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Geethadevi A, Ku Z, Tsaih SW, Parashar D, Kadamberi IP, Xiong W, Deng H, George J, Kumar S, Mittal S, Zhang N, Pradeep S, An Z, Chaluvally-Raghavan P. Blocking Oncostatin M receptor abrogates STAT3 mediated integrin signaling and overcomes chemoresistance in ovarian cancer. NPJ Precis Oncol 2024; 8:127. [PMID: 38839865 PMCID: PMC11153533 DOI: 10.1038/s41698-024-00593-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 04/30/2024] [Indexed: 06/07/2024] Open
Abstract
Chemotherapy such as cisplatin is widely used to treat ovarian cancer either before or after surgical debulking. However, cancer relapse due to chemotherapy resistance is a major challenge in the treatment of ovarian cancer. The underlying mechanisms related to chemotherapy resistance remain largely unclear. Therefore, identification of effective therapeutic strategies is urgently needed to overcome therapy resistance. Transcriptome-based analysis, in vitro studies and functional assays identified that cisplatin-resistant ovarian cancer cells express high levels of OSMR compared to cisplatin sensitive cells. Furthermore, OSMR expression associated with a module of integrin family genes and predominantly linked with integrin αV (ITGAV) and integrin β3 (ITGB3) for cisplatin resistance. Using ectopic expression and knockdown approaches, we proved that OSMR directly regulates ITGAV and ITGB3 gene expression through STAT3 activation. Notably, targeting OSMR using anti-OSMR human antibody inhibited the growth and metastasis of ovarian cancer cells and sensitized cisplatin treatment. Taken together, our results underscore the pivotal role of OSMR as a requirement for cisplatin resistance in ovarian cancer. Notably, OSMR fostered the expression of a distinct set of integrin genes, which in turn resulted into a crosstalk between OSMR and integrins for signaling activation that is critical for cisplatin resistance. Therefore, targeting OSMR emerges as a promising and viable strategy to reverse cisplatin-resistance in ovarian cancer.
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Affiliation(s)
- Anjali Geethadevi
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Zhiqiang Ku
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Shirng-Wern Tsaih
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Deepak Parashar
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
- Department of Medicine, Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Ishaque P Kadamberi
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Wei Xiong
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Hui Deng
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Jasmine George
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Sudhir Kumar
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Sonam Mittal
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Ningyan Zhang
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Sunila Pradeep
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Zhiqiang An
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX, USA.
| | - Pradeep Chaluvally-Raghavan
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA.
- Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA.
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Shigematsu Y, Tanaka K, Amori G, Kanda H, Takahashi Y, Takazawa Y, Takeuchi K, Inamura K. Potential involvement of oncostatin M in the immunosuppressive tumor immune microenvironment in hepatocellular carcinoma with vessels encapsulating tumor clusters. Hepatol Res 2024; 54:368-381. [PMID: 37950386 DOI: 10.1111/hepr.13988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 10/23/2023] [Accepted: 11/03/2023] [Indexed: 11/12/2023]
Abstract
AIM Vessels encapsulating tumor clusters (VETC) represents an adverse prognostic morphological feature of hepatocellular carcinoma (HCC), which is associated with an immunosuppressive tumor immune microenvironment (TIM). However, the underlying factors characterizing the TIM in HCC with a VETC pattern (VETC-positive HCC) remain uncertain. Oncostatin M (OSM), a pleiotropic cytokine of the interleukin-6 family, regulates various biological processes, including inflammation, proliferation, and invasiveness of tumor cells. We aimed to test a hypothesis that OSM is associated with the immunosuppressive TIM of VETC-positive HCC. METHODS A total of 397 consecutive HCC patients with curative-intent hepatectomy were included. OSM-positive cells and inflammatory cells including CD4-, CD8-, CD163-, and FOXP3-positive cells were immunohistochemically evaluated. We compared VETC-positive and VETC-negative HCCs in terms of the number of these cells. RESULTS We found the VETC pattern in 62 patients (15.6%). Our analysis revealed a significant decrease in the expression of arginase-1, a marker associated with mature hepatocyte differentiation, in VETC-positive HCC (p = 0.046). The number of tumor-infiltrating OSM-positive cells was significantly low in VETC-positive HCC (p = 0.0057). Notably, in VETC-positive HCC, the number of OSM-positive cells was not associated with vascular invasion, whereas in VETC-negative HCC, an increase in the number of OSM-positive cells was associated with vascular invasion (p = 0.042). CONCLUSIONS We identified an association between a decrease in OSM-positive cells and the VETC pattern. Additionally, our findings indicate that VETC-positive HCC is characterized by low hepatocyte differentiation and OSM-independent vascular invasion. These findings highlight the potential interaction between VETC-positive HCC cells and their TIM through the reduction of OSM-expressing cells.
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Affiliation(s)
- Yasuyuki Shigematsu
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
- Division of Pathology, Cancer Institute, JFCR, Tokyo, Japan
| | - Kazuhito Tanaka
- Department of Diagnostic Pathology, Kumamoto University Hospital, Chuo-ku, Japan
| | - Gulanbar Amori
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
- Division of Pathology, Cancer Institute, JFCR, Tokyo, Japan
| | - Hiroaki Kanda
- Department of Pathology, Saitama Cancer Center, Ina, Japan
| | - Yu Takahashi
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, JFCR, Tokyo, Japan
| | | | - Kengo Takeuchi
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
- Division of Pathology, Cancer Institute, JFCR, Tokyo, Japan
- Pathology Project for Molecular Targets, Cancer Institute, JFCR, Tokyo, Japan
| | - Kentaro Inamura
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
- Division of Pathology, Cancer Institute, JFCR, Tokyo, Japan
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Peyvandi S, Bulliard M, Yilmaz A, Kauzlaric A, Marcone R, Haerri L, Coquoz O, Huang YT, Duffey N, Gafner L, Lorusso G, Fournier N, Lan Q, Rüegg C. Tumor-educated Gr1+CD11b+ cells drive breast cancer metastasis via OSM/IL-6/JAK-induced cancer cell plasticity. J Clin Invest 2024; 134:e166847. [PMID: 38236642 PMCID: PMC10940099 DOI: 10.1172/jci166847] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 01/17/2024] [Indexed: 03/16/2024] Open
Abstract
Cancer cell plasticity contributes to therapy resistance and metastasis, which represent the main causes of cancer-related death, including in breast cancer. The tumor microenvironment drives cancer cell plasticity and metastasis, and unraveling the underlying cues may provide novel strategies for managing metastatic disease. Using breast cancer experimental models and transcriptomic analyses, we show that stem cell antigen-1 positive (SCA1+) murine breast cancer cells enriched during tumor progression and metastasis had higher in vitro cancer stem cell-like properties, enhanced in vivo metastatic ability, and generated tumors rich in Gr1hiLy6G+CD11b+ cells. In turn, tumor-educated Gr1+CD11b+ (Tu-Gr1+CD11b+) cells rapidly and transiently converted low metastatic SCA1- cells into highly metastatic SCA1+ cells via secreted oncostatin M (OSM) and IL-6. JAK inhibition prevented OSM/IL-6-induced SCA1+ population enrichment, while OSM/IL-6 depletion suppressed Tu-Gr1+CD11b+-induced SCA1+ population enrichment in vitro and metastasis in vivo. Moreover, chemotherapy-selected highly metastatic 4T1 cells maintained high SCA1+ positivity through autocrine IL-6 production, and in vitro JAK inhibition blunted SCA1 positivity and metastatic capacity. Importantly, Tu-Gr1+CD11b+ cells invoked a gene signature in tumor cells predicting shorter overall survival (OS), relapse-free survival (RFS), and lung metastasis in breast cancer patients. Collectively, our data identified OSM/IL-6/JAK as a clinically relevant paracrine/autocrine axis instigating breast cancer cell plasticity and triggering metastasis.
