Addressing activation of WNT beta-catenin pathway in diverse landscape of endometrial carcinogenesis.

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 (Un Colpevole Comune) 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. AJTR