Periostin介导的口腔鳞癌干细胞淋巴结转移前微环境构建的机制研究

The interaction between Cancer stem cells(CSCs) and pre-metastatic niche play an important role in tumor metastasis. Recent studies confirmed that periostin may regulate CSCs stemness and metastasis. However, its roles and detailed mechanism on pre-metastatic niche formation remain unclear. Our previous studies showed that the expression of periostin in tumor microenviroment was associated with metastasis of oral squamous cell carcinoma(OSCC), and it was up-regulated in metastatic lymph node fibroblastic reticular cells(FRCs), contributing to increasing in number of CSCs and recruitment of bone marrow-derived cells. Based on these results, we concluded that periostin may mediate construction of lymph node pre-metastatic niche to promote tumor metastasis. This study aimed to investigate the effects of periostin on lymph node pre-metastatic niche construction, and the promotion of CSCs metastasis and stemness maintenance by cell sorting, molecular intervention and antibody micro-arrays. It is great significance to reveal the regulation mechanism of periostin mediated lymph node pre-metastatic niche construction and CSCs metastasis, which may further provide some valuable clues and theoretical basis on early prediction and targeted therapy on OSCC metastasis.

肿瘤干细胞（CSCs）与转移前微环境的相互作用是肿瘤转移的重要条件。研究证实肿瘤微环境中periostin对调控CSCs及促进转移发挥重要作用，但其在转移前微环境形成中的作用和机制尚不明确。课题组前期研究发现，肿瘤微环境中periostin与口腔鳞癌（OSCC）淋巴结转移相关，并在OSCC转移淋巴结纤维网状细胞FRCs中表达上调，可促使口腔鳞癌CSCs数量增加，并招募骨髓衍生性细胞浸润。我们推测，periostin介导了OSCC淋巴结转移前微环境的构建，进而促进CSCs转移。本研究拟通过细胞分选、分子干预、抗体芯片等手段，探究periostin介导的OSCC淋巴结转移前微环境的形成过程，并确证其对CSCs干性维持和趋化作用。本研究的意义在于揭示periostin介导的淋巴结转移前微环境与口腔鳞癌CSCs的相互调控关系和可能的机制，为口腔鳞癌转移早期预测及靶向治疗提供有价值的线索和实验依据。

淋巴结转移是口腔鳞癌（OSCC）治疗方案选择和影响预后的重要因素，肿瘤干细胞（CSCs）与淋巴结转移前微环境的相互作用是肿瘤转移的重要条件。本研究证实，口腔癌转移淋巴结中的纤维网状细胞（FRC)高表达配periostin （POSTN）蛋白。CD166+的口腔鳞癌干细胞分泌较多的TGFβ，从而促进引流淋巴结FRC细胞表达POSTN。 此外，共免疫沉淀（co-IP）实验表明，CAFs分泌的POSTN是PTK7的一个潜在上游配体，可能作为受体。我们发现PTK7与Wnt/β-Catenin通路和肿瘤侵袭性临床病理特征在头颈部鳞状细胞癌（HNSCC）中具有显著相关性。同时动物实验证明，PTK7能增强口腔鳞癌细胞的耐药性和实验性肺转移。此外，口腔鳞癌微环境中的POSTN与PTK7的相互作用，通过调控Wnt/β-catenin通路促进OSCC的生长和侵袭及肿瘤干细胞特性。另一方面，转移的口腔鳞癌外泌体中磷酸化的IFNGR1通过活化FRC细胞JAK-STAT1通路，从而调控淋巴结中MDSC和Treg细胞增多，促进引流淋巴结的免疫抑制环境构建。因此，口腔鳞癌POSTN和外泌体中磷酸化的IFNGR1可能成为口腔鳞癌转移的预警新指标，为口腔鳞癌转移的靶向治疗提供有临床应用价值的分子靶标。