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Evaluation of the enhanced permeability and retention effect in the early stages of lymph node metastasis

Most solid cancers spread to new sites via the lymphatics before hematogenous dissemination. However, only a small fraction of an intravenously administered anti‐cancer drug enters the lymphatic system to reach metastatic lymph nodes (LN). Here, we show that the enhanced permeability and retention (...

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Autores principales: Mikada, Mamoru, Sukhbaatar, Ariunbuyan, Miura, Yoshinobu, Horie, Sachiko, Sakamoto, Maya, Mori, Shiro, Kodama, Tetsuya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448659/
https://www.ncbi.nlm.nih.gov/pubmed/28211204
http://dx.doi.org/10.1111/cas.13206
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author Mikada, Mamoru
Sukhbaatar, Ariunbuyan
Miura, Yoshinobu
Horie, Sachiko
Sakamoto, Maya
Mori, Shiro
Kodama, Tetsuya
author_facet Mikada, Mamoru
Sukhbaatar, Ariunbuyan
Miura, Yoshinobu
Horie, Sachiko
Sakamoto, Maya
Mori, Shiro
Kodama, Tetsuya
author_sort Mikada, Mamoru
collection PubMed
description Most solid cancers spread to new sites via the lymphatics before hematogenous dissemination. However, only a small fraction of an intravenously administered anti‐cancer drug enters the lymphatic system to reach metastatic lymph nodes (LN). Here, we show that the enhanced permeability and retention (EPR) effect is not induced during the early stages of LN metastasis. Luciferase‐expressing tumor cells were injected into the subiliac LN of the MXH10/Mo‐lpr/lpr mouse to induce metastasis to the proper axillary LN (PALN). In vivo biofluorescence imaging was used to confirm metastasis induction and to quantify the EPR effect, measured as PALN accumulation of intravenously injected indocyanine green (ICG) liposomes. PALN blood vessel volume changes were measured by contrast‐enhanced high‐frequency ultrasound imaging. The volume and density of blood vessels in the PALN increased until day 29 after inoculation, whereas the LN volume remained constant. ICG retention was first detected on day 29 post‐inoculation. While CD31‐positive cells increased up to day 29 post‐inoculation, α‐smooth muscle actin‐positive cells were detected on day 29 post‐inoculation for the first time. These results suggest that the EPR effect was not induced in the early stages of LN metastasis; therefore, systemic chemotherapy would likely not be beneficial during the early stages of LN metastasis. The development of an alternative drug delivery system, independent of the EPR effect, is required for the treatment of LN metastasis.
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spelling pubmed-54486592017-06-01 Evaluation of the enhanced permeability and retention effect in the early stages of lymph node metastasis Mikada, Mamoru Sukhbaatar, Ariunbuyan Miura, Yoshinobu Horie, Sachiko Sakamoto, Maya Mori, Shiro Kodama, Tetsuya Cancer Sci Original Articles Most solid cancers spread to new sites via the lymphatics before hematogenous dissemination. However, only a small fraction of an intravenously administered anti‐cancer drug enters the lymphatic system to reach metastatic lymph nodes (LN). Here, we show that the enhanced permeability and retention (EPR) effect is not induced during the early stages of LN metastasis. Luciferase‐expressing tumor cells were injected into the subiliac LN of the MXH10/Mo‐lpr/lpr mouse to induce metastasis to the proper axillary LN (PALN). In vivo biofluorescence imaging was used to confirm metastasis induction and to quantify the EPR effect, measured as PALN accumulation of intravenously injected indocyanine green (ICG) liposomes. PALN blood vessel volume changes were measured by contrast‐enhanced high‐frequency ultrasound imaging. The volume and density of blood vessels in the PALN increased until day 29 after inoculation, whereas the LN volume remained constant. ICG retention was first detected on day 29 post‐inoculation. While CD31‐positive cells increased up to day 29 post‐inoculation, α‐smooth muscle actin‐positive cells were detected on day 29 post‐inoculation for the first time. These results suggest that the EPR effect was not induced in the early stages of LN metastasis; therefore, systemic chemotherapy would likely not be beneficial during the early stages of LN metastasis. The development of an alternative drug delivery system, independent of the EPR effect, is required for the treatment of LN metastasis. John Wiley and Sons Inc. 2017-05-22 2017-05 /pmc/articles/PMC5448659/ /pubmed/28211204 http://dx.doi.org/10.1111/cas.13206 Text en © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Mikada, Mamoru
Sukhbaatar, Ariunbuyan
Miura, Yoshinobu
Horie, Sachiko
Sakamoto, Maya
Mori, Shiro
Kodama, Tetsuya
Evaluation of the enhanced permeability and retention effect in the early stages of lymph node metastasis
title Evaluation of the enhanced permeability and retention effect in the early stages of lymph node metastasis
title_full Evaluation of the enhanced permeability and retention effect in the early stages of lymph node metastasis
title_fullStr Evaluation of the enhanced permeability and retention effect in the early stages of lymph node metastasis
title_full_unstemmed Evaluation of the enhanced permeability and retention effect in the early stages of lymph node metastasis
title_short Evaluation of the enhanced permeability and retention effect in the early stages of lymph node metastasis
title_sort evaluation of the enhanced permeability and retention effect in the early stages of lymph node metastasis
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448659/
https://www.ncbi.nlm.nih.gov/pubmed/28211204
http://dx.doi.org/10.1111/cas.13206
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