Tumor cells are engaged to CAF via the paracrine/juxtacrine mode and vice versa 
. The mode of signal transduction between CAF and tumor cells has been referred to as the “Language of Cross-Talk”, and how the cross-talk is involved or initiates different functions in the tumor cell has been referred to as the “Agenda of Cross-Talk”. The agendas of the cross-talk are: (1) growth, (2) proliferation, (3) metastasis-associated phenotypes, (4) metabolic reprogramming, and (5) immunological reprogramming. Most studies have been conducted on the effect of the CAF-tumor cell interaction in mediating the growth and proliferation of endometrial tumor cells. Interestingly, most of the CAF-mediated growth involved estrogen signaling via CAF secretome. In contrast, functions like metastasis-associated phenotypes, EMT, progression, and stemness were mediated via transcriptional regulation of genes, exosomes, and miRNAs. Although the studies on metabolic and immunologic reprogramming are limited in the current time in endometrial cancers, future work will identify the precise nature of this cross-talk. The details of CAF’s influence on different features of endometrial tumor cells have been presented in the review.
7. CAF Influencing Proliferation and Growth of Tumor Cells in Endometrial Cancers
Role of CAF in "Steroid-Driven Proliferation of Endometrial Tumor Cells" and "Non-Steroidal Proliferation of Endometrial Tumor Cells" are presented in the review.
8. CAF Influencing Metastasis-Associated Phenotypes of Tumor Cells in Endometrial Cancers
Role of CAF in "Matrix Organization & Stromal Architecture", "EMT", and "Migration, Invasion, and Metastatic Progression" are presented in the review.
9. CAF Influencing Immune-Defense of the Host and Immune-Surveillance of Tumor Cells by the Host in Endometrial Cancers
Role of CAF in "immune reprogramming" are presented in the review.
Here we presented the functional characteristics of CAF in the context of their origin. We reviewed the nature of CAF’s involvement in regulating growth and several phenotypes of tumor cells involving different oncogenic pathways. Thus, we interrogated the functional characteristics of CAF in the light of its dialogue with tumor cells and other components of
TME towards developing a precision strategy of CAF-based therapy in solid tumors with particular reference to endometrial cancers.
A critical review of the subject at hand reveals two apparent facts in the context of CAF-tumor cell cross-talk in endometrial cancers. First, the literature for CAF is limited in endometrial cancers. Although a significant body of literature exists on the function of CAF and their deterministic role in shaping the disease progression in different solid tumors, like PDAC, breast cancers, lung cancers, colorectal cancers, and prostate cancers,
the literature is limited for gynecological cancers, especially endometrial cancers. The insufficiency of data can be partly attributed to the impossibility of obtaining longitudinal sampling of the same lesion throughout the disease progression or during treatment to study a real-time conversion between two states of CAF, benevolent and malevolent, as well as their co-evolution with the tumor cells. The scope of repeat biopsy remains limited in the endometrial tumors, as so in many other cases of solid tumors. Second, considering the undeniable role of CAF in progression and drug resistance, the two most critical deterministic factors in the clinical management of a disease, it is puzzling why a CAF-based
therapy has not evolved even in other solid tumors, where much more information exists. That brings us to the current state of the puzzle in CAF research. Literature from 1966–2021 favors the school of thought that CAFs are benevolent in suppressing the development of cancers [82,83]. It was demonstrated 50 years ago that normal fibroblasts inhibit the growth of polyoma virus-transformed cells . Thus, it is argued that during the initial phase of tumorigenesis, the CAF, in its presumably inactivated state, may not be supportive to the growth of tumor cells. Conspicuously, CAF in its activated form is not the same in effecting tumor growth and progression, keeping the debate in favor or against CAF (good-CAF versus bad-CAF) inconclusive and wide open even in the most studied solid tumors, wherein the contribution of stromal CAF is undeniable, including PDAC and breast cancers [3,4,14,22,84–86]. The malevolent transformation of CAF later is believed to be mediated through a number of tumor cell-initiated factors, immunogenic factors, and the physicochemical properties of stroma. In order to conclusively establish CAF as a target for a treatment, we need to establish definitive markers for good-CAF, which are mutually exclusive from the markers of bad-CAF, representing two distinct populations contextually connected to distinct clinical outcomes. To this end, a report by Mizutani et al. identified a Meflin-positive CAF in PDAC, which represented a cancer-restraining
population. Their data suggested that Meflin is a marker of cancer-restraining CAFs that suppress progression in PDAC [87,88]. Future studies may identify the presence of such markers in solid tumors, including endometrial cancers, and confirm their role in targeting such markers towards managing the disease.
From the interrogation of the current literature on the ambiguity of CAF, two relevant features surface. There are two characteristics of CAF that we know for certain. First is the heterogeneity in the CAF world, their origin, marker(s), and subpopulation(s). Second istheir undeniable role in initiating and the evolution of tumor cells that ultimately determine the disease’s outcome. The first one restricts us from targeting CAF to achieve a successful CAF-based therapeutic strategy. The second one prohibits us from denying the scope of the CAF-based therapeutic approach towards managing the disease. The fact that a number of cross-talks exist between tumor cells and CAF in endometrial cancers proves the importance of the intra-tumoral CAF-tumor cells ecosystem. Furthermore, it explains why and how CAFs co-evolve with tumor cells during the process of metastatic progression of the disease and/or during the development of drug resistance following a clinical intervention, the two most critical determinants of the disease outcome. The only way out
of this puzzle is to acquire more knowledge about the heterogeneity and function of CAF, to establish a CAF-based stromal-switch, and to address the dynamic contribution of CAF in the progression of cancer. As we begin an in-depth characterization of CAF and CAF’s functional choreograph with endometrial tumor cells as well as other stromal cells within the uterine TME, studies will unearth novel therapeutic targets . Future work will pave the way to stratify the approach to “normalize” the stromal switch by targeting CAF in endometrial cancers.