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Affiliation(s)
- Sanam Peyvandi
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Manon Bulliard
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Alev Yilmaz
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Annamaria Kauzlaric
- Translational Data Science Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Rachel Marcone
- Translational Data Science Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Lisa Haerri
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Oriana Coquoz
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Yu-Ting Huang
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Nathalie Duffey
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Laetitia Gafner
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Girieca Lorusso
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Nadine Fournier
- Translational Data Science Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Qiang Lan
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
- Cell and Tissue Dynamics Research Program, Institute of Biotechnology, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
| | - Curzio Rüegg
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
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Soler MF, Abaurrea A, Azcoaga P, Araujo AM, Caffarel MM. New perspectives in cancer immunotherapy: targeting IL-6 cytokine family. J Immunother Cancer 2023; 11:e007530. [PMID: 37945321 PMCID: PMC10649711 DOI: 10.1136/jitc-2023-007530] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2023] [Indexed: 11/12/2023] Open
Abstract
Chronic inflammation has been recognized as a canonical cancer hallmark. It is orchestrated by cytokines, which are master regulators of the tumor microenvironment (TME) as they represent the main communication bridge between cancer cells, the tumor stroma, and the immune system. Interleukin (IL)-6 represents a keystone cytokine in the link between inflammation and cancer. Many cytokines from the IL-6 family, which includes IL-6, oncostatin M, leukemia inhibitory factor, IL-11, IL-27, IL-31, ciliary neurotrophic factor, cardiotrophin 1, and cardiotrophin-like cytokine factor 1, have been shown to elicit tumor-promoting roles by modulating the TME, making them attractive therapeutic targets for cancer treatment.The development of immune checkpoint blockade (ICB) immunotherapies has radically changed the outcome of some cancers including melanoma, lung, and renal, although not without hurdles. However, ICB shows limited efficacy in other solid tumors. Recent reports support that chronic inflammation and IL-6 cytokine signaling are involved in resistance to immunotherapy. This review summarizes the available preclinical and clinical data regarding the implication of IL-6-related cytokines in regulating the immune TME and the response to ICB. Moreover, the potential clinical benefit of combining ICB with therapies targeting IL-6 cytokine members for cancer treatment is discussed.
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Affiliation(s)
- Maria Florencia Soler
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, Donostia-San Sebastian, Spain
| | - Andrea Abaurrea
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, Donostia-San Sebastian, Spain
| | - Peio Azcoaga
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, Donostia-San Sebastian, Spain
| | - Angela M Araujo
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, Donostia-San Sebastian, Spain
| | - Maria M Caffarel
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, Donostia-San Sebastian, Spain
- Ikerbasque Basque Foundation for Science, Bilbao, Spain
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Ninomiya I, Yamatoya K, Mashimo K, Matsuda A, Usui-Ouchi A, Araki Y, Ebihara N. Role of Oncostatin M in the Pathogenesis of Vernal Keratoconjunctivitis: Focus on the Barrier Function of the Epithelium and Interleukin-33 Production by Fibroblasts. Invest Ophthalmol Vis Sci 2022; 63:26. [PMID: 36580308 PMCID: PMC9804018 DOI: 10.1167/iovs.63.13.26] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Purpose Vernal keratoconjunctivitis (VKC) is a severe, recurrent allergic conjunctivitis. Previously, we found high concentrations of oncostatin M (OSM) in the tears of patients with VKC. Here, we investigated the role of OSM in VKC by focusing on epithelial barrier function and IL-33 production. Methods To assess the effect of OSM on the barrier function of human conjunctival epithelial cells (HConEpiCs), we measured transepithelial electrical resistance and dextran permeability. We also assessed expression of tight junction-related proteins such as E-cadherin and ZO-1 in HConEpiCs by Western blotting and immunofluorescence. Then we used immunohistochemistry to evaluate expression of Ki-67, E-cadherin, epithelial-mesenchymal transition-related proteins, and IL-33 in giant papillae (GPs) from patients with VKC. In addition, we used Western blotting, microarray, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay to examine whether OSM activates signal transducer and activator of transcription 1 (STAT1) or STAT3 and induces the expression of various genes in human conjunctival fibroblasts (HConFs). Results OSM reduced expression of E-cadherin and ZO-1 in HConEpiCs, indicating barrier dysfunction. In immunohistochemistry, Ki-67 expression was present in the lower epithelial layer of the GPs, and E-cadherin expression was reduced in the superficial and lower layers; double staining revealed that GPs had a high number of fibroblasts expressing IL-33. In addition, in HConFs, OSM phosphorylated both STAT1 and STAT3 and induced IL-33. Conclusions OSM has important roles in severe, prolonged allergic inflammation by inducing epithelial barrier dysfunction and IL-33 production by conjunctival fibroblasts.
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Affiliation(s)
- Ishin Ninomiya
- Juntendo University Graduate School of Medicine, Tokyo, Japan,Department of Ophthalmology, Juntendo University Urayasu Hospital, Chiba, Japan,Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan
| | - Kenji Yamatoya
- Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan
| | - Keitaro Mashimo
- Department of Ophthalmology, Juntendo University Urayasu Hospital, Chiba, Japan
| | - Akira Matsuda
- Department of Ophthalmology, Juntendo University School of Medicine, Tokyo, Japan
| | - Ayumi Usui-Ouchi
- Department of Ophthalmology, Juntendo University Urayasu Hospital, Chiba, Japan
| | - Yoshihiko Araki
- Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan
| | - Nobuyuki Ebihara
- Department of Ophthalmology, Juntendo University Urayasu Hospital, Chiba, Japan,Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine, Chiba, Japan
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Wu Y, Li X, Li Q, Cheng C, Zheng L. Adipose tissue-to-breast cancer crosstalk: Comprehensive insights. Biochim Biophys Acta Rev Cancer 2022; 1877:188800. [PMID: 36103907 DOI: 10.1016/j.bbcan.2022.188800] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/29/2022] [Accepted: 09/06/2022] [Indexed: 10/14/2022]
Abstract
The review focuses on mechanistic evidence for the link between obesity and breast cancer. According to the IARC study, there is sufficient evidence that obesity is closely related to a variety of cancers. Among them, breast cancer is particularly disturbed by adipose tissue due to the unique histological structure of the breast. The review introduces the relationship between obesity and breast cancer from two aspects, including factors that promote tumorigenesis or metastasis. We summarize alterations in adipokines and metabolic pathways that contribute to breast cancer development. Breast cancer metastasis is closely related to obesity-induced pro-inflammatory microenvironment, adipose stem cells, and miRNAs. Based on the mechanism by which obesity causes breast cancer, we list possible therapeutic directions, including reducing the risk of breast cancer and inhibiting the progression of breast cancer. We also discussed the risk of autologous breast remodeling and fat transplantation. Finally, the causes of the obesity paradox and the function of enhancing immunity are discussed. Evaluating the balance between obesity-induced inflammation and enhanced immunity warrants further study.
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Affiliation(s)
- Yuan Wu
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Xu Li
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, PR China
| | - Qiong Li
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Chienshan Cheng
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Lan Zheng
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China.
