Features of the cervicovaginal microenvironment drive cancer biomarker signatures in patients across cervical carcinogenesis
Features of the cervicovaginal microenvironment drive cancer biomarker signatures in patients across cervical carcinogenesis
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DOI：
10.1038/s41598-019-43849-5
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发表时间：
2019-05-14
影响因子：
4.6
通讯作者：
Herbst-Kralovetz, Melissa M.
中科院分区：
文献类型：
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作者：
Laniewski, Pawel;Cui, Haiyan;Herbst-Kralovetz, Melissa M.
持续性人乳头瘤病毒（HPV）感染是宫颈癌发生的重要因素;然而，局部宫颈阴道微环境（CVM）的其他特征可能在宫颈癌前病变和浸润性宫颈癌（ICC）的发展中起关键作用。在这里，我们研究了局部分泌的癌症生物标志物与局部CVM特征之间的关系，以更好地了解宿主，病毒和阴道微生物群（VMB）之间的复杂相互作用。我们招募了ICC、高级别和低级别鳞状上皮内病变以及HPV阳性和健康HPV阴性对照的女性。广泛的癌症生物标志物存在于局部CVM中，并且在ICC患者中特别升高。大多数癌症生物标志物与其他生物标志物呈正相关，并与生殖器炎症有关。几种癌症生物标志物也呈负相关，乳酸杆菌丰度和阴道pH值异常呈正相关。最后，癌症生物标志物和免疫介质的分层聚类分析显示三个患者集群，不同的癌症生物标志物，生殖器炎症，阴道pH值和VMB组成的水平。特定的癌症生物标志物区分具有CVM特征的患者，例如高度生殖器炎症，阴道pH值升高和微生态的非乳杆菌占优势的VMB，这些特征与HPV持续存在，发育不良和进展为ICC相关。
Persistent human papillomavirus (HPV) infection is the vital factor driving cervical carcinogenesis; however, other features of the local cervicovaginal microenvironment (CVM) may play a critical role in development of precancerous cervical dysplasia and progression to invasive cervical carcinoma (ICC). Here we investigated relationships between locally secreted cancer biomarkers and features of the local CVM to better understand the complex interplay between host, virus and vaginal microbiota (VMB). We enrolled women with ICC, high- and low-grade squamous intraepithelial lesions, as well as, HPV-positive and healthy HPV-negative controls. A broad range of cancer biomarkers was present in the local CVM and specifically elevated in ICC patients. The majority of cancer biomarkers were positively correlated to other biomarkers and linked to genital inflammation. Several cancer biomarkers were also negatively correlated to Lactobacillus abundance and positively correlated with abnormal vaginal pH. Finally, a hierarchical clustering analysis of cancer biomarkers and immune mediators revealed three patient clusters, which varied in levels of cancer biomarkers, genital inflammation, vaginal pH and VMB composition. Specific cancer biomarkers discriminated patients with features of the CVM, such as high genital inflammation, elevated vaginal pH and dysbiotic non-Lactobacillus-dominant VMB, that have been associated with HPV persistence, dysplasia and progression to ICC.