Section 3.3.4: Cancer-associated fibroblasts and CSCs (from DOI: 10.1038/s41392-020-0110-5)

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Article	Targeting cancer stem cell pathways for cancer therapy (DOI: 10.1038/s41392-020-0110-5)
Sections in this Publication
Section	Section 1: Introduction (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 2: The concept of CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 2.1: Biological characteristics of CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 2.2: Isolation and identification of CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3: Factors regulating CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.1: Major transcription factors in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2: Major signaling pathways in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.1: Wnt signaling pathway in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.2: Notch signaling pathway in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.3: Hh signaling pathway in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.4: NF-kappaB signaling pathway in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.5: JAK-STAT signaling pathway (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.6: TGF/SMAD signaling pathway in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.7PI3K/AKT/mTOR signaling pathway in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.8: PPAR signaling pathways in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.2.9: Interactions between signaling pathways in CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.3: The microenvironment of CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.3.1: Vascular niche microenvironments and CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.3.2: The hypoxia microenvironment and CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.3.3: Tumor-associated macrophages and CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.3.4: Cancer-associated fibroblasts and CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.3.5: Cancer-associated MSCs and CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.3.6: Extracellular matrix and CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 3.3.7: Exosomes in the TME and CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 4: Therapeutic targeting of CSCs (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 4.1: Agents targeting CSC-associated surface biomarkers in clinical trials (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 4.2: Agents targeting CSC-associated signaling pathways in clinical trials (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 4.3: Targeting the CSC microenvironment (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 4.4: CSC-directed immunotherapy (from DOI: 10.1038/s41392-020-0110-5)
Section	Section 5: Conclusions and perspectives (from DOI: 10.1038/s41392-020-0110-5)
Section	Competing interests (from DOI: 10.1038/s41392-020-0110-5)
Section	Bibliography (from DOI: 10.1038/s41392-020-0110-5)
Named Entities in this Section

From publication: "Targeting cancer stem cell pathways for cancer therapy" published as Signal Transduct Target Ther; 2020 ; 5 8; DOI: https://doi.org/10.1038/s41392-020-0110-5

Section 3.3.4: Cancer-associated fibroblasts and CSCs

CAFs are one of the most important components of the TME and are critical in tumor development and metastasis. The origin of these cells in the stroma is not entirely clear. Current studies hypothesize that there are five possible sources: (1) transference of fibroblasts in the host stroma; (2) EMT; (3) transdifferentiation of perivascular cells; (4) EMT; and (5) differentiation of MSCs derived from bone marrow. In addition, CAFs are also derived from other cell types, such as smooth muscle cells, pericytes, adipocytes, and immune cells. It is not clear whether there are differences in the functions of CAFs from different sources. CAFs affect cancer cell growth through cell-cell interactions and the secretion of various invasive molecules, such as cytokines, chemokines, and inflammatory mediators.

CAFs in the TME play an indispensable role in the generation and maintenance of CSCs. CAFs transform cancer cells into CSCs. Studies have shown that CAFs promote the EMT and enhance the expression of prostate CSC markers by secreting IL-6 and IL-1beta in breast cancer. CAFs also secrete TGF-beta and activate related pathways to increase ZEB1 transcription, which stimulate lung cancer cells to undergo EMT and CSC transformation. CAFs secrete matrix metalloproteinases, which induce the EMT and promote the growth of stem cell-specific components in tumors. Paracrine interaction between CAFs and CSCs is critical for maintaining the CSC niche of lung CSCs. Fibroblast-derived CCL-2 regulates CSCs through gap activation, thus promoting the progression of tumors. CAFs and adipocytes also secrete leptin, which increases the globulation rate of breast CSCs in vitro.

CAFs also regulate the proliferation of CSCs by other signaling pathways. For example, CAFs increase the secretion of CCL-2 to activate the Notch1/STAT3 pathway, which increases the expression of stem cell markers and upregulates the globulation rate in breast cancer. CAFs regulate TIC plasticity in HCC through c-Met/FRA1/HEY1 signaling. CAFs secrete high levels of IL-6 to activate Notch signaling through STAT3 Tyr705 phosphorylation, thus promoting the stem cell-like characteristics of HCC cells. Similar studies have shown that CAF-derived exons enhance colon stem cell resistance to 5-fluorouracil by activating the Wnt signaling pathway.