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*Recruitment of inflammatory cells to wound site *Survival and proliferation of cancer stem cells *Cell proliferation and migration of endothelial cells, keratinocytes, and fibroblasts at wound site
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*Induction of EMT to promote epithelial cell migration *Regulation of cancer stem cell proliferation and plasticity *Regulation of stem cell proliferation and plasticity 8 It has recently been recognized that the abundance of inflammatory cytokines and growth factors that occur during post-therapy wound healing can also contribute to survival and expansion of resistant CSCs. 7 Additionally, acute tissue injury associated with biopsy in rodent models of breast cancer is reported to promote lung metastasis. It has recently been shown that injection of wound fluid close to the tumor site in mice bearing syngeneic breast cancer xenografts resulted in increased tumor growth. 6 Wound healing responses associated with tissue injury have been shown to promote the growth of breast cancer ( Table 1). Environmental stimuli, such as hypoxia and DNA damaging agents, elicit secretion of chemokines from tumor cells that recruit pro-tumor inflammatory cells and help to shape the pro-tumor immune response. Tumor-associated macrophages (TAM), tumor-associated dendritic cells (TADC), and tumor infiltrating lymphocytes are a source of proinflammatory mediators in the tumor microenvironment. Infiltrating leukocytes present within the tumor and associated stroma stimulate tumor growth, invasion, and angiogenesis. The tumor microenvironment shares many features of a chronic wound. Likewise, chronic inflammation has been linked to tumorigenesis, tumor progression, and metastasis in many different cancers. Failure to exit the inflammatory stage results in improper tissue remodeling and is associated with impaired wound healing in many disorders including diabetes mellitus, pressure necrosis, and vasculitis.
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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.