Therapy-induced normal tissue damage promotes breast cancer metastasis
Summary: Disseminated tumor cells frequently exhibit a period of dormancy, rendering them chemotherapy insensitive; conversely, the systemic delivery of chemotherapies can result in normal tissue damage. Using multiple mouse and human breast cancer models, we demonstrate that prior chemotherapy admi...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223025804 |
| _version_ | 1827591148477087744 |
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| author | Douglas W. Perkins Ivana Steiner Syed Haider David Robertson Richard Buus Lynda O'Leary Clare M. Isacke |
| author_facet | Douglas W. Perkins Ivana Steiner Syed Haider David Robertson Richard Buus Lynda O'Leary Clare M. Isacke |
| author_sort | Douglas W. Perkins |
| collection | DOAJ |
| description | Summary: Disseminated tumor cells frequently exhibit a period of dormancy, rendering them chemotherapy insensitive; conversely, the systemic delivery of chemotherapies can result in normal tissue damage. Using multiple mouse and human breast cancer models, we demonstrate that prior chemotherapy administration enhances metastatic colonization and outgrowth. In vitro, chemotherapy-treated fibroblasts display a pro-tumorigenic senescence-associated secretory phenotype (SASP) and are effectively eliminated by targeting the anti-apoptotic protein BCL-xL. In vivo, chemotherapy treatment induces SASP expression in normal tissues; however, the accumulation of senescent cells is limited, and BCL-xL inhibitors are unable to reduce chemotherapy-enhanced metastasis. This likely reflects that chemotherapy-exposed stromal cells do not enter a BCL-xL-dependent phenotype or switch their dependency to other anti-apoptotic BCL-2 family members. This study highlights the role of the metastatic microenvironment in controlling outgrowth of disseminated tumor cells and the need to identify additional approaches to limit the pro-tumorigenic effects of therapy-induced normal tissue damage. |
| first_indexed | 2024-03-09T01:27:44Z |
| format | Article |
| id | doaj.art-c3757f74209d4ff49b816bc840451ae8 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-09T01:27:44Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-c3757f74209d4ff49b816bc840451ae82023-12-10T06:16:55ZengElsevieriScience2589-00422024-01-01271108503Therapy-induced normal tissue damage promotes breast cancer metastasisDouglas W. Perkins0Ivana Steiner1Syed Haider2David Robertson3Richard Buus4Lynda O'Leary5Clare M. Isacke6The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UKThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UKThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UKThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UKThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UKThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UKThe Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UK; Corresponding authorSummary: Disseminated tumor cells frequently exhibit a period of dormancy, rendering them chemotherapy insensitive; conversely, the systemic delivery of chemotherapies can result in normal tissue damage. Using multiple mouse and human breast cancer models, we demonstrate that prior chemotherapy administration enhances metastatic colonization and outgrowth. In vitro, chemotherapy-treated fibroblasts display a pro-tumorigenic senescence-associated secretory phenotype (SASP) and are effectively eliminated by targeting the anti-apoptotic protein BCL-xL. In vivo, chemotherapy treatment induces SASP expression in normal tissues; however, the accumulation of senescent cells is limited, and BCL-xL inhibitors are unable to reduce chemotherapy-enhanced metastasis. This likely reflects that chemotherapy-exposed stromal cells do not enter a BCL-xL-dependent phenotype or switch their dependency to other anti-apoptotic BCL-2 family members. This study highlights the role of the metastatic microenvironment in controlling outgrowth of disseminated tumor cells and the need to identify additional approaches to limit the pro-tumorigenic effects of therapy-induced normal tissue damage.http://www.sciencedirect.com/science/article/pii/S2589004223025804Cellular therapyCell biologyCancer |
| spellingShingle | Douglas W. Perkins Ivana Steiner Syed Haider David Robertson Richard Buus Lynda O'Leary Clare M. Isacke Therapy-induced normal tissue damage promotes breast cancer metastasis iScience Cellular therapy Cell biology Cancer |
| title | Therapy-induced normal tissue damage promotes breast cancer metastasis |
| title_full | Therapy-induced normal tissue damage promotes breast cancer metastasis |
| title_fullStr | Therapy-induced normal tissue damage promotes breast cancer metastasis |
| title_full_unstemmed | Therapy-induced normal tissue damage promotes breast cancer metastasis |
| title_short | Therapy-induced normal tissue damage promotes breast cancer metastasis |
| title_sort | therapy induced normal tissue damage promotes breast cancer metastasis |
| topic | Cellular therapy Cell biology Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223025804 |
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