Leukemia inhibitory factor produced by fibroblasts within tumor stroma participates in invasion of oral squamous cell carcinoma.
Leukemia inhibitory factor produced by fibroblasts within tumor stroma participates in invasion of oral squamous cell carcinoma.
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DOI：
10.1371/journal.pone.0191865
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Kayamori K
中科院分区：
文献类型：
--
作者：
Ohata Y;Tsuchiya M;Hirai H;Yamaguchi S;Akashi T;Sakamoto K;Yamaguchi A;Ikeda T;Kayamori K
在包括口腔癌在内的多种恶性肿瘤中，癌细胞与癌间质的相互作用在肿瘤的进展和转移中起着至关重要的作用。然而，这种相互作用的机制仍未完全阐明。在这里，为了研究口腔癌细胞和成纤维细胞之间的相互作用，成纤维细胞是肿瘤间质的主要细胞成分，我们利用人口腔鳞状细胞癌(OSCC)细胞系和正常人皮肤成纤维细胞(NHDF)进行了体外研究。Transwell实验结果显示，与NHDF共培养后，口腔鳞癌HO1-N-1和HSC3细胞的迁移和侵袭能力明显增强。为了研究促进肿瘤侵袭的因素，我们从与HO1-N-1细胞共培养的细胞中分离出NHDF，并进行了基因芯片分析。在上调的各种基因中，我们鉴定了编码白血病抑制因子(LIF)的基因，并在进一步的分析中重点研究了LIF。我们证实了所有OSCC来源的条件培养液都能有效地上调NHDF中LIF的表达，Transwell分析的结果表明，LIF中和抗体抑制了NHDF诱导的OSCC迁移和侵袭。此外，免疫组织化学分析显示，112例口腔鳞癌患者中有44例LIF在肿瘤间质中表达，尤其是在癌相关成纤维细胞(CAF)中，值得注意的是，临床病理分析证实CAF中LIF的表达与肿瘤侵袭深度显著相关。总之，我们的结果提示口腔鳞状细胞癌刺激成纤维细胞产生LIF，进而参与癌细胞的侵袭。我们的发现为口腔鳞癌患者的治疗提供了一种潜在的针对肿瘤间质的治疗策略。
The interaction between cancer cells and the cancer stroma plays a crucial role in tumor progression and metastasis in diverse malignancies, including oral cancer. However, the mechanism underlying this interaction remains incompletely elucidated. Here, to investigate the interaction between oral cancer cells and fibroblasts, which are major cellular components of the tumor stroma, we conducted an in vitro study by using human oral squamous cell carcinoma (OSCC) cell lines and normal human dermal fibroblasts (NHDFs). The results of transwell assays revealed that the migration and invasion of 2 OSCC cell lines, HO1-N-1 and HSC3, were markedly stimulated upon coculturing with NHDFs. To investigate the factors that promote tumor invasion, we isolated NHDFs from cocultures prepared with HO1-N-1 cells and performed microarray analysis. Among the various genes that were upregulated, we identified the gene encoding leukemia inhibitory factor (LIF), and we focused on LIF in further analyses. We confirmed that all OSCC-derived conditioned media potently upregulated LIF expression in NHDFs, and the results of our transwell analysis demonstrated that NHDF-induced OSCC migration and invasion were inhibited by LIF-neutralizing antibodies. Furthermore, immunohistochemical analysis of patient samples revealed that in 44 out of 112 OSCC cases, LIF was expressed in the tumor stroma, particularly in cancer-associated fibroblasts (CAFs), and, notably, clinicopathological analyses confirmed that LIF expression in CAFs was significantly correlated with increased depth of tumor invasion. Collectively, our results suggest that OSCC stimulates fibroblasts to produce LIF, which, in turn, participates in cancer-cell invasion. Our finding offers a potential therapeutic strategy targeting the cancer stroma for the treatment of OSCC patients.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
3.7
作者：
Fullar, Alexandra;Kovalszky, Ilona;Bitsche, Mario;Romani, Angela;Schartinger, Volker Hans;Sprinzl, Georg Mathias;Riechelmann, Herbert;Dudas, Jozsef
通讯作者：
Dudas, Jozsef
食管鳞状细胞癌中癌症相关成纤维细胞的预后意义。
影响因子：
3.7
作者：
Ha SY;Yeo SY;Xuan YH;Kim SH
通讯作者：
Kim SH
影响因子：
8.8
作者：
Nagasaki, T.;Hara, M.;Nakanishi, H.;Takahashi, H.;Sato, M.;Takeyama, H.
通讯作者：
Takeyama, H.
影响因子：
8.8
作者：
Dhanda J;Triantafyllou A;Liloglou T;Kalirai H;Lloyd B;Hanlon R;Shaw RJ;Sibson DR;Risk JM
通讯作者：
Risk JM