Cancer-Associated Fibroblasts in Conversation with Tumor Cells in Endometrial Cancers: A Partner in Crime

Abstract

A tumor cell carrying characteristic genomic alteration(s) exists within its host’s microenvironment. The tumor microenvironment (TME) renders holistic support to the tumor via cross-talk between tumor cells and three components of TME, immune components, vascular components, and fibroblast components. 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. TME (1) facilitates proliferation, and the ensuing metastasis-associated phenotypes, (2) perturbs immune surveillance and supports tumor cells in their effort to evade immune recognition, and (3) actively participates in developing drug-induced resistance in cancer cells. Cancer-Associated Fibroblast (CAF) is a unique component of TME. CAF is the host mesenchyme immediately surrounding the tumor cells in solid tumors. It facilitates tumor growth and progression and participates in developing drug resistance in tumor cells by playing a critical role in all the ways mentioned above. The clinical outcome of a disease is thus critically contributed to by the CAF component of TME. Although CAFs have been identified historically, the functional relevance of CAF-tumor cell cross-talk and their influence on angiogenic and immune-components of TME are yet to be characterized in solid tumors, especially in endometrial cancers. Currently, the standard of care for the treatment of endometrial cancers is primarily guided by therapies directed towards the disease’s tumor compartment and immune compartments. Unfortunately, in the current state of therapies, a complete response (CR) to the therapy is still limited despite a more commonly achieved partial response (PR) and stable disease (SD) in patients. Acknowledging the limitations of the current sets of therapies based on only the tumor and immune compartments of the disease, we sought to put forward this review based on the importance of the cross-talk between CAF of the tumor microenvironment and tumor cells. The premise of the review is to recognize the critical role of CAF in disease progression. This manuscript presents a systemic review of the role of CAF in endometrial cancers. We critically interrogated the active involvement of CAF in the tumor compartment of 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.

The function and decline of the female reproductive tract at single-cell resolution

“…Endometrial cancer is the six most commonly occurring cancer in women worldwide (Ferlay et al, 2021). Elevated levels of pro-inflammatory cytokines pose a major risk in endometrial cancer development (Dossus et al, 2013), and a fibrotic microenvironment appears to contributes to endometrial tumor aggressiveness and drug resistance (Pradip et al, 2021). The risk of developing endometrial carcinomas may also be shaped by events that alter the number of menstrual cycles, such as oral contraception usage, number of pregnancies, and age of menarche and menopause (Havrilesky et al, 2013; Iversen et al, 2017; Michels et al, 2018).…”

Development of Biomarker Signatures Associated with Anoikis to Predict Prognosis in Endometrial Carcinoma Patients

“…In addition, Li and his colleagues reported that Treg has a higher infiltration level in in the peripheral blood of EC cases than healthy control [ 30 ]. Also, cancer-associated fibroblast (CAF) is a major cell subpopulation in TME which affects the biological behavior of EC through CAF-tumor cell cross-talk [ 31 ]. Furthermore, CAF extracted from EC tissues could secrete IL-6, which subsequently boosts c-Myc expression to accelerate EC growth [ 32 ].…”

Cell Markers Present in the TGF-β-Activated Transdifferentiation of Normal Fibroblasts to Cancer-Associated Fibroblast in Endometrial Cancer

“…Truong | URNCST Journal (2022): Volume 6, Issue 8 Page 2 of 7 DOI Link: https://doi.org/10.26685/urncst.346 cell, including influencing the proliferation of the tumour cell through multiple signalling pathways [3], such as the TGF-β signalling pathway.…”

“…A particular cell of interest are cancerassociated fibroblasts (CAFs) which play a significant role in the growth and maintenance of cancers primarily through paracrine signalling and modification of the extracellular matrix [2]. In the EC TME, CAFs promote tumour proliferation, migration and invasion into neighbouring cells, tumorigenesis, and development of drug resistance [3]. Crosstalk between the tumour cells and CAFs initiates and sustains different functions of the endometrial tumour…”