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Halder S, Parte S, Kshirsagar P, Muniyan S, Nair HB, Batra SK, Seshacharyulu P. The Pleiotropic role, functions and targeted therapies of LIF/LIFR axis in cancer: Old spectacles with new insights. Biochim Biophys Acta Rev Cancer 2022; 1877:188737. [PMID: 35680099 PMCID: PMC9793423 DOI: 10.1016/j.bbcan.2022.188737] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/09/2022] [Accepted: 05/28/2022] [Indexed: 12/30/2022]
Abstract
The dysregulation of leukemia inhibitory factor (LIF) and its cognate receptor (LIFR) has been associated with multiple cancer initiation, progression, and metastasis. LIF plays a significant tumor-promoting role in cancer, while LIFR functions as a tumor promoter and suppressor. Epithelial and stromal cells secrete LIF via autocrine and paracrine signaling mechanism(s) that bind with LIFR and subsequently with co-receptor glycoprotein 130 (gp130) to activate JAK/STAT1/3, PI3K/AKT, mTORC1/p70s6K, Hippo/YAP, and MAPK signaling pathways. Clinically, activating the LIF/LIFR axis is associated with poor survival and anti-cancer therapy resistance. This review article provides an overview of the structure and ligands of LIFR, LIF/LIFR signaling in developmental biology, stem cells, cancer stem cells, genetics and epigenetics of LIFR, LIFR regulation by long non-coding RNAs and miRNAs, and LIF/LIFR signaling in cancers. Finally, neutralizing antibodies and small molecule inhibitors preferentially blocking LIF interaction with LIFR and antagonists against LIFR under pre-clinical and early-phase pre-clinical trials were discussed.
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Affiliation(s)
- Sushanta Halder
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Seema Parte
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Prakash Kshirsagar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Sakthivel Muniyan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | | | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA,Eppley Institute for Research in Cancer and Allied Diseases, USA,Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA,Corresponding authors at: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA. (S.K. Batra), (P. Seshacharyulu)
| | - Parthasarathy Seshacharyulu
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA,Eppley Institute for Research in Cancer and Allied Diseases, USA,Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA,Corresponding authors at: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA. (S.K. Batra), (P. Seshacharyulu)
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Di Maira G, Foglia B, Napione L, Turato C, Maggiora M, Sutti S, Novo E, Alvaro M, Autelli R, Colombatto S, Bussolino F, Carucci P, Gaia S, Rosso C, Biasiolo A, Pontisso P, Bugianesi E, Albano E, Marra F, Parola M, Cannito S. Oncostatin M is overexpressed in NASH-related hepatocellular carcinoma and promotes cancer cell invasiveness and angiogenesis. J Pathol 2022; 257:82-95. [PMID: 35064579 PMCID: PMC9315146 DOI: 10.1002/path.5871] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 12/03/2021] [Accepted: 01/13/2022] [Indexed: 12/03/2022]
Abstract
Oncostatin M (OSM) is a pleiotropic cytokine of the interleukin (IL)-6 family that contributes to the progression of chronic liver disease. Here we investigated the role of OSM in the development and progression of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). The role of OSM was investigated in (1) selected cohorts of NAFLD/NASH HCC patients, (2) liver cancer cells exposed to human recombinant OSM or stably transfected to overexpress human OSM, (3) murine HCC xenografts, and (4) a murine NASH-related model of hepatic carcinogenesis. OSM was found to be selectively overexpressed in HCC cells of NAFLD/NASH patients, depending on tumor grade. OSM serum levels, barely detectable in patients with simple steatosis or NASH, were increased in patients with cirrhosis and more evident in those carrying HCC. In this latter group, OSM serum levels were significantly higher in the subjects with intermediate/advanced HCCs and correlated with poor survival. Cell culture experiments indicated that OSM upregulation in hepatic cancer cells contributes to HCC progression by inducing epithelial-to-mesenchymal transition and increased invasiveness of cancer cells as well as by inducing angiogenesis, which is of critical relevance. In murine xenografts, OSM overexpression was associated with slower tumor growth but an increased rate of lung metastases. Overexpression of OSM and its positive correlation with the angiogenic switch were also confirmed in a murine model of NAFLD/NASH-related hepatocarcinogenesis. Consistent with this, analysis of liver specimens from human NASH-related HCCs with vascular invasion showed that OSM was expressed by liver cancer cells invading hepatic vessels. In conclusion, OSM upregulation appears to be a specific feature of HCC arising on a NAFLD/NASH background, and it correlates with clinical parameters and disease outcome. Our data highlight a novel pro-carcinogenic contribution for OSM in NAFLD/NASH, suggesting a role of this factor as a prognostic marker and a putative potential target for therapy. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Giovanni Di Maira
- Department of Clinical and Experimental Medicine and Center DenotheUniversity of FirenzeFirenzeItaly
| | - Beatrice Foglia
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical PathologyUniversity of TorinoTorinoItaly
| | - Lucia Napione
- Laboratory of Vascular Oncology Candiolo Cancer Institute – FPO IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico)TorinoItaly
- Department of Applied Science and TechnologyPolitecnico di TorinoTorinoItaly
| | - Cristian Turato
- Department of Molecular MedicineUniversity of PaviaPaviaItaly
| | - Marina Maggiora
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical PathologyUniversity of TorinoTorinoItaly
| | - Salvatore Sutti
- Department of Health Sciences and Interdisciplinary Research Center for Autoimmune DiseasesUniversity Amedeo Avogadro of East PiedmontNovaraItaly
| | - Erica Novo
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical PathologyUniversity of TorinoTorinoItaly
| | - Maria Alvaro
- Laboratory of Vascular Oncology Candiolo Cancer Institute – FPO IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico)TorinoItaly
- Department of OncologyUniversity of TorinoTorinoItaly
| | - Riccardo Autelli
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical PathologyUniversity of TorinoTorinoItaly
| | | | - Federico Bussolino
- Laboratory of Vascular Oncology Candiolo Cancer Institute – FPO IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico)TorinoItaly
- Department of OncologyUniversity of TorinoTorinoItaly
| | - Patrizia Carucci
- Division of GastroenterologyCittà della Salute e della Scienza University‐HospitalTurinItaly
| | - Silvia Gaia
- Division of GastroenterologyCittà della Salute e della Scienza University‐HospitalTurinItaly
| | - Chiara Rosso
- Department of Medical SciencesUniversity of TorinoTorinoItaly
| | | | | | | | - Emanuele Albano
- Department of Health Sciences and Interdisciplinary Research Center for Autoimmune DiseasesUniversity Amedeo Avogadro of East PiedmontNovaraItaly
| | - Fabio Marra
- Department of Clinical and Experimental Medicine and Center DenotheUniversity of FirenzeFirenzeItaly
| | - Maurizio Parola
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical PathologyUniversity of TorinoTorinoItaly
| | - Stefania Cannito
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical PathologyUniversity of TorinoTorinoItaly
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Li Q, Wang Y, Li Z, Su M, Song Y, Hu Q, Zhou B, Zhang L. Association of oncostatin M receptor polymorphisms with clinical recurrence of ovarian cancer in the Chinese Han population. Biomark Med 2022; 16:461-471. [PMID: 35321549 DOI: 10.2217/bmm-2021-0989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Aim: Ovarian cancer (OC) is a gynecological malignancy with a challenging judgment of prognosis due to complicated etiology and high recurrence rate. The oncostatin M receptor (OSMR) from members of the IL-6 receptor family is associated with tumor development. This study aims to explore the correlations between OSMR gene polymorphisms (rs2278329 [G/A, missense, Asp553Asn], rs2292016 [G/T, promoter, -100G/T]) and OC. Methods: This study enrolled 160 OC patients and 397 healthy controls. Genotypes of two single-nucleotide polymorphisms were distinguished using TaqMan SNP Genotyping Assay, and statistical analysis was performed using SPSS software. Results: A significantly decreased overall survival rate was found in serous OC patients carrying rs2278329 GA/AA genotypes. Meanwhile, TT genotype carriers of rs2292016 had an improved relapse rate, and the GT genotype showed a definitive correlation with a lower relapse rate. Conclusion: OSMR gene polymorphisms may be related to recurrence and overall survival of serous OC patients.
