HPV associated tumor cells control tumor microenvironment and leukocytosis in experimental models.
HPV associated tumor cells control tumor microenvironment and leukocytosis in experimental models.
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DOI：
10.1002/iid3.21
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发表时间：
2014-08
影响因子：
3.2
通讯作者：
Lepique, Ana Paula
中科院分区：
文献类型：
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作者：
Stone, Simone Cardozo;Rossetti, Renata Ariza Marques;Lima, Aleida Maria;Lepique, Ana Paula
人乳头瘤病毒（HPV）是宫颈癌的主要致病因子。HPV也与其他肛门生殖器和口咽肿瘤有关。HPV相关的肿瘤是常见的，构成了一个公共卫生问题，主要是在发展中国家。治疗这种肿瘤通常是切除，造成医源性发病率。因此，需要开发新疗法的策略。肿瘤微环境对于肿瘤生长是必不可少的，其中炎症是重要的组成部分，在肿瘤进展中发挥核心作用。炎症可能是一种致病因子，抑制抗肿瘤T细胞反应，或可能在血管生成，耐药性和转移中发挥作用。这项工作的目的是研究HPV转化细胞在肿瘤微环境中的作用以及肿瘤对宿主淋巴器官中髓系细胞群的影响。我们使用了实验模型，其中我们将宫颈癌衍生的细胞系注射到免疫缺陷小鼠中，比较HPV阳性SiHa和HeLa细胞（分别为HPV 16和HPV 18）与HPV阴性细胞系C33 A。我们的数据表明，HPV阳性细胞系比HPV阴性细胞系更有效地将白细胞募集到肿瘤微环境中，并增加骨髓和脾脏中的骨髓细胞增殖。我们还观察到HPV阳性细胞系表达显著更高水平的IL-6和IL-8，而C33 A表达显著更高水平的IL-16和IL-17。最后，尽管肿瘤细胞分泌细胞因子，但浸润SiHa和HeLa肿瘤的白细胞显示几乎可忽略的STAT 3和无NFκB磷酸化。只有C33 A肿瘤的炎性浸润中有NFκB和STAT 3激活的亚型。我们的研究结果表明，虽然来自相同的解剖部位，子宫颈，这些细胞系显示出重要的差异炎症。这些结果对于设计针对宫颈癌的免疫疗法以及可能针对其他解剖部位中的HPV相关肿瘤的免疫疗法是重要的。
Human papillomavirus (HPV) is the main etiological factor for cervical cancer development. HPV is also associated with other anogenital and oropharyngeal tumors. HPV associated tumors are frequent and constitute a public health problem, mainly in developing countries. Therapy against such tumors is usually excisional, causing iatrogenic morbidity. Therefore, development of strategies for new therapies is desirable. The tumor microenvironment is essential for tumor growth, where inflammation is an important component, displaying a central role in tumor progression. Inflammation may be a causal agent, suppressor of anti-tumor T cell responses, or may have a role in angiogenesis, drug resistance, and metastasis. The aim of this work was to investigate the role of HPV transformed cells in the tumor microenvironment and tumor effects on myeloid populations in lymphoid organs in the host. We used experimental models, where we injected cervical cancer derived cell lines in immunodeficient mice, comparing HPV positive, SiHa, and HeLa cells (HPV 16 and HPV18, respectively), with HPV negative cell line, C33A. Our data shows that HPV positive cell lines were more efficient than the HPV negative cell line in leukocyte recruitment to the tumor microenvironment and increase in myeloid cell proliferation in the bone marrow and spleen. We also observed that HPV positive cells lines expressed significantly higher levels of IL-6 and IL-8, while C33A expressed significantly higher levels of IL-16 and IL-17. Finally, in spite of cytokine secretion by tumor cells, leukocytes infiltrating SiHa and HeLa tumors displayed almost negligible STAT3 and no NFκB phosphorylation. Only the inflammatory infiltrate of C33A tumors had NFκB and STAT3 activated isoforms. Our results indicate that, although from the same anatomical site, the uterine cervix, these cell lines display important differences regarding inflammation. These results are important for the design of immunotherapies against cervical cancer, and possibly against HPV associated tumors in other anatomical sites.