Abstract
Simple SummaryIntratumoral hypoxia is a negative prognostic factor in breast cancer progression and recurrence. By implementing a hypoxia fate-mapping system, we followed cells that experience intratumoral hypoxia in vivo and determined that these cells have an increased ability to metastasize compared to cells that were never exposed to hypoxia. In this work, we investigate whether cells that experienced intratumoral hypoxia are also resistant to chemotherapy. By utilizing both in vivo and ex vivo models, we conclude that metastatic cells found in the lung and liver, that were exposed to hypoxia in the primary tumor, are less sensitive to doxorubicin and paclitaxel and drive recurrence after treatment. Our studies also suggest that chemoresistance is associated with a cancer stem cell-like phenotype that is maintained in post-hypoxic cells.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.
Highlights
By incorporating this system in an MDA-MB-231 orthotopic mouse model of breast cancer metastasis, we previously reported that post-hypoxic cancer cells (GFP+) have a survival advantage in the bloodstream leading to a 5-fold increase in their ability to metastasize to the lung (Figure 1a) [25]
(1-way ANOVA with Dunnett multiple comparison test). (g,h) The percentage of DsRed+ and GFP+ cells portantly, our results demonstrate that even though the primary tumor was composed of only 20% GFP+ cells at the time of tumor resection, GFP+ cells contributed 2–3 times more than DsRed+ cells to metastatic recurrence in the lung and liver
By utilizing Gene set enrichment analysis (GSEA), our results demonstrate that cells that experience intratumoral hypoxia and form distant metastasis in the lung have enrichment in hallmark hypoxia and cancer stem cell-like signaling pathways
Summary
It is estimated that 30% of patients with advanced breast cancer will develop distant metastasis [3], which is the main cause of treatment failure and mortality, leading to 90% of cancer-related deaths [4]. Metastatic lesions may arise from the clonal evolution of selected aggressive cancer cells that overcome a series of obstacles to thrive at a distant site [7]. In breast cancer, these cells are often pre-exposed to systemic therapy used to treat the primary tumor or to prevent recurrence [8]. These circumstances make metastatic disease nearly incurable [9]
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