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Affiliation(s)
- Qin Li
- Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects & Related Diseases of Women & Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, PR, 610041, China
| | - Yanyun Wang
- Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects & Related Diseases of Women & Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, PR, 610041, China
| | - Zhilong Li
- Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects & Related Diseases of Women & Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, PR, 610041, China
| | - Min Su
- Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects & Related Diseases of Women & Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, PR, 610041, China
| | - Yaping Song
- Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects & Related Diseases of Women & Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, PR, 610041, China
| | - Qian Hu
- Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects & Related Diseases of Women & Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, PR, 610041, China
| | - Bin Zhou
- Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects & Related Diseases of Women & Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, PR, 610041, China
| | - Lin Zhang
- Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects & Related Diseases of Women & Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, PR, 610041, China
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10
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Tu CF, Li FA, Li LH, Yang RB. Quantitative glycoproteomics analysis identifies novel FUT8 targets and signaling networks critical for breast cancer cell invasiveness. Breast Cancer Res 2022; 24:21. [PMID: 35303925 PMCID: PMC8932202 DOI: 10.1186/s13058-022-01513-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 02/25/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND We recently showed that fucosyltransferase 8 (FUT8)-mediated core fucosylation of transforming growth factor-β receptor enhances its signaling and promotes breast cancer invasion and metastasis. However, the complete FUT8 target glycoproteins and their downstream signaling networks critical for breast cancer progression remain largely unknown. METHOD We performed quantitative glycoproteomics with two highly invasive breast cancer cell lines to unravel a comprehensive list of core-fucosylated glycoproteins by comparison to parental wild-type and FUT8-knockout counterpart cells. In addition, ingenuity pathway analysis (IPA) was performed to highlight the most enriched biological functions and signaling pathways mediated by FUT8 targets. Novel FUT8 target glycoproteins with biological interest were functionally studied and validated by using LCA (Lens culinaris agglutinin) blotting and LC-MS/MS (liquid chromatography-tandem mass spectrometry) analysis. RESULTS Loss-of-function studies demonstrated that FUT8 knockout suppressed the invasiveness of highly aggressive breast carcinoma cells. Quantitative glycoproteomics identified 140 common target glycoproteins. Ingenuity pathway analysis (IPA) of these target proteins gave a global and novel perspective on signaling networks essential for breast cancer cell migration and invasion. In addition, we showed that core fucosylation of integrin αvβ5 or IL6ST might be crucial for breast cancer cell adhesion to vitronectin or enhanced cellular signaling to interleukin 6 and oncostatin M, two cytokines implicated in the breast cancer epithelial-mesenchymal transition and metastasis. CONCLUSIONS Our report reveals a comprehensive list of core-fucosylated target proteins and provides novel insights into signaling networks crucial for breast cancer progression. These findings will assist in deciphering the complex molecular mechanisms and developing diagnostic or therapeutic approaches targeting these signaling pathways in breast cancer metastasis.
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Affiliation(s)
- Cheng-Fen Tu
- Institute of Biomedical Sciences, Academia Sinica, 128 Academia Rd., Sec. 2, Taipei, 115201, Taiwan
| | - Fu-An Li
- Institute of Biomedical Sciences, Academia Sinica, 128 Academia Rd., Sec. 2, Taipei, 115201, Taiwan
| | - Ling-Hui Li
- Institute of Biomedical Sciences, Academia Sinica, 128 Academia Rd., Sec. 2, Taipei, 115201, Taiwan
| | - Ruey-Bing Yang
- Institute of Biomedical Sciences, Academia Sinica, 128 Academia Rd., Sec. 2, Taipei, 115201, Taiwan. .,Biomedical Translation Research Center, Academia Sinica, Taipei, 115202, Taiwan. .,Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, 110301, Taiwan.
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11
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Felcher CM, Bogni ES, Kordon EC. IL-6 Cytokine Family: A Putative Target for Breast Cancer Prevention and Treatment. Int J Mol Sci 2022; 23:ijms23031809. [PMID: 35163731 PMCID: PMC8836921 DOI: 10.3390/ijms23031809] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/11/2022] Open
Abstract
The IL-6 cytokine family is a group of signaling molecules with wide expression and function across vertebrates. Each member of the family signals by binding to its specific receptor and at least one molecule of gp130, which is the common transmembrane receptor subunit for the whole group. Signal transduction upon stimulation of the receptor complex results in the activation of multiple downstream cascades, among which, in mammary cells, the JAK-STAT3 pathway plays a central role. In this review, we summarize the role of the IL-6 cytokine family—specifically IL-6 itself, LIF, OSM, and IL-11—as relevant players during breast cancer progression. We have compiled evidence indicating that this group of soluble factors may be used for early and more precise breast cancer diagnosis and to design targeted therapy to treat or even prevent metastasis development, particularly to the bone. Expression profiles and possible therapeutic use of their specific receptors in the different breast cancer subtypes are also described. In addition, participation of these cytokines in pathologies of the breast linked to lactation and involution of the gland, as post-partum breast cancer and mastitis, is discussed.
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Affiliation(s)
- Carla M. Felcher
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Universidad de Buenos Aires—Consejo Nacional de Investigaciones Científicas y Técnicas (IFIBYNE-UBA-CONICET), Ciudad Autónoma de Buenos Aires (CABA) 1428, Argentina; (C.M.F.); (E.S.B.)
| | - Emilia S. Bogni
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Universidad de Buenos Aires—Consejo Nacional de Investigaciones Científicas y Técnicas (IFIBYNE-UBA-CONICET), Ciudad Autónoma de Buenos Aires (CABA) 1428, Argentina; (C.M.F.); (E.S.B.)
| | - Edith C. Kordon
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Universidad de Buenos Aires—Consejo Nacional de Investigaciones Científicas y Técnicas (IFIBYNE-UBA-CONICET), Ciudad Autónoma de Buenos Aires (CABA) 1428, Argentina; (C.M.F.); (E.S.B.)
