Therapy-induced normal tissue damage promotes breast cancer metastasis
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2023 Nov 22;27(1):108503.
doi: 10.1016/j.isci.2023.108503.
eCollection 2024 Jan 19.
Douglas W Perkins 1 ,
Ivana Steiner 1 ,
Syed Haider 1 ,
David Robertson 1 ,
Richard Buus 1 ,
Lynda O'Leary 1 ,
Clare M Isacke 1
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Affiliation
1 The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UK.
PMID: 38161426
PMCID: PMC10755366
DOI: 10.1016/j.isci.2023.108503
Free PMC article
Douglas W Perkins et al.
iScience .
2023 .
Free PMC article
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2023 Nov 22;27(1):108503.
doi: 10.1016/j.isci.2023.108503.
eCollection 2024 Jan 19.
Authors
Douglas W Perkins 1 ,
Ivana Steiner 1 ,
Syed Haider 1 ,
David Robertson 1 ,
Richard Buus 1 ,
Lynda O'Leary 1 ,
Clare M Isacke 1
Affiliation
1 The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UK.
PMID: 38161426
PMCID: PMC10755366
DOI: 10.1016/j.isci.2023.108503
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Abstract
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.
Keywords: Cancer; Cell biology; Cellular therapy.
Crown Copyright © 2023.
PubMed Disclaimer
Conflict of interest statement
The authors have no financial or non-financial competing interests to declare.
Figures
Graphical abstract
Graphical abstract
Figure 1
Prior chemotherapy treatment increases metastatic…
Figure 1
Prior chemotherapy treatment increases metastatic colonization (A) Schedule of chemotherapy (doxorubicin 2.7 mg…
Figure 2
Characterization of the chemotherapy-treated mouse…
Figure 2
Characterization of the chemotherapy-treated mouse lung (A) Schedule of the chemotherapy or vehicle…
Figure 3
Fibroblast responses to chemotherapy treatment…
Figure 3
Fibroblast responses to chemotherapy treatment (A) BALB/c mice (n = 3 per group)…
Figure 4
Figure 4
Figure 5
Navitoclax eliminates chemotherapy-induced senescent fibroblasts…
Figure 5
Navitoclax eliminates chemotherapy-induced senescent fibroblasts in vitro (A) Details of the BCL-2 family…
Figure 6
Effect of combined chemotherapy and…
Figure 6
Effect of combined chemotherapy and navitoclax treatment on metastasis and survival (A) Schedule…
Figure 7
Navitoclax does not reverse chemotherapy-induced…
Figure 7
Navitoclax does not reverse chemotherapy-induced tissue damage in vivo (A) Schedule for the…
See this image and copyright information in PMC
References
Chandler C., Liu T., Buckanovich R., Coffman L.G. The double edge sword of fibrosis in cancer. Transl. Res. 2019;209:55–67. - PMC - PubMed
Turrell F.K., Orha R., Guppy N.J., Gillespie A., Guelbert M., Starling C., Haider S., Isacke C.M. Age-associated microenvironmental changes highlight the role of PDGF-C in ER(+) breast cancer metastatic relapse. Nat. Cancer. 2023;4:468–484. - PMC - PubMed
Nolan E., Bridgeman V.L., Ombrato L., Karoutas A., Rabas N., Sewnath C.A.N., Vasquez M., Rodrigues F.S., Horswell S., Faull P., et al. Radiation exposure elicits a neutrophil-driven response in healthy lung tissue that enhances metastatic colonization. Nat. Cancer. 2022;3:173–187. - PMC - PubMed
Baker D.J., Perez-Terzic C., Jin F., Pitel K.S., Niederlander N.J., Jeganathan K., Yamada S., Reyes S., Rowe L., Hiddinga H.J., et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat. Cell Biol. 2008;10:825–836. - PMC - PubMed
Baker D.J., Childs B.G., Durik M., Wijers M.E., Sieben C.J., Zhong J., Saltness R.A., Jeganathan K.B., Verzosa G.C., Pezeshki A., et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature. 2016;530:184–189. - PMC - PubMed
