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Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment
More than half of all patients with colorectal cancer (CRC) develop distant metastasis and, depending on the local stage of the primary tumor, up to 48% of patients present peritoneal carcinomatosis (PC). PC is often considered as a widespread metastatic disease, which is almost resistant to current...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279937/ https://www.ncbi.nlm.nih.gov/pubmed/35844581 http://dx.doi.org/10.3389/fimmu.2022.908449 |
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author | Braumüller, Heidi Mauerer, Bernhard Berlin, Christopher Plundrich, Dorothea Marbach, Patrick Cauchy, Pierre Laessle, Claudia Biesel, Esther Holzner, Philipp Anton Kesselring, Rebecca |
author_facet | Braumüller, Heidi Mauerer, Bernhard Berlin, Christopher Plundrich, Dorothea Marbach, Patrick Cauchy, Pierre Laessle, Claudia Biesel, Esther Holzner, Philipp Anton Kesselring, Rebecca |
author_sort | Braumüller, Heidi |
collection | PubMed |
description | More than half of all patients with colorectal cancer (CRC) develop distant metastasis and, depending on the local stage of the primary tumor, up to 48% of patients present peritoneal carcinomatosis (PC). PC is often considered as a widespread metastatic disease, which is almost resistant to current systemic therapies like chemotherapeutic and immunotherapeutic regimens. Here we could show that tumor cells of PC besides being senescent also exhibit stem cell features. To investigate these surprising findings in more detail, we established a murine model based on tumor organoids that resembles the clinical setting. In this murine orthotopic transplantation model for peritoneal carcinomatosis, we could show that the metastatic site in the peritoneum is responsible for senescence and stemness induction in tumor cells and that induction of senescence is not due to oncogene activation or therapy. In both mouse and human PC, senescence is associated with a senescence-associated secretory phenotype (SASP) influencing the tumor microenvironment (TME) of PC. SASP factors are able to induce a senescence phenotype in neighbouring cells. Here we could show that SASP leads to enhanced immunosenescence in the TME of PC. Our results provide a new immunoescape mechanism in PC explaining the resistance of PC to known chemo- and immunotherapeutic approaches. Therefore, senolytic approaches may represent a novel roadmap to target this terminal stage of CRC. |
format | Online Article Text |
id | pubmed-9279937 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92799372022-07-15 Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment Braumüller, Heidi Mauerer, Bernhard Berlin, Christopher Plundrich, Dorothea Marbach, Patrick Cauchy, Pierre Laessle, Claudia Biesel, Esther Holzner, Philipp Anton Kesselring, Rebecca Front Immunol Immunology More than half of all patients with colorectal cancer (CRC) develop distant metastasis and, depending on the local stage of the primary tumor, up to 48% of patients present peritoneal carcinomatosis (PC). PC is often considered as a widespread metastatic disease, which is almost resistant to current systemic therapies like chemotherapeutic and immunotherapeutic regimens. Here we could show that tumor cells of PC besides being senescent also exhibit stem cell features. To investigate these surprising findings in more detail, we established a murine model based on tumor organoids that resembles the clinical setting. In this murine orthotopic transplantation model for peritoneal carcinomatosis, we could show that the metastatic site in the peritoneum is responsible for senescence and stemness induction in tumor cells and that induction of senescence is not due to oncogene activation or therapy. In both mouse and human PC, senescence is associated with a senescence-associated secretory phenotype (SASP) influencing the tumor microenvironment (TME) of PC. SASP factors are able to induce a senescence phenotype in neighbouring cells. Here we could show that SASP leads to enhanced immunosenescence in the TME of PC. Our results provide a new immunoescape mechanism in PC explaining the resistance of PC to known chemo- and immunotherapeutic approaches. Therefore, senolytic approaches may represent a novel roadmap to target this terminal stage of CRC. Frontiers Media S.A. 2022-06-30 /pmc/articles/PMC9279937/ /pubmed/35844581 http://dx.doi.org/10.3389/fimmu.2022.908449 Text en Copyright © 2022 Braumüller, Mauerer, Berlin, Plundrich, Marbach, Cauchy, Laessle, Biesel, Holzner and Kesselring https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Braumüller, Heidi Mauerer, Bernhard Berlin, Christopher Plundrich, Dorothea Marbach, Patrick Cauchy, Pierre Laessle, Claudia Biesel, Esther Holzner, Philipp Anton Kesselring, Rebecca Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment |
title | Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment |
title_full | Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment |
title_fullStr | Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment |
title_full_unstemmed | Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment |
title_short | Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment |
title_sort | senescent tumor cells in the peritoneal carcinomatosis drive immunosenescence in the tumor microenvironment |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279937/ https://www.ncbi.nlm.nih.gov/pubmed/35844581 http://dx.doi.org/10.3389/fimmu.2022.908449 |
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