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires (CABA) 1428, Argentina
- Correspondence:
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12
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Omokehinde T, Jotte A, Johnson RW. gp130 Cytokines Activate Novel Signaling Pathways and Alter Bone Dissemination in ER+ Breast Cancer Cells. J Bone Miner Res 2022; 37:185-201. [PMID: 34477239 PMCID: PMC8828687 DOI: 10.1002/jbmr.4430] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 08/09/2021] [Accepted: 08/29/2021] [Indexed: 02/03/2023]
Abstract
Breast cancer cells frequently home to the bone marrow, where they encounter signals that promote survival and quiescence or stimulate their proliferation. The interleukin-6 (IL-6) cytokines signal through the co-receptor glycoprotein130 (gp130) and are abundantly secreted within the bone microenvironment. Breast cancer cell expression of leukemia inhibitory factor (LIF) receptor (LIFR)/STAT3 signaling promotes tumor dormancy in the bone, but it is unclear which, if any of the cytokines that signal through LIFR, including LIF, oncostatin M (OSM), and ciliary neurotrophic factor (CNTF), promote tumor dormancy and which signaling pathways are induced. We first confirmed that LIF, OSM, and CNTF and their receptor components were expressed across a panel of breast cancer cell lines, although expression was lower in estrogen receptor-negative (ER- ) bone metastatic clones compared with parental cell lines. In estrogen receptor-positive (ER+ ) cells, OSM robustly stimulated phosphorylation of known gp130 signaling targets STAT3, ERK, and AKT, while CNTF activated STAT3 signaling. In ER- breast cancer cells, OSM alone stimulated AKT and ERK signaling. Overexpression of OSM, but not CNTF, reduced dormancy gene expression and increased ER+ breast cancer bone dissemination. Reverse-phase protein array revealed distinct and overlapping pathways stimulated by OSM, LIF, and CNTF with known roles in breast cancer progression and metastasis. In breast cancer patients, downregulation of the cytokines or receptors was associated with reduced relapse-free survival, but OSM was significantly elevated in patients with invasive disease and distant metastasis. Together these data indicate that the gp130 cytokines induce multiple signaling cascades in breast cancer cells, with a potential pro-tumorigenic role for OSM and pro-dormancy role for CNTF. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Tolu Omokehinde
- Graduate Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA.,Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alec Jotte
- Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Biochemistry, Vanderbilt University, Nashville, TN, USA
| | - Rachelle W Johnson
- Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
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13
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Cosialls E, El Hage R, Dos Santos L, Gong C, Mehrpour M, Hamaï A. Ferroptosis: Cancer Stem Cells Rely on Iron until "to Die for" It. Cells 2021; 10:cells10112981. [PMID: 34831207 PMCID: PMC8616391 DOI: 10.3390/cells10112981] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/29/2021] [Accepted: 10/29/2021] [Indexed: 12/13/2022] Open
Abstract
Cancer stem cells (CSCs) are a distinct subpopulation of tumor cells with stem cell-like features. Able to initiate and sustain tumor growth and mostly resistant to anti-cancer therapies, they are thought responsible for tumor recurrence and metastasis. Recent accumulated evidence supports that iron metabolism with the recent discovery of ferroptosis constitutes a promising new lead in the field of anti-CSC therapeutic strategies. Indeed, iron uptake, efflux, storage and regulation pathways are all over-engaged in the tumor microenvironment suggesting that the reprogramming of iron metabolism is a crucial occurrence in tumor cell survival. In particular, recent studies have highlighted the importance of iron metabolism in the maintenance of CSCs. Furthermore, the high concentration of iron found in CSCs, as compared to non-CSCs, underlines their iron addiction. In line with this, if iron is an essential macronutrient that is nevertheless highly reactive, it represents their Achilles’ heel by inducing ferroptosis cell death and therefore providing opportunities to target CSCs. In this review, we first summarize our current understanding of iron metabolism and its regulation in CSCs. Then, we provide an overview of the current knowledge of ferroptosis and discuss the role of autophagy in the (regulation of) ferroptotic pathways. Finally, we discuss the potential therapeutic strategies that could be used for inducing ferroptosis in CSCs to treat cancer.
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Affiliation(s)
- Emma Cosialls
- Institut Necker-Enfants Malades (INEM), Inserm U1151-CNRS UMR 8253, Université Paris Descartes-Sorbonne Paris Cité, F-75993 Paris, France; (E.C.); (R.E.H.); (L.D.S.)
| | - Rima El Hage
- Institut Necker-Enfants Malades (INEM), Inserm U1151-CNRS UMR 8253, Université Paris Descartes-Sorbonne Paris Cité, F-75993 Paris, France; (E.C.); (R.E.H.); (L.D.S.)
| | - Leïla Dos Santos
- Institut Necker-Enfants Malades (INEM), Inserm U1151-CNRS UMR 8253, Université Paris Descartes-Sorbonne Paris Cité, F-75993 Paris, France; (E.C.); (R.E.H.); (L.D.S.)
| | - Chang Gong
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Guangzhou 510120, China;
| | - Maryam Mehrpour
- Institut Necker-Enfants Malades (INEM), Inserm U1151-CNRS UMR 8253, Université Paris Descartes-Sorbonne Paris Cité, F-75993 Paris, France; (E.C.); (R.E.H.); (L.D.S.)
- Correspondence: (M.M.); (A.H.)
| | - Ahmed Hamaï
- Institut Necker-Enfants Malades (INEM), Inserm U1151-CNRS UMR 8253, Université Paris Descartes-Sorbonne Paris Cité, F-75993 Paris, France; (E.C.); (R.E.H.); (L.D.S.)
- Correspondence: (M.M.); (A.H.)
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14
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Jakob L, Müller TA, Rassner M, Kleinfelder H, Veratti P, Mitschke J, Miething C, Oostendorp RAJ, Pfeifer D, Waterhouse M, Duyster J. Murine Oncostatin M Has Opposing Effects on the Proliferation of OP9 Bone Marrow Stromal Cells and NIH/3T3 Fibroblasts Signaling through the OSMR. Int J Mol Sci 2021; 22:11649. [PMID: 34769079 PMCID: PMC8584221 DOI: 10.3390/ijms222111649] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/14/2021] [Accepted: 10/25/2021] [Indexed: 12/31/2022] Open
Abstract
The IL-6 family cytokine Oncostatin M (OSM) is involved in cell development, growth, hematopoiesis, inflammation, and cancer. Intriguingly, OSM has proliferative and antiproliferative effects depending on the target cell. The molecular mechanisms underlying these opposing effects are not fully understood. Previously, we found OSM upregulation in different myeloproliferative syndromes. However, OSM receptor (OSMR) expression was detected on stromal cells but not the malignant cells themselves. In the present study, we, therefore, investigated the effect of murine OSM (mOSM) on proliferation in stromal and fibroblast cell lines. We found that mOSM impairs the proliferation of bone marrow (BM) stromal cells, whereas fibroblasts responded to mOSM with increased proliferation. When we set out to reveal the mechanisms underlying these opposing effects, we detected increased expression of the OSM receptors OSMR and LIFR in stromal cells. Interestingly, Osmr knockdown and Lifr overexpression attenuated the OSM-mediated effect on proliferation in both cell lines indicating that mOSM affected the proliferation signaling mainly through the OSMR. Furthermore, mOSM induced activation of the JAK-STAT, PI3K-AKT, and MAPK-ERK pathways in OP9 and NIH/3T3 cells with differences in total protein levels between the two cell lines. Our findings offer new insights into the regulation of proliferation by mOSM.
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Affiliation(s)
- Lena Jakob
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany; (L.J.); (T.A.M.); (M.R.); (H.K.); (P.V.); (J.M.); (C.M.); (D.P.); (M.W.)
| | - Tony Andreas Müller
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany; (L.J.); (T.A.M.); (M.R.); (H.K.); (P.V.); (J.M.); (C.M.); (D.P.); (M.W.)
- Center for Integrated Oncology (CIO), Department I of Internal Medicine, Aachen-Bonn-Cologne-Duesseldorf, Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne (UoC), 50937 Cologne, Germany
| | - Michael Rassner
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany; (L.J.); (T.A.M.); (M.R.); (H.K.); (P.V.); (J.M.); (C.M.); (D.P.); (M.W.)
| | - Helen Kleinfelder
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany; (L.J.); (T.A.M.); (M.R.); (H.K.); (P.V.); (J.M.); (C.M.); (D.P.); (M.W.)
| | - Pia Veratti
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany; (L.J.); (T.A.M.); (M.R.); (H.K.); (P.V.); (J.M.); (C.M.); (D.P.); (M.W.)
| | - Jan Mitschke
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany; (L.J.); (T.A.M.); (M.R.); (H.K.); (P.V.); (J.M.); (C.M.); (D.P.); (M.W.)
| | - Cornelius Miething
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany; (L.J.); (T.A.M.); (M.R.); (H.K.); (P.V.); (J.M.); (C.M.); (D.P.); (M.W.)
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Robert A. J. Oostendorp
- Department of Internal Medicine III, Technical University of Munich, Klinikum Rechts der Isar, 81675 Munich, Germany;
| | - Dietmar Pfeifer
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany; (L.J.); (T.A.M.); (M.R.); (H.K.); (P.V.); (J.M.); (C.M.); (D.P.); (M.W.)
| | - Miguel Waterhouse
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany; (L.J.); (T.A.M.); (M.R.); (H.K.); (P.V.); (J.M.); (C.M.); (D.P.); (M.W.)
| | - Justus Duyster
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany; (L.J.); (T.A.M.); (M.R.); (H.K.); (P.V.); (J.M.); (C.M.); (D.P.); (M.W.)
