原发灶-靶器官氧分压动态变化调控涎腺腺样囊性癌播散肿瘤细胞休眠和远处转移的分子机制

Tumor dormancy has been defined as the leading cause of late recurrence and metastasis after removing the primary tumor. Late metastatic lesions mainly develop from disseminated tumor cells (DTCs) that can remain dormant. Recently, it is shown that the distant tumor microenvironment, as well as the primary tumor, can regulate the transition of DTCs into a dormant phenotype with the ability to outgrowth as recurrent disease. And, in contrast to hypoxia in primary tumor, the high oxygen pressure of lung tissue plays an important role in leading to eruption of metastatic disease. Thus, owing to these evidences and our previous data of the relationship between hypoxia and the metastasis of salivary adenoid cystic carcinoma (SACC), we hypothesize that the oxygen pressure dynamic change of primary and second lesions may regulate the dormancy and distant metastasis of DTCs in SACC. In this project, we will discuss how hypoxia microenvironment of the primary tumor induces the product of DTCs with dormancy in the distant lesion, elucidate the cell-intrinsic programs that maintain the latent state of DTCs and explore the influence of the high oxygen pressure of lung tissue on shifting DTCs into a state of eruption from a state of dormancy. The resolve of the mechanism of the dynamic oxygen pressure of primary and second lesions regulating the dormancy and distant metastasis of DTCs may elucidate the clinical characteristic of SACC with the nice short-prognosis and bad distant-prognosis, provide new theory with elucidating or maintaining tumor dormancy cells and keep patients alive, and yield a novel therapeutic strategy to the medication prevention of SACC metastasis in the future.

肿瘤休眠是原发肿瘤切除后延迟复发和转移的根源，播散肿瘤细胞（DTCs）是肿瘤休眠的关键细胞。研究显示：不仅靶器官微环境可调控DTCs休眠，而且原发灶微环境就可决定靶器官DTCs休眠命运。更为重要的是，与原发灶缺氧相反，肺内氧分压的增高在转移灶形成中可能发挥重要作用。基于此，本课题在原有研究缺氧与涎腺腺样囊性癌（SACC）转移关系基础上，提出假设：原发灶-转移靶器官氧分压动态变化在调控SACC的 DTCs休眠和激活中发挥重要作用。围绕此假设，拟从原发灶缺氧诱导SACC产生在靶器官具有休眠特性DTCs的固有分子程序、DTCs休眠状态维持和存活、靶器官氧分压微环境调控DTCs细胞休眠向增殖转换三个层面，研究原发灶和靶器官氧分压动态改变协同调控SACC的DTCs休眠和转移的分子机制，结果将为阐明SACC近期预后好而远期生存率低的生物学特性、为消灭或长期维持肿瘤休眠实现SACC长期生存提供理论基础。

肿瘤休眠是原发肿瘤切除后延迟复发和转移的根源，播散肿瘤细胞（DTCs）是肿瘤休眠的关键细胞。研究显示：不仅靶器官微环境可调控DTCs休眠，而且原发灶微环境就可决定靶器官DTCs休眠命运。更为重要的是，与原发灶缺氧相反，肺内氧分压的增高在转移灶形成中可能发挥重要作用。基于此，本课题在原有研究缺氧与涎腺腺样囊性癌（SACC）转移关系基础上，研究氧分压动态变化在调控SACC的 DTCs休眠和激活中发挥重要作用。结果显示：缺氧微环境能够诱导涎腺腺样囊性癌细胞休眠，其作用效果与CoCl2作用相类似；NR2F1是涎腺腺样囊性癌休眠的重要标记物，CXCL12/CXCR4信号通路是NR2F1促进腺样囊性癌休眠的重要分子机制；DEC1/DEC2是涎腺腺样囊性癌休眠的重要标记物。结果将为阐明SACC近期预后好而远期生存率低的生物学特性、为消灭或长期维持肿瘤休眠实现SACC长期生存提供理论基础。