药的关键调节因素。癌细胞如何适应低氧微环境，并将致癌因子转移到周围细胞，仍然是一个模糊的问题。在这项研究中，我们确定了低氧对卵巢癌(OvCar)细胞系中SEV生物活性的影响。获得的数据表明，当暴露在低氧分压(1%氧气)下时，OvCar细胞会产生不同程度的铂耐药。使用定量质谱学(序列窗口获取所有理论碎片离子质谱图，SWATH)和靶向多反应监测(MRM)，我们鉴定了一组与糖酵解相关的蛋白质，这些蛋白质在细胞和SEV中在低氧条件下发生变化。有趣的是，我们在OvCar细胞系及其分泌的SEV中发现了对缺氧的不同反应，突显了细胞的异质性。蛋白质参与代谢重编程，如糖酵解，包括可能的己糖激酶(HK)、UDP-葡萄糖醛酸基转移酶1-6(UD16)和6-磷酸葡萄糖内酯酶(6-PGL)，它们的存在与铂耐药的诱导有关。此外，当常氧细胞暴露于来自低氧细胞的SEV时，对铂的抗性显著增加(p<；0.05)。化疗耐药性的改变与糖酵解和脂肪酸合成的变化有关。最后，从临床队列(n=31)分离的SEV也被发现富含糖酵解途径蛋白，特别是在复发性疾病患者中。这些数据支持这样的假设，即低氧导致SEV组成和生物活性的变化，从而使靶细胞对卡铂产生耐药。此外，我们认为SEV相关糖酵解途径蛋白的表达可以预测卵巢癌的复发，并在疾病治疗中具有临床应用价值。
Ovarian cancer is one of the most lethal cancers affecting women worldwide. Its high mortality rate is often attributed to the non-specific nature of early symptoms of the disease. Developing a better understanding of the disease progression and identifying clinically useful biomarkers that aid in clinical management are requisite to reducing the mortality rate of ovarian cancer. Reduced oxygen tension (i.e., hypoxia) is not only a characteristic of solid tumors but may also enhance the metastatic capacity of tumors by inducing the release of tumor growth promoting factors. Recently, it has been proposed that small tumor-derived extracellular vesicles (sEVs) facilitate cancer progression. In this study, we established that sEVs produced under low oxygen tension induce a metabolic switch in ovarian cancer cells associated with changes in glycolytic pathway proteins that promote resistance to carboplatin. Significantly, we identified a suite of sEV-associated glycolysis pathway proteins that are present in patients with ovarian cancer that can predict disease recurrence with over 90% accuracy. Hypoxia is a key regulator of cancer progression and chemoresistance. Ambiguity remains about how cancer cells adapt to hypoxic microenvironments and transfer oncogenic factors to surrounding cells. In this study, we determined the effects of hypoxia on the bioactivity of sEVs in a panel of ovarian cancer (OvCar) cell lines. The data obtained demonstrate a varying degree of platinum resistance induced in OvCar cells when exposed to low oxygen tension (1% oxygen). Using quantitative mass spectrometry (Sequential Window Acquisition of All Theoretical Fragment Ion Mass Spectra, SWATH) and targeted multiple reaction monitoring (MRM), we identified a suite of proteins associated with glycolysis that change under hypoxic conditions in cells and sEVs. Interestingly, we identified a differential response to hypoxia in the OvCar cell lines and their secreted sEVs, highlighting the cells’ heterogeneity. Proteins are involved in metabolic reprogramming such as glycolysis, including putative hexokinase (HK), UDP-glucuronosyltransferase 1–6 (UD16), and 6-phosphogluconolactonase (6 PGL), and their presence correlates with the induction of platinum resistance. Furthermore, when normoxic cells were exposed to sEVs from hypoxic cells, platinum-resistance increased significantly (p < 0.05). Altered chemoresistance was associated with changes in glycolysis and fatty acid synthesis. Finally, sEVs isolated from a clinical cohort (n = 31) were also found to be enriched in glycolysis-pathway proteins, especially in patients with recurrent disease. These data support the hypothesis that hypoxia induces changes in sEVs composition and bioactivity that confers carboplatin resistance on target cells. Furthermore, we propose that the expression of sEV-associated glycolysis-pathway proteins is predictive of ovarian cancer recurrence and is of clinical utility in disease management.
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影响因子：
--
作者：
Crow J;Atay S;Banskota S;Artale B;Schmitt S;Godwin AK
通讯作者：
Godwin AK
评估上皮性卵巢癌组织学亚型的遗传结构。
影响因子：
5.3
作者：
Cuellar-Partida G;Lu Y;Dixon SC;Australian Ovarian Cancer Study;Fasching PA;Hein A;Burghaus S;Beckmann MW;Lambrechts D;Van Nieuwenhuysen E;Vergote I;Vanderstichele A;Doherty JA;Rossing MA;Chang-Claude J;Rudolph A;Wang-Gohrke S;Goodman MT;Bogdanova N;Dörk T;Dürst M;Hillemanns P;Runnebaum IB;Antonenkova N;Butzow R;Leminen A;Nevanlinna H;Pelttari LM;Edwards RP;Kelley JL;Modugno F;Moysich KB;Ness RB;Cannioto R;Høgdall E;Høgdall C;Jensen A;Giles GG;Bruinsma F;Kjaer SK;Hildebrandt MA;Liang D;Lu KH;Wu X;Bisogna M;Dao F;Levine DA;Cramer DW;Terry KL;Tworoger SS;Stampfer M;Missmer S;Bjorge L;Salvesen HB;Kopperud RK;Bischof K;Aben KK;Kiemeney LA;Massuger LF;Brooks-Wilson A;Olson SH;McGuire V;Rothstein JH;Sieh W;Whittemore AS;Cook LS;Le ND;Blake Gilks C;Gronwald J;Jakubowska A;Lubiński J;Kluz T;Song H;Tyrer JP;Wentzensen N;Brinton L;Trabert B;Lissowska J;McLaughlin JR;Narod SA;Phelan C;Anton-Culver H;Ziogas A;Eccles D;Campbell I;Gayther SA;Gentry-Maharaj A;Menon U;Ramus SJ;Wu AH;Dansonka-Mieszkowska A;Kupryjanczyk J;Timorek A;Szafron L;Cunningham JM;Fridley BL;Winham SJ;Bandera EV;Poole EM;Morgan TK;Goode EL;Schildkraut JM;Pearce CL;Berchuck A;Pharoah PD;Webb PM;Chenevix-Trench G;Risch HA;MacGregor S
通讯作者：
MacGregor S
影响因子：
12.4
作者：
Fan, Jia;Wei, Qian;Hu, Ye
通讯作者：
Hu, Ye
影响因子：
6.6
作者：
Jacobsson, Hanna;Harrison, Hannah;Landberg, Goran
通讯作者：
Landberg, Goran
影响因子：
4.4
作者：
Guduric-Fuchs J;O'Connor A;Camp B;O'Neill CL;Medina RJ;Simpson DA
通讯作者：
Simpson DA