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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15
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The Role of the IL-6 Cytokine Family in Epithelial-Mesenchymal Plasticity in Cancer Progression. Int J Mol Sci 2021; 22:ijms22158334. [PMID: 34361105 PMCID: PMC8347315 DOI: 10.3390/ijms22158334] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/12/2021] [Accepted: 07/28/2021] [Indexed: 02/07/2023] Open
Abstract
Epithelial–mesenchymal plasticity (EMP) plays critical roles during embryonic development, wound repair, fibrosis, inflammation and cancer. During cancer progression, EMP results in heterogeneous and dynamic populations of cells with mixed epithelial and mesenchymal characteristics, which are required for local invasion and metastatic dissemination. Cancer development is associated with an inflammatory microenvironment characterized by the accumulation of multiple immune cells and pro-inflammatory mediators, such as cytokines and chemokines. Cytokines from the interleukin 6 (IL-6) family play fundamental roles in mediating tumour-promoting inflammation within the tumour microenvironment, and have been associated with chronic inflammation, autoimmunity, infectious diseases and cancer, where some members often act as diagnostic or prognostic biomarkers. All IL-6 family members signal through the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway and are able to activate a wide array of signalling pathways and transcription factors. In general, IL-6 cytokines activate EMP processes, fostering the acquisition of mesenchymal features in cancer cells. However, this effect may be highly context dependent. This review will summarise all the relevant literature related to all members of the IL-6 family and EMP, although it is mainly focused on IL-6 and oncostatin M (OSM), the family members that have been more extensively studied.
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16
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Rajamäki K, Taira A, Katainen R, Välimäki N, Kuosmanen A, Plaketti RM, Seppälä TT, Ahtiainen M, Wirta EV, Vartiainen E, Sulo P, Ravantti J, Lehtipuro S, Granberg KJ, Nykter M, Tanskanen T, Ristimäki A, Koskensalo S, Renkonen-Sinisalo L, Lepistö A, Böhm J, Taipale J, Mecklin JP, Aavikko M, Palin K, Aaltonen LA. Genetic and Epigenetic Characteristics of Inflammatory Bowel Disease-Associated Colorectal Cancer. Gastroenterology 2021; 161:592-607. [PMID: 33930428 DOI: 10.1053/j.gastro.2021.04.042] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 04/16/2021] [Accepted: 04/16/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder associated with an elevated risk of colorectal cancer (CRC). IBD-associated CRC (IBD-CRC) may represent a distinct pathway of tumorigenesis compared to sporadic CRC (sCRC). Our aim was to comprehensively characterize IBD-associated tumorigenesis integrating multiple high-throughput approaches, and to compare the results with in-house data sets from sCRCs. METHODS Whole-genome sequencing, single nucleotide polymorphism arrays, RNA sequencing, genome-wide methylation analysis, and immunohistochemistry were performed using fresh-frozen and formalin-fixed tissue samples of tumor and corresponding normal tissues from 31 patients with IBD-CRC. RESULTS Transcriptome-based tumor subtyping revealed the complete absence of canonical epithelial tumor subtype associated with WNT signaling in IBD-CRCs, dominated instead by mesenchymal stroma-rich subtype. Negative WNT regulators AXIN2 and RNF43 were strongly down-regulated in IBD-CRCs and chromosomal gains at HNF4A, a negative regulator of WNT-induced epithelial-mesenchymal transition (EMT), were less frequent compared to sCRCs. Enrichment of hypomethylation at HNF4α binding sites was detected solely in sCRC genomes. PIGR and OSMR involved in mucosal immunity were dysregulated via epigenetic modifications in IBD-CRCs. Genome-wide analysis showed significant enrichment of noncoding mutations to 5'untranslated region of TP53 in IBD-CRCs. As reported previously, somatic mutations in APC and KRAS were less frequent in IBD-CRCs compared to sCRCs. CONCLUSIONS Distinct mechanisms of WNT pathway dysregulation skew IBD-CRCs toward mesenchymal tumor subtype, which may affect prognosis and treatment options. Increased OSMR signaling may favor the establishment of mesenchymal tumors in patients with IBD.
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Affiliation(s)
- Kristiina Rajamäki
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
| | - Aurora Taira
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Riku Katainen
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Niko Välimäki
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Anna Kuosmanen
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Roosa-Maria Plaketti
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Toni T Seppälä
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland; Department of Surgery, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland; Department of Surgical Oncology, Johns Hopkins University, Baltimore, Maryland
| | - Maarit Ahtiainen
- Department of Pathology, Central Finland Health Care District, Jyväskylä, Finland
| | - Erkki-Ville Wirta
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland
| | - Emilia Vartiainen
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Päivi Sulo
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Janne Ravantti
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Suvi Lehtipuro
- Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Tays Cancer Center, Tampere University Hospital, Tampere, Finland
| | - Kirsi J Granberg
- Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Tays Cancer Center, Tampere University Hospital, Tampere, Finland
| | - Matti Nykter
- Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Tays Cancer Center, Tampere University Hospital, Tampere, Finland
| | - Tomas Tanskanen
- Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland
| | - Ari Ristimäki
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland; Department of Pathology, HUSLAB, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Selja Koskensalo
- Department of Gastrointestinal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Laura Renkonen-Sinisalo
- Department of Gastrointestinal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Anna Lepistö
- Department of Gastrointestinal Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Jan Böhm
- Department of Pathology, Central Finland Health Care District, Jyväskylä, Finland
| | - Jussi Taipale
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland; Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Department of Biochemistry, University of Cambridge, Cambridge, UK
| | - Jukka-Pekka Mecklin
- Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland; Department of Education and Research, Central Finland Central Hospital, Jyväskylä, Finland
| | - Mervi Aavikko
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Kimmo Palin
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Lauri A Aaltonen
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
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O'Neill RS, Stoita A. Biomarkers in the diagnosis of pancreatic cancer: Are we closer to finding the golden ticket? World J Gastroenterol 2021; 27:4045-4087. [PMID: 34326612 PMCID: PMC8311531 DOI: 10.3748/wjg.v27.i26.4045] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/24/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is a leading cause of cancer related mortality on a global scale. The disease itself is associated with a dismal prognosis, partly due to its silent nature resulting in patients presenting with advanced disease at the time of diagnosis. To combat this, there has been an explosion in the last decade of potential candidate biomarkers in the research setting in the hope that a diagnostic biomarker may provide a glimmer of hope in what is otherwise quite a substantial clinical dilemma. Currently, serum carbohydrate antigen 19-9 is utilized in the diagnostic work-up of patients diagnosed with PC however this biomarker lacks the sensitivity and specificity associated with a gold-standard marker. In the search for a biomarker that is both sensitive and specific for the diagnosis of PC, there has been a paradigm shift towards a focus on liquid biopsy and the use of diagnostic panels which has subsequently proved to have efficacy in the diagnosis of PC. Currently, promising developments in the field of early detection on PC using diagnostic biomarkers include the detection of microRNA (miRNA) in serum and circulating tumour cells. Both these modalities, although in their infancy and yet to be widely accepted into routine clinical practice, possess merit in the early detection of PC. We reviewed over 300 biomarkers with the aim to provide an in-depth summary of the current state-of-play regarding diagnostic biomarkers in PC (serum, urinary, salivary, faecal, pancreatic juice and biliary fluid).
