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.

Keywords: cancer-associated fibroblasts; immune-defense; metastasis-associated phenotypes; stromagenesis; tumor micro-environment.

Figure 1

Diagrammatic representation of the compartmentalized relationship of cancer-associated fibroblasts (CAF) with tumor cells and other components of the tumor microenvironment (TME): CAF interacts and has a bidirectional influence on other two major components of TME, including the immune component and vascular component (vertical brown arrows). All three components of TME interact (vertical brown arrows) and have bidirectional interaction with the tumor compartment (horizontal cyan arrows). The bidirectional interactions are not compartmentalized in space as all the components are in close proximity for autocrine/paracrine interactions but compartmentalized on a cell-to-cell basis. CAFs have distinctly compartmentalized bidirectional interactions with cells of the immune component and vascular component of TME, which are distinct from the bidirectional interactions with tumor cells. These characteristic interactions are (1) via secretomes, (2) autocrine, paracrine, and angiocrine in nature, and/or (3) cell-to-cell interactions. Interestingly, the bidirectional interactions are also in real-time. For example, CAF’s interaction with other components of TME and tumor cells changes following treatment of the tumor with drug(s), which may be functionally connected to the development of resistance. Schematically, each component of TME is compartmentalized, and a few cells of each component are presented within the tumor compartment. Heterogeneity of CAF is represented in two shades of color.