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首页> 美国卫生研究院文献>Cancer Biology Therapy >A novel 3-dimensional culture system uncovers growth stimulatory actions by TGFβ in pancreatic cancer cells
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A novel 3-dimensional culture system uncovers growth stimulatory actions by TGFβ in pancreatic cancer cells

机译：一种新颖的三维培养系统揭示了TGFβ在胰腺癌细胞中的生长刺激作用

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Transforming Growth Factor-β (TGFβ) exerts cell type-specific and context-dependent effects. Understanding the intrinsic actions of TGFβ on cancer cells in pancreatic ductal adenocarcinoma (PDAC) is a prerequisite for rationalizing clinical implementation of TGFβ targeted therapies. Since the tumor microenvironment can affect how cancer cells respond to TGFβ, we employed a novel 3-dimensional (3D) culturing system to recapitulate stromal and extracellular matrix interactions. We show here that TGFβ stimulates the growth of several human and murine pancreatic cancer cell lines (PCCs) when embedded in a 3% collagen IV/laminin-rich gelatinous medium (Matrigel™) over a solidified layer of soft agar. Moreover, in this novel 3D model, concomitant treatment with TGFβ1 and epidermal growth factor (EGF) enhanced PCC growth to a greater extent than either growth factor alone and conferred increased chemoresistance to cytotoxic compounds. These cooperative growth-stimulatory effects were blocked by pharmacological inhibition of either the TGFβ type I receptor with SB431542 or the EGF receptor with erlotinib. Co-incubation with SB431542 and erlotinib enhanced the efficacy of gemcitabine and cisplatin in PCCs and in primary cell cultures established from pancreata of genetically-engineered mouse models of PDAC. These findings suggest that concomitant inhibition of TGFβ and EGF signaling may represent an effective therapeutic strategy in PDAC, and that this 3D culturing system could be utilized to test ex vivo the therapeutic response of pancreatic tumor biopsies from PDAC patients, thereby providing a functional assay to facilitate personalized targeted therapies.
机译：转化生长因子-β（TGFβ）发挥细胞类型特异性和背景依赖性的作用。了解TGFβ对胰腺导管腺癌（PDAC）癌细胞的内在作用是合理化TGFβ靶向疗法临床应用的先决条件。由于肿瘤微环境会影响癌细胞对TGFβ的反应，因此我们采用了新颖的3D（3D）培养系统来概括基质和细胞外基质的相互作用。我们在此显示，当将TGFβ嵌入3％胶原IV /富含层粘连蛋白的凝胶状培养基（Matrigel™）覆盖在软琼脂的凝固层上时，它会刺激几种人类和鼠类胰腺癌细胞系（PCC）的生长。此外，在这个新颖的3D模型中，与单独使用任一生长因子相比，与TGFβ1和表皮生长因子（EGF）一起进行的治疗在更大程度上增强了PCC的生长，并增强了对细胞毒性化合物的化学耐药性。这些协同的生长刺激作用被药理学抑制的SB431542的TGFβI型受体或厄洛替尼的EGF受体抑制。与SB431542和厄洛替尼共同孵育可增强吉西他滨和顺铂在PCC和从PDAC基因工程小鼠模型的胰腺建立的原代细胞培养物中的功效。这些发现表明，同时抑制TGFβ和EGF信号可能代表PDAC的有效治疗策略，并且该3D培养系统可用于离体测试PDAC患者胰腺肿瘤活检的治疗反应，从而为促进个性化靶向治疗。

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