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Cancer Stem Cells
Cancer stem cells are a renewable population of cells within the tumor microenvironment. Similar to normal stem cells, cancer stem cells give rise to several cell types including other stem cells and progenitor cells which go on to differentiate guided by intrinsic programs and influenced by extrinsic cues. Within tumors, cancer stem cells are present in a small proportion, however they are responsible for tumor progression and metastasis and are associated with tumor recurrence after therapy. The origin of cancer stem cells is not fully elucidated, and several mechanisms have been proposed including cumulative mutations in normal stem cells or progenitor cells as drivers for cancer stem cell development. Additionally, de-differentiation mechanisms have been implicated in the origin of cancer stem cells as exemplified by the process of epithelial to mesenchymal transition (EMT) in carcinomas.
Tumor stromal cells influence the survival and self-renewal of Cancer Stem Cells
The Tumor Microenvironment (TME) contains several cell types including endothelial cells, fibroblasts, mesenchymal stem cells and infiltrating immune cells as well as their derived soluble factors (e.g., cytokines and chemokines) which influence cancer stem cell properties and functions. In turn cancer stem cells, via various signaling mechanisms (e.g., IL-6, PDGF, VEGF and bFGF), modulate the activities and properties of stromal cells to ensure that the TME supports the survival of cancer stem cells, formation of new cancer stem cells and tumor expansion. The mTOR signaling pathway is implicated in the regulation of immune responses and angiogenesis within the TME thus shaping tumor progression and therapeutic responses.
Cancer Stem Cell Markers
Cancer stem cells are believed to underscore tumor heterogeneity and are themselves phenotypically diverse. Expression of specific stem cell markers (e.g., CD44, CD90, CD133) serve to isolate cancer stem cells in several solid tumors, but the specific combination of cellular markers expressed by cancer stem cell types is highly heterogeneous and dependent on the type of tumor and affected tissue. Significant variability in cancer stem cell phenotypes occurs within tumors which may arise through various mechanisms including clonal evolution, phenotype instability and resurgence from dormancy.
EMT and Cancer Stem Cells
The precise mechanisms leading to the development of cancer stem cells are not fully resolved. Several paths to stemness and tumor initiation have been proposed including:
The process of epithelial cell de-differentiation leading to a mesenchymal phenotype has been well described for various carcinoma types including hepatocellular, breast, pancreatic, colorectal carcinoma and more. In carcinoma, hypoxia represents a trigger for the induction of EMT programs leading to the development of stemness. Hypoxia, through the stabilization of HIF-1 alpha and HIF-2 alpha, is a driver for the development and maintenance of cancer stem cells.
Induction of HIF signaling, the principal transcriptional regulator of the hypoxic response, is associated with the expression of pluripotency markers, supporting the initiation and maintenance of stem cells. Several transcription factors induced in hypoxia are downstream of HIFs and play key roles in cancer cell-renewal including Oct4, NANOG, and Sox2.
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