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Search in PubMed. Search in NLM Catalog. Add to Search. . 2023 Nov 22;27(1):108503. doi: 10.1016/j.isci.2023.108503. eCollection 2024 Jan 19. Douglas W Perkins 1 , Ivana Steiner 1 , Syed Haider 1 , David Robertson 1 , Richard Buus 1 , Lynda O'Leary 1 , Clare M Isacke 1. Expand. Affiliation. 1 The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UK. PMID: 38161426. PMCID: PMC10755366. DOI: 10.1016/j.isci.2023.108503. Free PMC article. Douglas W Perkins et al. iScience . 2023 . Free PMC article. Show details. Display options. Format. Search in PubMed. Search in NLM Catalog. Add to Search. . 2023 Nov 22;27(1):108503. doi: 10.1016/j.isci.2023.108503. eCollection 2024 Jan 19. Authors. Douglas W Perkins 1 , Ivana Steiner 1 , Syed Haider 1 , David Robertson 1 , Richard Buus 1 , Lynda O'Leary 1 , Clare M Isacke 1. Affiliation. 1 The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, UK. PMID: 38161426. PMCID: PMC10755366. DOI: 10.1016/j.isci.2023.108503. Cite. Display options. Format. Abstract. 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. Keywords: Cancer; Cell biology; Cellular therapy. Crown Copyright © 2023. PubMed Disclaimer. Conflict of interest statement. The authors have no financial or non-financial competing interests to declare. Figures. Graphical abstract. Graphical abstract. Figure 1. Prior chemotherapy treatment increases metastatic… Figure 1. Prior chemotherapy treatment increases metastatic colonization (A) Schedule of chemotherapy (doxorubicin 2.7 mg… Figure 2. Characterization of the chemotherapy-treated mouse… Figure 2. Characterization of the chemotherapy-treated mouse lung (A) Schedule of the chemotherapy or vehicle… Figure 3. Fibroblast responses to chemotherapy treatment… Figure 3. Fibroblast responses to chemotherapy treatment (A) BALB/c mice (n = 3 per group)… Figure 4. Figure 4. Figure 5. Navitoclax eliminates chemotherapy-induced senescent fibroblasts… Figure 5. Navitoclax eliminates chemotherapy-induced senescent fibroblasts in vitro (A) Details of the BCL-2 family… Figure 6. Effect of combined chemotherapy and… Figure 6. Effect of combined chemotherapy and navitoclax treatment on metastasis and survival (A) Schedule… Figure 7. Navitoclax does not reverse chemotherapy-induced… Figure 7. Navitoclax does not reverse chemotherapy-induced tissue damage in vivo (A) Schedule for the… See this image and copyright information in PMC. References. Chandler C., Liu T., Buckanovich R., Coffman L.G. The double edge sword of fibrosis in cancer. Transl. Res. 2019;209:55–67. - PMC - PubMed. Turrell F.K., Orha R., Guppy N.J., Gillespie A., Guelbert M., Starling C., Haider S., Isacke C.M. Age-associated microenvironmental changes highlight the role of PDGF-C in ER(+) breast cancer metastatic relapse. Nat. Cancer. 2023;4:468–484. - PMC - PubMed. Nolan E., Bridgeman V.L., Ombrato L., Karoutas A., Rabas N., Sewnath C.A.N., Vasquez M., Rodrigues F.S., Horswell S., Faull P., et al. Radiation exposure elicits a neutrophil-driven response in healthy lung tissue that enhances metastatic colonization. Nat. Cancer. 2022;3:173–187. - PMC - PubMed. Baker D.J., Perez-Terzic C., Jin F., Pitel K.S., Niederlander N.J., Jeganathan K., Yamada S., Reyes S., Rowe L., Hiddinga H.J., et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat. Cell Biol. 2008;10:825–836. - PMC - PubMed. Baker D.J., Childs B.G., Durik M., Wijers M.E., Sieben C.J., Zhong J., Saltness R.A., Jeganathan K.B., Verzosa G.C., Pezeshki A., et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature. 2016;530:184–189. - PMC - PubMed. Related information. MedGen. LinkOut - more resources. Full Text Sources Elsevier Science Europe PubMed Central PubMed Central. Research Materials NCI CPTC Antibody Characterization Program.