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The evolving relationship of wound healing and tumor stroma
Deshka S. Foster, R. Ellen Jones, Ryan C. Ransom, Michael T. Longaker, Jeffrey A. Norton
Deshka S. Foster, R. Ellen Jones, Ryan C. Ransom, Michael T. Longaker, Jeffrey A. Norton
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Review

The evolving relationship of wound healing and tumor stroma

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Abstract

The stroma in solid tumors contains a variety of cellular phenotypes and signaling pathways associated with wound healing, leading to the concept that a tumor behaves as a wound that does not heal. Similarities between tumors and healing wounds include fibroblast recruitment and activation, extracellular matrix (ECM) component deposition, infiltration of immune cells, neovascularization, and cellular lineage plasticity. However, unlike a wound that heals, the edges of a tumor are constantly expanding. Cell migration occurs both inward and outward as the tumor proliferates and invades adjacent tissues, often disregarding organ boundaries. The focus of our review is cancer associated fibroblast (CAF) cellular heterogeneity and plasticity and the acellular matrix components that accompany these cells. We explore how similarities and differences between healing wounds and tumor stroma continue to evolve as research progresses, shedding light on possible therapeutic targets that can result in innovative stromal-based treatments for cancer.

Authors

Deshka S. Foster, R. Ellen Jones, Ryan C. Ransom, Michael T. Longaker, Jeffrey A. Norton

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Figure 2

Detailed illustration of the tumor microenvironment showing representative cell types, tissues, and signaling factors involved.

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Detailed illustration of the tumor microenvironment showing representati...
Fibroblasts are recruited by cancer cells and activated in the local environment via TGF-β, PDGF, HGF, and other signaling molecules. CAFs secrete TGF-β, which provides both a positive feedback mechanism encouraging fibroblast activation, as well as guiding the TME. CAFs also secrete paracrine signaling factors including IL-6, IL-8, NFκB, IFN-γ, HGF, CTGF, CCL5, and PGE2, as well as ECM molecules such as collagens, MMPs, tenascin C, and periostin. Immune cells respond to the tumor, including neutrophils, lymphocytes, macrophages, and NK cells. Cytokines are secreted. Both cancer cells, via VEGF secretion, and CAFs are involved in stimulating angiogenesis. These new vessels are leaky and dysfunctional, which can limit immune access to the tumor. CAFs regulate the immune response. Cancer cells, under the influence of CAF signaling, can undergo EMT with downregulation of E-cadherin expression and upregulation of β-catenin and Twist, and escape through the basement membrane with access to vasculature for metastatic spread. Cancer cells can also collect in the lymph nodes and metastasize through the lymphatics. Illustrated by Mao Miyamoto.

Copyright © 2025 American Society for Clinical Investigation
ISSN 2379-3708

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