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首頁> 外文學(xué)位 >Development of Novel Microfluidic-Based Pancreaticcancer-On-A-Chip Models =Entwicklung von neuartigen mikrofluiden Organ-on-a-Chip Modellen für die Behandlung von Bauchspeicheldrüsenkrebs
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Development of Novel Microfluidic-Based Pancreaticcancer-On-A-Chip Models =Entwicklung von neuartigen mikrofluiden Organ-on-a-Chip Modellen für die Behandlung von Bauchspeicheldrüsenkrebs

機(jī)譯：基于微流控的新型胰腺癌芯片模型的開發(fā) =開發(fā)用于治療胰腺癌的新型微流控器官芯片模型

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摘要

Pancreatic Ductal Adenocarcinoma (PDAC) shows mortality rates of up to 93%, as it is often detected at a late stage. Only 20% of the tumors are resectable, and therefore 80% of cases must be treated with either chemotherapeutics or immunotherapies. Nevertheless, chemotherapies usually only prolong the patient`s life for a few months and immunotherapies remain ineffective. The high-density stroma, which induces hypoxic conditions and high interstitial pressure, plays a major role in treatment resistance. These factors impact carcinogenesis and support the formation of an immunosuppressive microenvironment. Current platforms used to study PDAC often lack important features of the complex in vivo situation. Models, that incorporate stromal elements, including pancreatic stellate cells (PSCs), extracellular matrix (ECM), and immune cells, as well as in vivo like culture conditions are urgently needed to study these treatments and the potential causes of failures. Here, a model for testing chemotherapy treatment on PDAC organoids including PSCs as stromal compartment and hypoxia was established. The cells were subjected to Gemcitabine in combination with compounds targeting specific pathways under normoxic and hypoxic conditions. Gene expression analysis revealed different genetic programs of cells grown in the two oxygen conditions, that could explain treatment specific responses. Two groups of treatment responders were identified, showing either a better effect in monoculture or co-culture and between normoxia and hypoxia. In addition, the challenge of the different culture setups with Hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) inhibitor led to a significant increase in cell survival. This study highlights the importance of adjusting experimental conditions to in vivo like conditions and thus to include relevant oxygen levels. Moreover, it also indicates the relevance of direct HIF inhibitors or PHD enhancers as single or combination treatment for PDAC patients, that could be used in the future.In addition, to gain new insights about the effects of the complex tumor microenvironment (TME) in PDAC, a new model was created. This was employed to investigate the role of the endothelium and the stroma in immune migration as well as applying the model as a screening platform for stromal targeting as a potential treatment strategy. Within one model, immune cells attached to the endothelial tube, extravasated from the vessel to the stroma, and migrated towards the tumor cells. The role of the stroma could be divided into a physical barrier, that shields the cancer cells from migrating immune cells, as well as a biochemical barrier, leading to attraction of immune cells towards PSCs.This thesis focuses on the establishment and application of PDAC-on-a chip models to recreate the TME and its influence on treatment responses. These 3D tumor models could be used for both, fundamental as well as preclinical research.
機(jī)譯：胰腺導(dǎo)管腺癌 （PDAC） 的死亡率高達(dá) 93%，因?yàn)樗ǔＴ谕砥诒话l(fā)現(xiàn)。只有 20% 的腫瘤是可切除的，因此 80% 的病例必須接受化療或免疫療法治療。然而，化療通常只能將患者的生命延長幾個月，免疫療法仍然無效。誘導(dǎo)低氧條件和高間質(zhì)壓的高密度基質(zhì)在治療耐藥性中起主要作用。這些因素影響致癌作用并支持免疫抑制微環(huán)境的形成。當(dāng)前用于研究 PDAC 的平臺通常缺乏復(fù)雜體內(nèi)情況的重要特征。迫切需要包含基質(zhì)元件的模型，包括胰腺星狀細(xì)胞 （PSC）、細(xì)胞外基質(zhì) （ECM） 和免疫細(xì)胞，以及類似體內(nèi)的培養(yǎng)條件，以研究這些治療方法和失敗的潛在原因。在這里，建立了一個在 PDAC 類器官上測試化療治療的模型，包括 PSC 作為基質(zhì)隔室和缺氧。在常氧和低氧條件下，將細(xì)胞與靶向特定通路的化合物聯(lián)合使用吉西他濱?；虮磉_(dá)分析揭示了在兩種氧氣條件下生長的細(xì)胞的不同遺傳程序，這可以解釋治療特異性反應(yīng)。確定了兩組治療反應(yīng)者，在單一培養(yǎng)或共培養(yǎng)以及常氧和缺氧之間顯示出更好的效果。此外，低氧誘導(dǎo)因子 （HIF） 脯氨酰羥化酶 （PHD） 抑制劑對不同培養(yǎng)設(shè)置的挑戰(zhàn)導(dǎo)致細(xì)胞存活率顯著提高。這項(xiàng)研究強(qiáng)調(diào)了將實(shí)驗(yàn)條件調(diào)整為體內(nèi)類似條件的重要性，從而包括相關(guān)的氧水平。此外，它還表明直接 HIF 抑制劑或 PHD 增強(qiáng)劑作為 PDAC 患者單藥或聯(lián)合治療的相關(guān)性，將來可能會使用。此外，為了獲得有關(guān) PDAC 中復(fù)雜腫瘤微環(huán)境 （TME） 影響的新見解，創(chuàng)建了一個新模型。這被用于研究內(nèi)皮細(xì)胞和基質(zhì)在免疫遷移中的作用，以及將該模型用作基質(zhì)靶向的篩選平臺作為潛在的治療策略。在一個模型中，免疫細(xì)胞附著在內(nèi)皮管上，從血管外滲到基質(zhì)，并向腫瘤細(xì)胞遷移?；|(zhì)的作用可以分為物理屏障，保護(hù)癌細(xì)胞免受免疫細(xì)胞遷移，以及生化屏障，導(dǎo)致免疫細(xì)胞被吸引到 PSCs。這些 3D 腫瘤模型可用于基礎(chǔ)和臨床前研究。

著錄項(xiàng)

  • 作者

    Geyer, Marlene.;

  • 作者單位

    Friedrich-Alexander-Universitaet Erlangen-Nuernberg (Germany).;

    Friedrich-Alexander-Universitaet Erlangen-Nuernberg (Germany).;

    Friedrich-Alexander-Universitaet Erlangen-Nuernberg (Germany).;

  • 授予單位 Friedrich-Alexander-Universitaet Erlangen-Nuernberg (Germany).;Friedrich-Alexander-Universitaet Erlangen-Nuernberg (Germany).;Friedrich-Alexander-Universitaet Erlangen-Nuernberg (Germany).;
  • 學(xué)科 Tumor necrosis factor-TNF.;Epidermal growth factor.;Vascular endothelial growth factor.
  • 學(xué)位
  • 年度 2023
  • 頁碼 117
  • 總頁數(shù) 117
  • 原文格式 PDF
  • 正文語種 eng
  • 中圖分類
  • 關(guān)鍵詞

    Tumor necrosis factor-TNF.; Epidermal growth factor.; Vascular endothelial growth factor.;

    機(jī)譯：腫瘤壞死因子-TNF.;表皮生長因子。;血管內(nèi)皮生長因子。;
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