Stromal fibroblasts are predictors of disease-related mortality in esophageal squamous cell carcinoma.
Stromal fibroblasts are predictors of disease-related mortality in esophageal squamous cell carcinoma.
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DOI：
10.3892/or.2014.3216
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发表时间：
2014-07
期刊：
影响因子：
4.2
通讯作者：
Shin Saito;K. Morishima;T. Ui;D. Matsubara;Tomoko Tamura;S. Oguni;Y. Hosoya;N. Sata;A. Lefor;Y. Yasuda;T. Niki
中科院分区：
文献类型：
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作者：
Shin Saito;K. Morishima;T. Ui;D. Matsubara;Tomoko Tamura;S. Oguni;Y. Hosoya;N. Sata;A. Lefor;Y. Yasuda;T. Niki
人类癌症的生长、侵袭和转移不仅由癌细胞决定，还由其微环境决定。活化的间质成纤维细胞通过分泌生长因子促进肿瘤进展。在本研究中，我们专注于肿瘤和成纤维细胞，肿瘤间质的主要成分之间的相互关系。我们回顾性分析了97例食管鳞状细胞癌（ESCC）患者的死亡率与临床、病理和α-平滑肌肌动蛋白（α-SMA）特征的关系。在体外，我们使用TE-11，KYSE 150和KYSE 220 ESCC细胞系和分离的食管基质成纤维细胞，其中一些是永生化的。进行迁移测定以评估成纤维细胞对癌细胞迁移和三维器官型培养物的影响。在体内，TE-11和KYSE 220细胞加上永生化成纤维细胞共移植到Nod/Scid小鼠皮下，以评估成纤维细胞对致瘤性的影响。临床病理学上，癌间质α-SMA表达与静脉浸润（p<0.01）、淋巴结受累（p=0.02）、复发（p=0.01）相关，并且是I期和II期ESCC患者生存率的预测因子（p=0.04）。在体外，成纤维细胞的存在强烈促进TE-11，KYSE 150和KYSE 220细胞的迁移。在器官型培养中，只有在永生化成纤维细胞存在的情况下才观察到间质浸润。在体内，肿瘤在植入后以成纤维细胞依赖的方式发展或生长。我们的研究结果提供了间质成纤维细胞和肿瘤细胞相互作用促进ESCC肿瘤进展的证据。在早期ESCC患者中，α-SMA可能是死亡率的预测因子。抑制与肿瘤成纤维细胞相关的旁分泌系统可能会减缓或逆转肿瘤进展，可能导致新的靶向治疗的发展。
The growth, invasiveness and metastasis of human cancers are determined not only by cancer cells, but also by their microenvironment. Activated stromal fibroblasts promote tumor progression by secreting growth factors. In the present study, we focused on interrelations between cancer and fibroblasts, the main component of tumor stroma. We retrospectively analyzed the relations of mortality to clinical, pathological, and α-smooth muscle actin (α-SMA) characteristics in 97 consecutive patients with esophageal squamous cell carcinoma (ESCC). In vitro, we used TE-11, KYSE150 and KYSE220 ESCC cell lines and isolated esophageal stromal fibroblasts, some of which were immortalized. Migration assays were conducted to assess the effects of fibroblasts on cancer-cell migration and 3-dimensional organotypic cultures. In vivo, TE-11 and KYSE220 cells plus immortalized fibroblasts were co-transplanted subcutaneously in Nod/Scid mice to assess the effects of fibroblasts on tumorigenicity. Clinicopathologically, the α-SMA expression of cancer stroma was correlated with venous invasion (p<0.01), nodal involvement (p=0.02), recurrence (p=0.01), and was a predictor of survival in patients with stage I and II ESCC (p=0.04). In vitro, the presence of fibroblasts strongly promoted the migration of TE-11, KYSE150 and KYSE220 cells. On organotypic culture, stromal invasion was observed only in the presence of immortalized fibroblasts. In vivo, tumors developed or grew in a fibroblast‑dependent manner after implantation. Our findings provide evidence that stromal fibroblasts and tumor cells interact to promote tumor progression in ESCC. In patients with earlier stage ESCC, α-SMA may be a predictor of mortality. Inhibition of paracrine systems associated with tumor fibroblasts may slow or reverse tumor progression, potentially leading to the development of new targeted therapies.