Section 3.3.1: Vascular niche microenvironments 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 3.3.1: Vascular niche microenvironments and CSCs

The normal vasculature is composed of ECs, basement membranes, and parietal cells. ECs are the basis for the formation of the inner surface of blood vessels. Studies reported that glioblastoma stem cells are located around the blood vessels, and the concept of the cancer microvascular environment was first proposed. Calabrese et al. demonstrated that direct contact between ECs and CSCs occurs in brain tumors. CSCs are also found near ECs in other cancers, such as papilloma and colorectal cancer. A study also showed that CD133+/CD144- glioma stem cell-like cells differentiate into cancer cells and endothelial progenitor cells and finally into mature ECs. CSCs differentiate into cancer vascular stem cells/progenitor cells and are directly involved in angiogenesis or form vasculogenic mimicry that is directly involved in the microcirculation of tumors. ECs also promote CSC-like transformation and cell growth through Shh activation of Hh signaling. Moreover, secreted microvesicles of CSCs promote the proliferation of human umbilical vein ECs and form a tube-like structure in vitro and in vivo in mice. This CSC plasticity has also been demonstrated in other tumors, including neuroblastoma, renal, breast, and ovarian cancer.

The vascular microenvironment maintains the initial undifferentiated dormancy of stem cells, supports self-renewal, invasion and metastasis of CSCs, and protects CSCs from any injury. The role of the EC signaling system has been proven in maintaining the survival and self-renewal of head and neck SC stem cells. Pasquier and colleagues showed that treatment with EC microparticles in breast and ovarian cancer models increased the number of CSCs and promoted sphere formation of CSCs. The interaction between CSCs and blood vessels promotes the self-renewal of CSCs through the VEGF-Nrp1 loop. CSCs promote cancer angiogenesis by inducing secretion of the cytokines VEGF and hepatocyte growth factor (HGF) from ECs. VEGF receptor 2 plays a key role in vasculogenic mimicry formation, neovascularization, and tumor initiation of glioma stem-like cells. As a result, the secretion of VEGF in stem cell-like glioma cells is higher than that in normal cancer cells and regulates the proliferation of glioma stem cells through the mTOR signaling pathway. Subsequent studies have further shown that multiple signals, such as integrin, Notch, and growth factor receptors, are linked to each other on the cell surface to maintain the stemness of CSCs.