Post-Hypoxic Cells Promote Metastatic Recurrence after Chemotherapy Treatment in TNBC

Hypoxia occurs in 90% of solid tumors and is associated with treatment failure, relapse, and mortality. HIF-1α signaling promotes resistance to chemotherapy in cancer cell lines and murine models via multiple mechanisms including the enrichment of breast cancer stem cells (BCSCs). In this work, we u...

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Autores principales:	Inês Godet, Mahelet Mamo, Andrea Thurnheer, D. Marc Rosen, Daniele M. Gilkes
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	intratumoral hypoxia breast cancer metastasis recurrence Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/edee0cfbbc51437ca7bef0f721d1a1a4
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spelling	oai:doaj.org-article:edee0cfbbc51437ca7bef0f721d1a1a42021-11-11T15:33:47ZPost-Hypoxic Cells Promote Metastatic Recurrence after Chemotherapy Treatment in TNBC10.3390/cancers132155092072-6694https://doaj.org/article/edee0cfbbc51437ca7bef0f721d1a1a42021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5509https://doaj.org/toc/2072-6694Hypoxia occurs in 90% of solid tumors and is associated with treatment failure, relapse, and mortality. HIF-1α signaling promotes resistance to chemotherapy in cancer cell lines and murine models via multiple mechanisms including the enrichment of breast cancer stem cells (BCSCs). In this work, we utilize a hypoxia fate-mapping system to determine whether triple-negative breast cancer (TNBC) cells that experience hypoxia in the primary tumor are resistant to chemotherapy at sites of metastasis. Using two orthotopic mouse models of TNBC, we demonstrate that cells that experience intratumoral hypoxia and metastasize to the lung and liver have decreased sensitivity to doxorubicin and paclitaxel but not cisplatin or 5-FU. Resistance to therapy leads to metastatic recurrence caused by post-hypoxic cells. We further determined that the post-hypoxic cells that metastasize are enriched in pathways related to cancer stem cell gene expression. Overall, our results show that even when hypoxic cancer cells are reoxygenated in the bloodstream they retain a hypoxia-induced cancer stem cell-like phenotype that persists and promotes resistance and eventually recurrence.Inês GodetMahelet MamoAndrea ThurnheerD. Marc RosenDaniele M. GilkesMDPI AGarticleintratumoral hypoxiabreast cancer metastasisrecurrenceNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5509, p 5509 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	intratumoral hypoxia breast cancer metastasis recurrence Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	intratumoral hypoxia breast cancer metastasis recurrence Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Inês Godet Mahelet Mamo Andrea Thurnheer D. Marc Rosen Daniele M. Gilkes Post-Hypoxic Cells Promote Metastatic Recurrence after Chemotherapy Treatment in TNBC
description	Hypoxia occurs in 90% of solid tumors and is associated with treatment failure, relapse, and mortality. HIF-1α signaling promotes resistance to chemotherapy in cancer cell lines and murine models via multiple mechanisms including the enrichment of breast cancer stem cells (BCSCs). In this work, we utilize a hypoxia fate-mapping system to determine whether triple-negative breast cancer (TNBC) cells that experience hypoxia in the primary tumor are resistant to chemotherapy at sites of metastasis. Using two orthotopic mouse models of TNBC, we demonstrate that cells that experience intratumoral hypoxia and metastasize to the lung and liver have decreased sensitivity to doxorubicin and paclitaxel but not cisplatin or 5-FU. Resistance to therapy leads to metastatic recurrence caused by post-hypoxic cells. We further determined that the post-hypoxic cells that metastasize are enriched in pathways related to cancer stem cell gene expression. Overall, our results show that even when hypoxic cancer cells are reoxygenated in the bloodstream they retain a hypoxia-induced cancer stem cell-like phenotype that persists and promotes resistance and eventually recurrence.
format	article
author	Inês Godet Mahelet Mamo Andrea Thurnheer D. Marc Rosen Daniele M. Gilkes
author_facet	Inês Godet Mahelet Mamo Andrea Thurnheer D. Marc Rosen Daniele M. Gilkes
author_sort	Inês Godet
title	Post-Hypoxic Cells Promote Metastatic Recurrence after Chemotherapy Treatment in TNBC
title_short	Post-Hypoxic Cells Promote Metastatic Recurrence after Chemotherapy Treatment in TNBC
title_full	Post-Hypoxic Cells Promote Metastatic Recurrence after Chemotherapy Treatment in TNBC
title_fullStr	Post-Hypoxic Cells Promote Metastatic Recurrence after Chemotherapy Treatment in TNBC
title_full_unstemmed	Post-Hypoxic Cells Promote Metastatic Recurrence after Chemotherapy Treatment in TNBC
title_sort	post-hypoxic cells promote metastatic recurrence after chemotherapy treatment in tnbc
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/edee0cfbbc51437ca7bef0f721d1a1a4
work_keys_str_mv	AT inesgodet posthypoxiccellspromotemetastaticrecurrenceafterchemotherapytreatmentintnbc AT maheletmamo posthypoxiccellspromotemetastaticrecurrenceafterchemotherapytreatmentintnbc AT andreathurnheer posthypoxiccellspromotemetastaticrecurrenceafterchemotherapytreatmentintnbc AT dmarcrosen posthypoxiccellspromotemetastaticrecurrenceafterchemotherapytreatmentintnbc AT danielemgilkes posthypoxiccellspromotemetastaticrecurrenceafterchemotherapytreatmentintnbc
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Post-Hypoxic Cells Promote Metastatic Recurrence after Chemotherapy Treatment in TNBC

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