In the final phase of wound healing, the maturation phase, wound contraction, and differentiation of fibroblasts to myofibroblasts result in the formation of scar tissue. Epithelial cells undergo epithelial–mesenchymal transition (EMT) and migrate to the edges of the wound to impart re-epithelialization of the damaged tissue. 2 At this stage, granulation tissue forms, angiogenesis is induced, and new extracellular matrix (ECM) is secreted. Infiltrating leukocytes play a major role in secretion of inflammatory cytokines, growth factors, and chemokines, which stimulate proliferation of progenitor cells and recruitment of keratinocytes and endothelial cells during the proliferative phase of wound healing. Tissue injury induces immediate recruitment of neutrophils, which are later replaced by macrophages and lymphocytes. In normal tissue, the inflammatory phase is limited, lasting only 3–14 days. Wound healing is a dynamic process that consists of an inflammatory phase followed by epithelial cell proliferation and tissue remodeling. Wound Healing, Chronic Inflammation, and the Tumor Microenvironment We propose that the presence of inflammation in the tumor microenvironment may contribute to tumor aggressiveness and treatment resistance by shifting the equilibrium between differentiated and undifferentiated tumor cells toward a CSC phenotype. In this review, we focus on breast CSCs and highlight proinflammatory factors, which are involved in regulation of normal adult stem cells during tissue repair and have also been shown to promote survival and proliferation of CSCs in breast cancer. CSCs have been identified in a number of solid tumors and are thought to be a subpopulation of tumor cells that resemble normal stem cells and continuously undergo differentiation to populate the heterogeneous tumor. Many of the factors involved in the inflammatory micro-environment have also been identified as key contributors to the cancer stem cell (CSC) niche. Among these are morphogens that are commonly associated with embryonic development. 2, 3 Additionally, numerous potent growth factors released by macrophages and lymphocytes during wound healing promote stem cell proliferation and plasticity. During tissue injury, replenishment of epithelial cell loss is ensured by the proliferation of these stem cells and their progeny in response to proinflammatory cytokines. Normal epithelial tissue exists in a state of homeostasis where tissue regeneration is tightly regulated by epithelial stem cells located within highly specialized niches. 1 Recently, inflammatory processes that occur during normal wound healing have been linked to the pathological state of many tumors. Tumors have been described as wounds that do not heal.
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