PDF(Pubmed)
Abstract：
Currently, there are no specific antiviral therapeutic approaches targeting Human papillomaviruses (HPVs), which cause around 5% of all human cancers. Specific antiviral reagents are particularly needed for HPV-related oropharyngeal cancers (HPV+OPCs) whose incidence is increasing and for which there are no early diagnostic tools available. We and others have demonstrated that the estrogen receptor alpha (ERalpha) is overexpressed in HPV+OPCs, compared to HPV-negative cancers in this region, and that these elevated levels are associated with an improved disease outcome. Utilizing this HPV+ specific overexpression profile, we previously demonstrated that estrogen attenuates the growth and cell viability of HPV+ keratinocytes and HPV+ cancer cells in vitro. Expansion of this work in vivo failed to replicate this sensitization. The role of stromal support from the tumor microenvironment (TME) has previously been tied to both the HPV lifecycle and in vivo therapeutic responses. Our investigations revealed that in vitro co-culture with fibroblasts attenuated HPV+ specific estrogen growth responses. Continuing to monopolize on the HPV+ specific overexpression of ERalpha, our co-culture models then assessed the suitability of the selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen, and showed growth attenuation in a variety of our models to one or both of these drugs in vitro. Utilization of these SERMs in vivo closely resembled the sensitization predicted by our co-culture models. Therefore, the in vitro fibroblast co-culture model better predicts in vivo responses. We propose that utilization of our co-culture in vitro model can accelerate cancer therapeutic drug discovery.
摘要：
目前,目前尚无针对人乳头瘤病毒（HPV）的特异性抗病毒治疗方法，这导致了大约5%的人类癌症。特定的抗病毒试剂对于HPV相关的口咽癌症(HPV+OPCs)是特别需要的,其发病率正在增加并且对于其没有可用的早期诊断工具。我们和其他人已经证明，雌激素受体α（ERα）在HPV+OPCs中过度表达，与该地区的HPV阴性癌症相比，这些升高的水平与改善的疾病结果有关。利用这种HPV+特异性过表达谱，我们以前证明雌激素在体外减弱HPV+角质形成细胞和HPV+癌细胞的生长和细胞活力.这项工作在体内的扩展未能复制这种致敏作用。来自肿瘤微环境(TME)的基质支持的作用先前已经与HPV生命周期和体内治疗反应两者相关联。我们的研究表明，与成纤维细胞的体外共培养减弱了HPV特异性雌激素生长反应。继续垄断HPV+特异性过表达ERα，然后，我们的共培养模型评估了选择性雌激素受体调节剂（SERM）的适用性，雷洛昔芬和他莫昔芬，并在我们的各种模型中显示出体外对这些药物中的一种或两种的生长减弱。这些SERM在体内的利用与我们的共培养模型预测的敏化非常相似。因此,体外成纤维细胞共培养模型更好地预测体内反应。我们建议利用我们的共培养体外模型可以加速癌症治疗药物的发现。
与人乳头瘤病毒相关的癌症（HPV+癌症）仍然是一个重大的公共卫生问题，和特定的临床方法是迫切需要的。在将药物反应数据从体外转化为体内时，相邻基质支持网络的成纤维细胞起关键作用。我们的研究提出了利用成纤维细胞2D共培养系统来更好地预测HPV+癌症的转化药物评估。我们还建议将这种共培养系统用于其他翻译方法。用共培养模型预测甚至一部分可能在体内失败的治疗范例将产生显著的时间。努力,资源，和成本效率。
与人乳头瘤病毒相关的癌症（HPV+癌症）仍然是一个重大的公共卫生问题，和特定的临床方法是迫切需要的。在将药物反应数据从体外转化为体内时，相邻基质支持网络的成纤维细胞起关键作用。我们的研究提出了利用成纤维细胞2D共培养系统来更好地预测HPV+癌症的转化药物评估。我们还建议将这种共培养系统用于其他翻译方法。用共培养模型预测甚至一部分可能在体内失败的治疗范例将产生显著的时间。努力,资源，和成本效率。
