IP-10 (CXCL10) Can Trigger Emergence of Dormant Breast Cancer Cells in a Metastatic Liver Microenvironment
Metastatic breast cancer remains a largely incurable and fatal disease with liver involvement bearing the worst prognosis. The danger is compounded by a subset of disseminated tumor cells that may lie dormant for years to decades before re-emerging as clinically detectable metastases. Pathophysiolog...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-05-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.676135/full |
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| author | Amanda M. Clark Amanda M. Clark Amanda M. Clark Haley L. Heusey Haley L. Heusey Linda G. Griffith Douglas. A. Lauffenburger Alan Wells Alan Wells Alan Wells Alan Wells |
| author_facet | Amanda M. Clark Amanda M. Clark Amanda M. Clark Haley L. Heusey Haley L. Heusey Linda G. Griffith Douglas. A. Lauffenburger Alan Wells Alan Wells Alan Wells Alan Wells |
| author_sort | Amanda M. Clark |
| collection | DOAJ |
| description | Metastatic breast cancer remains a largely incurable and fatal disease with liver involvement bearing the worst prognosis. The danger is compounded by a subset of disseminated tumor cells that may lie dormant for years to decades before re-emerging as clinically detectable metastases. Pathophysiological signals can drive these tumor cells to emerge. Prior studies indicated CXCR3 ligands as being the predominant signals synergistically and significantly unregulated during inflammation in the gut-liver axis. Of the CXCR3 ligands, IP-10 (CXCL10) was the most abundant, correlated significantly with shortened survival of human breast cancer patients with metastatic disease and was highest in those with triple negative (TNBC) disease. Using a complex ex vivo all-human liver microphysiological (MPS) model of dormant-emergent metastatic progression, CXCR3 ligands were found to be elevated in actively growing populations of metastatic TNBC breast cancer cells whereas they remained similar to the tumor-free hepatic niche in those with dormant breast cancer cells. Subsequent stimulation of dormant breast cancer cells in the ex vivo metastatic liver MPS model with IP-10 triggered their emergence in a dose-dependent manner. Emergence was indicated to occur indirectly possibly via activation of the resident liver cells in the surrounding metastatic microenvironment, as stimulation of breast cancer cells with exogenous IP-10 did not significantly change their migratory, invasive or proliferative behavior. The findings reveal that IP-10 is capable of triggering the emergence of dormant breast cancer cells within the liver metastatic niche and identifies the IP-10/CXCR3 as a candidate targetable pathway for rational approaches aimed at maintaining dormancy. |
| first_indexed | 2024-12-19T10:25:18Z |
| format | Article |
| id | doaj.art-f388283e67f24b669df2281c62c26233 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-19T10:25:18Z |
| publishDate | 2021-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-f388283e67f24b669df2281c62c262332022-12-21T20:25:55ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-05-011110.3389/fonc.2021.676135676135IP-10 (CXCL10) Can Trigger Emergence of Dormant Breast Cancer Cells in a Metastatic Liver MicroenvironmentAmanda M. Clark0Amanda M. Clark1Amanda M. Clark2Haley L. Heusey3Haley L. Heusey4Linda G. Griffith5Douglas. A. Lauffenburger6Alan Wells7Alan Wells8Alan Wells9Alan Wells10Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United StatesPittsburgh VA Medical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, United StatesHillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United StatesDepartment of Pathology, University of Pittsburgh, Pittsburgh, PA, United StatesPittsburgh VA Medical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, United StatesDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United StatesDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United StatesDepartment of Pathology, University of Pittsburgh, Pittsburgh, PA, United StatesPittsburgh VA Medical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, United StatesHillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United StatesMcGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United StatesMetastatic breast cancer remains a largely incurable and fatal disease with liver involvement bearing the worst prognosis. The danger is compounded by a subset of disseminated tumor cells that may lie dormant for years to decades before re-emerging as clinically detectable metastases. Pathophysiological signals can drive these tumor cells to emerge. Prior studies indicated CXCR3 ligands as being the predominant signals synergistically and significantly unregulated during inflammation in the gut-liver axis. Of the CXCR3 ligands, IP-10 (CXCL10) was the most abundant, correlated significantly with shortened survival of human breast cancer patients with metastatic disease and was highest in those with triple negative (TNBC) disease. Using a complex ex vivo all-human liver microphysiological (MPS) model of dormant-emergent metastatic progression, CXCR3 ligands were found to be elevated in actively growing populations of metastatic TNBC breast cancer cells whereas they remained similar to the tumor-free hepatic niche in those with dormant breast cancer cells. Subsequent stimulation of dormant breast cancer cells in the ex vivo metastatic liver MPS model with IP-10 triggered their emergence in a dose-dependent manner. Emergence was indicated to occur indirectly possibly via activation of the resident liver cells in the surrounding metastatic microenvironment, as stimulation of breast cancer cells with exogenous IP-10 did not significantly change their migratory, invasive or proliferative behavior. The findings reveal that IP-10 is capable of triggering the emergence of dormant breast cancer cells within the liver metastatic niche and identifies the IP-10/CXCR3 as a candidate targetable pathway for rational approaches aimed at maintaining dormancy.https://www.frontiersin.org/articles/10.3389/fonc.2021.676135/fullmetastasistumor dormancytumor emergenceIP-10CXCL10breast cancer dormancy |
| spellingShingle | Amanda M. Clark Amanda M. Clark Amanda M. Clark Haley L. Heusey Haley L. Heusey Linda G. Griffith Douglas. A. Lauffenburger Alan Wells Alan Wells Alan Wells Alan Wells IP-10 (CXCL10) Can Trigger Emergence of Dormant Breast Cancer Cells in a Metastatic Liver Microenvironment Frontiers in Oncology metastasis tumor dormancy tumor emergence IP-10 CXCL10 breast cancer dormancy |
| title | IP-10 (CXCL10) Can Trigger Emergence of Dormant Breast Cancer Cells in a Metastatic Liver Microenvironment |
| title_full | IP-10 (CXCL10) Can Trigger Emergence of Dormant Breast Cancer Cells in a Metastatic Liver Microenvironment |
| title_fullStr | IP-10 (CXCL10) Can Trigger Emergence of Dormant Breast Cancer Cells in a Metastatic Liver Microenvironment |
| title_full_unstemmed | IP-10 (CXCL10) Can Trigger Emergence of Dormant Breast Cancer Cells in a Metastatic Liver Microenvironment |
| title_short | IP-10 (CXCL10) Can Trigger Emergence of Dormant Breast Cancer Cells in a Metastatic Liver Microenvironment |
| title_sort | ip 10 cxcl10 can trigger emergence of dormant breast cancer cells in a metastatic liver microenvironment |
| topic | metastasis tumor dormancy tumor emergence IP-10 CXCL10 breast cancer dormancy |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.676135/full |
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