# Cancer-Associated Fibroblasts Arising from Endothelial-to-Mesenchymal Transition: Induction Factors, Functional Roles, and Transcriptomic Evidence

## TL;DR

This review explores how endothelial cells transform into cancer-associated fibroblasts, their role in tumor progression, and the factors involved in this transition.

## Contribution

The paper provides a comprehensive overview of endothelial-to-mesenchymal transition as a source of cancer-associated fibroblasts and its impact on tumor progression.

## Key findings

- Endothelial-to-mesenchymal transition (EndMT) contributes to the formation of cancer-associated fibroblasts (CAFs).
- EndMT is associated with poor survival and therapy resistance in cancer patients.
- Transcriptomic and proteomic evidence supports the role of EndMT in tumor progression and microenvironment remodeling.

## Abstract

The tumor microenvironment, the surrounding milieu in which a tumor grows, promotes tumor proliferation and metastasis and enables immune evasion; among its key constituents is the cancer-associated fibroblast. To treat cancer and understand it more deeply, the study of cancer-associated fibroblasts is essential; these cells are known to arise from diverse sources, one of which is the vascular endothelium. Endothelial cells line the inner wall of blood vessels, and through endothelial-to-mesenchymal transition they lose their cobblestone morphology, tight intercellular adhesion, and endothelial functions, adopt a fibroblast-like spindle shape, loosen cell-to-cell contacts, and release abundant extracellular matrix components such as collagen and fibronectin. In this review, we describe the diverse factors that induce endothelial-to-mesenchymal transition and discuss how mesenchymalized endothelial cells influence tumor progression and the tumor microenvironment. We also present evidence from genome-wide profiling technologies for endothelial-to-mesenchymal transition-like cells across patient tumors and their impact on clinical outcomes.

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that influence cancer progression via extracellular matrix (ECM) remodeling and secretion of growth factors and cytokines. Endothelial-to-mesenchymal transition (EndMT) is emerging as an important axis among the heterogeneous origins of CAFs. This review introduces the diverse methods used to induce EndMT in cancer—mouse tumor models, conditioned-medium treatment, co-culture, targeted gene perturbation, ligand stimulation, exosome exposure, irradiation, viral infection, and three-dimensional (3D) culture systems—and summarizes EndMT cell-type evidence uncovered using transcriptomic and proteomic technologies. Hallmark EndMT features include spindle-like morphology, increased motility, impaired angiogenesis and barrier function, decreased endothelial markers (CD31, VE-cadherin), and increased mesenchymal markers (α-SMA, FN1). Reported mechanisms include signaling via TGF-β, cytoskeletal/mechanical stress, reactive oxygen species, osteopontin, PAI-1, IL-1β, GSK-3β, HSP90α, Tie1, TNF-α, HSBP1, and NOTCH. Cancer-induced EndMT affects tumors and surrounding TME—promoting tumor growth and metastasis, expanding cancer stem cell-like cells, driving macrophage differentiation, and redistributing pericytes—and is closely associated with poor survival and therapy resistance. Finally, we indicate each study’s stance: some frame cancer-induced EndMT as a source of CAFs, whereas others, from an endothelial perspective, emphasize barrier weakening and promotion of metastasis.