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Affiliation(s)
- Robert S O'Neill
- Department of Gastroenterology, St Vincent's Hospital Sydney, Sydney 2010, Australia
- St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney 2010, Australia
| | - Alina Stoita
- Department of Gastroenterology, St Vincent's Hospital Sydney, Sydney 2010, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney 2010, Australia
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Dinca SC, Greiner D, Weidenfeld K, Bond L, Barkan D, Jorcyk CL. Novel mechanism for OSM-promoted extracellular matrix remodeling in breast cancer: LOXL2 upregulation and subsequent ECM alignment. Breast Cancer Res 2021; 23:56. [PMID: 34011405 PMCID: PMC8132418 DOI: 10.1186/s13058-021-01430-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 04/20/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Invasive ductal carcinoma (IDC) is a serious problem for patients as it metastasizes, decreasing 5-year patient survival from > 95 to ~ 27%. The breast tumor microenvironment (TME) is often saturated with proinflammatory cytokines, such as oncostatin M (OSM), which promote epithelial-to-mesenchymal transitions (EMT) in IDC and increased metastasis. The extracellular matrix (ECM) also plays an important role in promoting invasive and metastatic potential of IDC. Specifically, the reorganization and alignment of collagen fibers in stromal ECM leads to directed tumor cell motility, which promotes metastasis. Lysyl oxidase like-2 (LOXL2) catalyzes ECM remodeling by crosslinking of collagen I in the ECM. We propose a novel mechanism whereby OSM induces LOXL2 expression, mediating stromal ECM remodeling of the breast TME. METHODS Bioinformatics was utilized to determine survival and gene correlation in patients. IDC cell lines were treated with OSM (also IL-6, LIF, and IL-1β) and analyzed for LOXL2 expression by qRT-PCR and immunolabelling techniques. Collagen I contraction assays, 3D invasion assays, and confocal microscopy were performed with and without LOXL2 inhibition to determine the impact of OSM-induced LOXL2 on the ECM. RESULTS Our studies demonstrate that IDC patients with high LOXL2 and OSM co-expression had worse rates of metastasis-free survival than those with high levels of either, individually, and LOXL2 expression is positively correlated to OSM/OSM receptor (OSMR) expression in IDC patients. Furthermore, human IDC cells treated with OSM resulted in a significant increase in LOXL2 mRNA, which led to upregulated protein expression of secreted, glycosylated, and enzymatically active LOXL2. The expression of LOXL2 in IDC cells did not affect OSM-promoted EMT, and LOXL2 was localized to the cytoplasm and/or secreted. OSM-induced LOXL2 promoted an increase in ECM collagen I fiber crosslinking, which led to significant fiber alignment between cells and increased IDC cell invasion. CONCLUSIONS Aligned collagen fibers in the ECM provide pathways for tumor cells to migrate more easily through the stroma to nearby vasculature and tissue. These results provide a new paradigm through which proinflammatory cytokine OSM promotes tumor progression. Understanding the nuances in IDC metastasis will lead to better potential therapeutics to combat against the possibility.
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Affiliation(s)
- Simion C. Dinca
- Biomolecular Sciences Graduate Program, Boise State University, 1910 University Drive, MS1515, Boise, ID 83725 USA
| | - Daniel Greiner
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112 USA
- Department of Biological Sciences, Boise State University, 1910 University Drive, MS1515, Boise, ID 83725 USA
| | - Keren Weidenfeld
- Department of Human Biology and Medical Sciences, University of Haifa, Haifa, Israel
| | - Laura Bond
- Biomolecular Research Center, Boise State University, 1910 University Drive, MS1515, Boise, ID 83725 USA
| | - Dalit Barkan
- Department of Human Biology and Medical Sciences, University of Haifa, Haifa, Israel
| | - Cheryl L. Jorcyk
- Biomolecular Sciences Graduate Program, Boise State University, 1910 University Drive, MS1515, Boise, ID 83725 USA
- Department of Biological Sciences, Boise State University, 1910 University Drive, MS1515, Boise, ID 83725 USA
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Wuhrer A, Uhlig S, Tuschy B, Berlit S, Sperk E, Bieback K, Sütterlin M. Wound Fluid from Breast Cancer Patients Undergoing Intraoperative Radiotherapy Exhibits an Altered Cytokine Profile and Impairs Mesenchymal Stromal Cell Function. Cancers (Basel) 2021; 13:2140. [PMID: 33946741 PMCID: PMC8124792 DOI: 10.3390/cancers13092140] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/18/2021] [Accepted: 04/27/2021] [Indexed: 12/16/2022] Open
Abstract
Intraoperative radiotherapy (IORT) displays an increasingly used treatment option for early breast cancer. It exhibits non-inferiority concerning the risk of recurrence compared to conventional external irradiation (EBRT) in suitable patients with early breast cancer. Since most relapses occur in direct proximity of the former tumor site, the reduction of the risk of local recurrence effected by radiotherapy might partially be due to an alteration of the irradiated tumor bed's micromilieu. Our aim was to investigate if IORT affects the local micromilieu, especially immune cells with concomitant cytokine profile, and if it has an impact on growth conditions for breast cancer cells as well as mammary mesenchymal stromal cells (MSC), the latter considered as a model of the tumor bed stroma.42 breast cancer patients with breast-conserving surgery were included, of whom 21 received IORT (IORT group) and 21 underwent surgery without IORT (control group). Drainage wound fluid (WF) was collected from both groups 24 h after surgery for flow cytometric analysis of immune cell subset counts and potential apoptosis and for multiplex cytokine analyses (cytokine array and ELISA). It served further as a supplement in cultures of MDA-MB 231 breast cancer cells and mammary MSC for functional analyses, including proliferation, wound healing and migration. Furthermore, the cytokine profile within conditioned media from WF-treated MSC cultures was assessed. Flow cytometric analysis showed no group-related changes of cell count, activation state and apoptosis rates of myeloid, lymphoid leucocytes and regulatory T cells in the WF. Multiplex cytokine analysis of the WF revealed group-related differences in the expression levels of several cytokines, e.g., oncostatin-M, leptin and IL-1β. The application of WF in MDA-MB 231 cultures did not show a group-related difference in proliferation, wound healing and chemotactic migration. However, WF from IORT-treated patients significantly inhibited mammary MSC proliferation, wound healing and migration compared to WF from the control group. The conditioned media collected from WF-treated MSC-cultures also exhibited altered concentrations of VEGF, RANTES and GROα. IORT causes significant changes in the cytokine profile and MSC growth behavior. These changes in the tumor bed could potentially contribute to the beneficial oncological outcome entailed by this technique. The consideration whether this alteration also affects MSC interaction with other stroma components presents a promising gateway for future investigations.
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Affiliation(s)
- Anne Wuhrer
- Department of Obstetrics and Gynecology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (B.T.); (S.B.); (M.S.)
| | - Stefanie Uhlig
- FlowCore Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (S.U.); (K.B.)
| | - Benjamin Tuschy
- Department of Obstetrics and Gynecology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (B.T.); (S.B.); (M.S.)
| | - Sebastian Berlit
- Department of Obstetrics and Gynecology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (B.T.); (S.B.); (M.S.)
| | - Elena Sperk
- Department of Radiation Oncology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany;
| | - Karen Bieback
- FlowCore Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (S.U.); (K.B.)
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, German Red Cross Blood Donor Services, Heidelberg University, 68167 Mannheim, Germany
- Mannheim Institute for Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Marc Sütterlin
- Department of Obstetrics and Gynecology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (B.T.); (S.B.); (M.S.)
