De Pradip, Aske Jennifer Carlson, Dale Adam, Rojas Espaillat Luis, Starks David, Dey Nandini
Translational Oncology Laboratory, Avera Cancer Institute Sioux Falls, SD 57105, USA.
Division of Gynecological Oncology, Avera Cancer Institute Sioux Falls, SD 57105, USA.
Am J Transl Res. 2021 Nov 15;13(11):12168-12180. eCollection 2021.
The WNT-beta-catenin pathway (WP) is one of the major oncogenic pathways in solid tumors. Wnt beta-catenin pathway plays a unique role in a wide range of endometrial dysfunctions, from embryo implantation failure to severe pathogenic changes like endometriosis and endometrial cancer. Although abnormal activation of the pathway has long been known to be associated with endometrial tumorigenesis, the pathway's exact mode of involvement remains to be understood. As more evidence has been presented in favor of a crucial role of the WP in solid tumors, including endometrial cancer, anti-WP drugs are currently being tested to manage the disease. Aggressive tumor cells are nurtured by the tumor microenvironment (TME). The genetic alterations within tumor cells are the primary driving force to activate the extra-tumoral micro-environment. TME (a) provides metabolic support for the proliferation of tumor cells, (b) orchestrates immune-evasion, (c) initiates mechanistic signaling for several metastasis-associated phenotypes, and (d) supports cellular events for the development of drug resistance. To get metabolic as well as immune support from the tumor microenvironment, tumor cells cross-talk with components of the TME, most critically to the cancer-associated fibroblasts. Thus it is expected that the tumor-TME cross-talk throughout the process of tumorigenesis and metastasis is one of the characteristic features of an aggressive tumor. Here we review the WP's mechanistic involvement as a common culprit () in endometrial tumor cells and endometrial cancer-associated fibroblast (CAF). In this review, we have attempted to discuss the activation of the WP in the genesis and progression of endometrial cancers, including endometrial tumor biology, tumor microenvironment, cancer-associated fibroblasts, and wnt-beta catenin genetic alteration. We interrogated the available literature on the various aspects of endometrial carcinogenesis leading to the pathway's activation. We examined how genetic alterations in WP directly influence tumor cell signaling to bring out different tumor cell phenotypes, and present palpable evidence to envision a role of WP inhibitors in the future management of the disease.
WNT-β-连环蛋白通路（WP）是实体瘤中的主要致癌通路之一。Wnt-β-连环蛋白通路在多种子宫内膜功能障碍中发挥独特作用，从胚胎着床失败到诸如子宫内膜异位症和子宫内膜癌等严重病变。尽管长期以来已知该通路的异常激活与子宫内膜肿瘤发生有关，但其确切参与模式仍有待了解。随着越来越多的证据表明WP在包括子宫内膜癌在内的实体瘤中起关键作用，目前正在测试抗WP药物来治疗该疾病。侵袭性肿瘤细胞由肿瘤微环境（TME）滋养。肿瘤细胞内的基因改变是激活肿瘤外微环境的主要驱动力。TME（a）为肿瘤细胞增殖提供代谢支持，（b）协调免疫逃逸，（c）启动多种转移相关表型的机制信号，以及（d）支持耐药性发展的细胞事件。为了从肿瘤微环境中获得代谢和免疫支持，肿瘤细胞与TME的成分相互作用，最关键的是与癌症相关成纤维细胞相互作用。因此，预计在肿瘤发生和转移的整个过程中肿瘤与TME的相互作用是侵袭性肿瘤的特征之一。在这里，我们综述了WP作为子宫内膜肿瘤细胞和子宫内膜癌相关成纤维细胞（CAF）中常见罪魁祸首的机制参与情况。在本综述中，我们试图讨论WP在子宫内膜癌发生和进展中的激活情况，包括子宫内膜肿瘤生物学、肿瘤微环境、癌症相关成纤维细胞和wnt-β-连环蛋白基因改变。我们审视了关于导致该通路激活的子宫内膜癌发生各个方面的现有文献。我们研究了WP中的基因改变如何直接影响肿瘤细胞信号传导以产生不同的肿瘤细胞表型，并提供切实证据以设想WP抑制剂在该疾病未来治疗中的作用。
