Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden
Khalid Abubaker,Khalid Abubaker,Rodney B. Luwor,Hong-Jian Zhu,Orla McNally,Orla McNally,Michael A. Quinn,Michael A. Quinn,Christopher J. Burns,Erik W. Thompson,Jock K. Findlay,Jock K. Findlay,Jock K. Findlay,Nuzhat Ahmed +13 more
TLDR
This proof of principle study demonstrates that inhibition of the JAK2/STAT3 pathway by the addition of CYT387 suppresses the ‘stemness’ profile in chemotherapy-treated residual cells in vitro, which is replicated in vivo, leading to a reduced tumor burden.Abstract:
Current treatment of ovarian cancer patients with chemotherapy leaves behind a residual tumor which results in recurrent ovarian cancer within a short time frame. We have previously demonstrated that a single short-term treatment of ovarian cancer cells with chemotherapy in vitro resulted in a cancer stem cell (CSC)-like enriched residual population which generated significantly greater tumor burden compared to the tumor burden generated by control untreated cells. In this report we looked at the mechanisms of the enrichment of CSC-like residual cells in response to paclitaxel treatment. The mechanism of survival of paclitaxel-treated residual cells at a growth inhibitory concentration of 50% (GI50) was determined on isolated tumor cells from the ascites of recurrent ovarian cancer patients and HEY ovarian cancer cell line by in vitro assays and in a mouse xenograft model. Treatment of isolated tumor cells from the ascites of ovarian cancer patients and HEY ovarian cancer cell line with paclitaxel resulted in a CSC-like residual population which coincided with the activation of Janus activated kinase 2 (JAK2) and signal transducer and activation of transcription 3 (STAT3) pathway in paclitaxel surviving cells. Both paclitaxel-induced JAK2/STAT3 activation and CSC-like characteristics were inhibited by a low dose JAK2-specific small molecule inhibitor CYT387 (1 μM) in vitro. Subsequent, in vivo transplantation of paclitaxel and CYT387-treated HEY cells in mice resulted in a significantly reduced tumor burden compared to that seen with paclitaxel only-treated transplanted cells. In vitro analysis of tumor xenografts at protein and mRNA levels demonstrated a loss of CSC-like markers and CA125 expression in paclitaxel and CYT387-treated cell-derived xenografts, compared to paclitaxel only-treated cell-derived xenografts. These results were consistent with significantly reduced activation of JAK2 and STAT3 in paclitaxel and CYT387-treated cell-derived xenografts compared to paclitaxel only-treated cell derived xenografts. This proof of principle study demonstrates that inhibition of the JAK2/STAT3 pathway by the addition of CYT387 suppresses the ‘stemness’ profile in chemotherapy-treated residual cells in vitro, which is replicated in vivo, leading to a reduced tumor burden. These findings have important implications for ovarian cancer patients who are treated with taxane and/or platinum-based therapies.read more
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Cancer stem cells: Role in tumor growth, recurrence, metastasis, and treatment resistance.
TL;DR: Several different approaches to treatment aimed at overcoming the intrinsic resistance of CSCs to conventional therapies are currently being developed, including agents targeting tumorigenic pathways, and immunotherapies, including vaccines and natural killer cells employed to induce a T cell response.
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Jak Stat signaling and cancer: Opportunities, benefits and side effects of targeted inhibition.
TL;DR: The direct and mediated mechanisms of Jak stat signaling in and on tumors cells, the interactions with other signaling pathways and transcription factors and the targeting of the functionally crucial secondary modifications of Stat molecules suggest novel approaches to the future development of Jak Stat based cancer therapeutics.
Journal ArticleDOI
Insights into new mechanisms and models of cancer stem cell multidrug resistance
TL;DR: An integrated picture of the MDR mechanisms that operate in CSCs' behavior is provided and a novel model of tumor evolution during chemotherapy is proposed, suggesting underlying additional causes for CSC resilience.
Journal ArticleDOI
Tissue-resident macrophages in omentum promote metastatic spread of ovarian cancer.
Anders Etzerodt,Anders Etzerodt,Morgane Moulin,Morgane Moulin,Thomas Koed Doktor,Marcello Delfini,Noushine Mossadegh-Keller,Marc Bajénoff,Michael H. Sieweke,Michael H. Sieweke,Søren K. Moestrup,Søren K. Moestrup,Nathalie Auphan-Anezin,Toby Lawrence,Toby Lawrence,Toby Lawrence +15 more
TL;DR: A unique subset of CD163+ Tim4+ tissue-resident macrophages in omentum that are maintained independently of bone marrow–derived monocytes and have a specific role in the metastatic spread of ovarian cancer cells are identified.
Journal ArticleDOI
The JAK2/STAT3/CCND2 Axis promotes colorectal Cancer stem cell persistence and radioresistance
So-Yeon Park,Choong-Jae Lee,Jang-Hyun Choi,Jee-Heun Kim,Ji-Won Kim,Ji-Young Kim,Jeong-Seok Nam +6 more
TL;DR: JAK2/STAT3/CCND2 signaling was identified as a resistance mechanism for the persistent growth of CSCs after RT, suggesting potential biomarkers and regimens for improving outcomes among CRC patients.
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