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. 2021 Dec 15;12:7300. doi: 10.1038/s41467-021-27308-2

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 6 — a Still image from Supplementary Movie 13 of SORE6>GFP xenograft MDA-MB-231 tumor in Rag2KO mice, showing CSCs (yellow: tdTomato volume marker + SORE6-GFP or green: SORE6-GFP only) enriched in perivascular regions and in contact with perivascular macrophages (cyan). Blood vessels shown in gray. b A composite image of TMEM staining (pink: Mena^Hi tumor cells, brown: macrophages, blue: endothelial cells) and FLAG+ stem cells (green). TMEM doorway ROI are highlighted with red circles. Zoomed images show an example of FLAG+ stem cell (α-FLAG IF panel) being associated with the TMEM doorway (TMEM IHC panel) when panels are aligned. Triple-stained TMEM IHC image is further deconvolved into individual channels and shows that TMEM (marked with triangle) is composed of a TMEM tumor cell (TTC) (Mena^Hi), TMEM macrophage (TM) (Iba1), and an TMEM endothelial cell (TEC) (endomucin). Image is a representative of similar results found in n = 4 mice. c The schematic shows how the region containing TMEM within the section is assigned a boundary surrounded by concentric contours radiating out from the TMEM in 40 μm intervals. d Percentage CSCs distribution from the nearest TMEM in fixed MDA-MB-231 mammary tumor tissue. n = 4 fields of 2.2 × 2.2 mm² from 4 mice; data plotted as mean ± SD. e Schematic shows how the region containing a blood vessel without TMEM within the section is assigned a boundary surrounded by concentric contours radiating out from the blood vessel in 40 μm intervals. f Percentage CSCs distribution from the nearest blood vessel without TMEM in fixed MDA-MB-231 mammary tumor tissue. n = 4 fields of 2.2 × 2.2 mm² from four mice; data plotted as mean ± SD. g Percentage CSCs (anti-Sox9 stained) distribution from the nearest TMEM in fixed PyMT mammary tumor tissue. n = 8 fields of 2–3 mm² from 4 mice; data plotted as mean ± SD. h Percentage CSCs (anti-Sox9 stained) distribution from the nearest blood vessel without TMEM in fixed PyMT mammary tumor tissue. n = 11 fields of 2–3 mm² from 5 mice; data plotted as mean ± SD. i Panels from Supplementary Movie 14 showing intravasation of SORE6+ CSC (outlined in green) into blood vessels (gray, outlined by white dotted lines) in the primary tumor. Right panels (taken from the same X–Y field but adjacent Z-planes, as the TMEM doorway is above the point of intravasation of tumor cells as described previously¹⁷), show that intravasation occurs at TMEM. It is noteworthy that the TMEM structure is stable and is seen in the beginning of the time course till the end. It is noteworthy that TMEM tumor cell (TTC) is different from the intravasating CSC shown in left panels and does not intravasate as consistent with previous work¹⁷.