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Blood vessels provide a niche that supports self-renewal of stem cell populations in normal organs. This role also extends to the field of cancer biology. Cancer stem/initiating cells (CSCs/CICs), which are responsible for tumor growth, have been implicated in hematological and solid cancers. Identification of these cells and their niche is critical for elucidating molecular targets to inhibit their growth and to destroy their niche. For this purpose, sorting of living CSCs is required to monitor their presence in the presumptive niche in order to establish whether a CSC candidate actually shows malignant features. We created carcinoma cells expressing EGFP under the transcriptional control of the PSF1 promoter and found that these EGFPhigh cells possess high proliferative activity, serial transplantation potential and metastatic ability as observed in CSCs. They display ES cell-like gene expression signatures, show resistance against anti-cancer drugs, and mostly localize near the perivascular region of the tumor rim. Recently, while improved efficacy of angiogenesis inhibitors applied together with anti-cancer drugs has been reported, cancer cell invasion from the edge of the tumor into the periphery has been regarded as a problem after such treatment. As it has been suggested that cancer cells migrate along tracks made of ECM collagen fibers, we hypothesized that blood vessels at the tumor edge, matured as a result of using angiogenesis inhibitors, may provide such a scaffold because it is well known that mature blood vessels are sheathed with extracellular matrix. As expected, immature blood vessels were destroyed, but maturing blood vessels in which endothelial cells are covered with mural cells remained visible and showed a less dilated character, suggesting that maturing blood vessels became well matured ones, after angiogenesis inhibitor treatment in the fibrous cap surrounding tumor. Our data indicate the importance of destroying the maturing blood vessels outside the tumor parenchyma to prevent cancer cell invasion.

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