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CAF partners with Endometrial Tumor-Cells
A tumor cell carrying characteristic genomic alteration(s) exists within its host’s microenvironment. The tempero-spatial interaction of tumor cells with its microenvironment is the deterministic factor for tumor growth, progression, resistance to therapy, and its outcome in clinics. This manuscript presents a systemic review of the role of CAF in endometrial cancers. Here we present the functional characteristics of CAF in the context of endometrial cancers. We review (1) the characteristics of CAF, (2) their evolution from being anti-tumor to pro-tumor, (3) their involvement in regulating growth and several metastasis-associated phenotypes of tumor cells, (4) their participation in perturbing immune defense and evading immune surveillance, and (5) their role in mediating drug resistance via tumor-CAF cross-talk with particular reference to endometrial cancers. We interrogate the functional characteristics of CAF in the light of its dialogue with tumor cells and other components of TME towards developing a CAF-based strategy for precision therapy to supplement tumor-based therapy. The purpose of the review is to present a new vision and initiate a thought process which recognizes the importance of CAF in a tumor, thereby resulting in a novel approach to the design and management of the disease in endometrial cancers.
1. Definition of CAF
2. CAF as an Evolving Component of Tumor Microenvironment (TME)
3. CAF & CAF Conundrum
4. CAF in Endometrial Cancers
5. Characteristics of CAF-Tumor Cross-Talk
6. Language and Topic of Cross-Talk between CAF and Tumor Cells in Endometrial Cancers
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.
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.
The entry is from 10.3390/ijms22179121
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