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20
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Ma J, Hu X, Dai B, Wang Q, Wang H. Bioinformatics analysis of laryngeal squamous cell carcinoma: seeking key candidate genes and pathways. PeerJ 2021; 9:e11259. [PMID: 33954053 PMCID: PMC8052978 DOI: 10.7717/peerj.11259] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 03/22/2021] [Indexed: 12/20/2022] Open
Abstract
Background Laryngeal squamous cell carcinoma (LSCC) is the second most aggressive head and neck squamous cell carcinoma. Although much work has been done to optimize its treatment, patients with LSCC still have poor prognosis. Therefore, figuring out differentially expressed genes (DEGs) contained in the progression of LSCC and employing them as potential therapeutic targets or biomarkers for LSCC is extremely meaningful. Methods Overlapping DEGs were screened from two standalone Gene Expression Omnibus datasets, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. By applying STRING and Cytoscape, a protein–protein network was built, and module analysis was carried out. The hub genes were selected by maximal clique centrality with the CytoHubba plugin of Cytoscape. UALCAN and GEPIA data were examined to validate the gene expression findings. Moreover, the connection of the hub genes with LSCC patient overall survival was studied employing The Cancer Genome Atlas. Then, western blot, qRT-PCR, CCK-8, wound healing and transwell assays were bring to use for further verify the key genes. Results A total of 235 DEGs were recorded, including 83 upregulated and 152 downregulated genes. A total of nine hub genes that displayed a high degree of connectivity were selected. UALCAN and GEPIA databases verified that these genes were highly expressed in LSCC tissues. High expression of the SPP1, SERPINE1 and Matrix metalloproteinases 1 (MMP1) genes was connected to worse prognosis in patients with LSCC, according to the GEPIA online tool. Western blot and qRT-PCR testify SPP1, SERPINE1 and MMP1 were upregulated in LSCC cells. Inhibition of SPP1, SERPINE1 and MMP1 suppressed cell proliferation, invasion and migration. Conclusion The work here identified effective and reliable diagnostic and prognostic molecular biomarkers by unified bioinformatics analysis and experimental verification, indicating novel and necessary therapeutic targets for LSCC.
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Affiliation(s)
- Jinhua Ma
- Department of Otolaryngology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Xiaodong Hu
- Department of Otolaryngology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Baoqiang Dai
- Department of Otolaryngology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Qiang Wang
- Department of Otolaryngology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Hongqin Wang
- Department of Otolaryngology, Cangzhou Central Hospital, Cangzhou, Hebei, China
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21
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Vella V, De Francesco EM, Lappano R, Muoio MG, Manzella L, Maggiolini M, Belfiore A. Microenvironmental Determinants of Breast Cancer Metastasis: Focus on the Crucial Interplay Between Estrogen and Insulin/Insulin-Like Growth Factor Signaling. Front Cell Dev Biol 2020; 8:608412. [PMID: 33364239 PMCID: PMC7753049 DOI: 10.3389/fcell.2020.608412] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 11/09/2020] [Indexed: 12/12/2022] Open
Abstract
The development and progression of the great majority of breast cancers (BCs) are mainly dependent on the biological action elicited by estrogens through the classical estrogen receptor (ER), as well as the alternate receptor named G-protein–coupled estrogen receptor (GPER). In addition to estrogens, other hormones and growth factors, including the insulin and insulin-like growth factor system (IIGFs), play a role in BC. IIGFs cooperates with estrogen signaling to generate a multilevel cross-communication that ultimately facilitates the transition toward aggressive and life-threatening BC phenotypes. In this regard, the majority of BC deaths are correlated with the formation of metastatic lesions at distant sites. A thorough scrutiny of the biological and biochemical events orchestrating metastasis formation and dissemination has shown that virtually all cell types within the tumor microenvironment work closely with BC cells to seed cancerous units at distant sites. By establishing an intricate scheme of paracrine interactions that lead to the expression of genes involved in metastasis initiation, progression, and virulence, the cross-talk between BC cells and the surrounding microenvironmental components does dictate tumor fate and patients’ prognosis. Following (i) a description of the main microenvironmental events prompting BC metastases and (ii) a concise overview of estrogen and the IIGFs signaling and their major regulatory functions in BC, here we provide a comprehensive analysis of the most recent findings on the role of these transduction pathways toward metastatic dissemination. In particular, we focused our attention on the main microenvironmental targets of the estrogen-IIGFs interplay, and we recapitulated relevant molecular nodes that orientate shared biological responses fostering the metastatic program. On the basis of available studies, we propose that a functional cross-talk between estrogens and IIGFs, by affecting the BC microenvironment, may contribute to the metastatic process and may be regarded as a novel target for combination therapies aimed at preventing the metastatic evolution.
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Affiliation(s)
- Veronica Vella
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | - Ernestina Marianna De Francesco
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | - Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Maria Grazia Muoio
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy.,Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Livia Manzella
- Center of Experimental Oncology and Hematology, Azienda Ospedaliera Universitaria (A.O.U.) Policlinico Vittorio Emanuele, Catania, Italy.,Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Antonino Belfiore
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
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22
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Oncostatin M: A mysterious cytokine in cancers. Int Immunopharmacol 2020; 90:107158. [PMID: 33187910 DOI: 10.1016/j.intimp.2020.107158] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 10/04/2020] [Accepted: 10/26/2020] [Indexed: 02/07/2023]
Abstract
Oncostatin M (OSM), as a member of the Interleukin-6 family cytokines, plays a significant role in inflammation, autoimmunity, and cancers. It is mainly secreted by T lymphocytes, neutrophils, and macrophages and was initially introduced as anti-cancer agent. However, in some cases, it promotes cancer progression. Overexpression of OSM and OSM receptor has been detected in various cancers including colon cancer, breast cancer, pancreatic cancer, myeloma, brain tumors, chronic lymphocytic leukemia, and hepatoblastoma. STAT3 is the main downstream signaling molecule of OSM, which operates the leading role in modifications of cancer cells and enhancing cell growth, invasion, survival, and all other hallmarks of cancer cells. However, due to the presence of multiple signaling pathways, it can act contradictory in some cancers. In this review, we will discuss the emerging roles of OSM in cancer and elucidate its function in tumor control or progression and finally discuss therapeutic approaches designed to manipulate this cytokine in cancer.
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23
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Peng ZP, Jiang ZZ, Guo HF, Zhou MM, Huang YF, Ning WR, Huang JH, Zheng L, Wu Y. Glycolytic activation of monocytes regulates the accumulation and function of neutrophils in human hepatocellular carcinoma. J Hepatol 2020; 73:906-917. [PMID: 32407813 DOI: 10.1016/j.jhep.2020.05.004] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 04/30/2020] [Accepted: 05/03/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Neutrophils are one of the most abundant components in human hepatocellular carcinoma (HCC) and have been shown to play important roles in regulating disease progression. However, neutrophils are very short-lived cells in circulation, and mechanisms regulating their accumulation and functions in HCC are not yet fully understood. METHODS Monocytes were purified from non-tumor or paired tumor tissues of patients with HCC, and their production of neutrophil-attracting chemokines was evaluated. Mechanisms regulating the expression of CXCL2/8 by tumor monocytes, and the role of tumor monocyte-derived chemokines and cytokines in modulating neutrophil accumulation and functions were studied with both ex vivo analyses and in vitro experiments. RESULTS Monocyte-derived CXCL2 and CXCL8 were major factors in regulating the recruitment of neutrophils into tumor milieus. These chemokines, in addition to tumor-derived soluble factors, could inhibit apoptosis and sustain survival of neutrophils, thus leading to neutrophil accumulation in tumor tissues. Moreover, monocyte-derived TNF-α acted synergistically with tumor-derived soluble factors to induce the production of the pro-metastasis factor OSM by neutrophils. Further, the glycolytic switch in tumor-infiltrating monocytes mediated their production of CXCL2 and CXCL8 via the PFKFB3-NF-κB signaling pathway. Accordingly, levels of PFKFB3, CXCL2/CXCL8 production in monocytes and infiltration of OSM-producing neutrophils were positively correlated in human HCC tissues. CONCLUSIONS Our results unveiled a previously unappreciated link between monocytes and neutrophils in human HCC, identifying possible targets that could be therapeutically exploited in the future. LAY SUMMARY Neutrophils constitute a major but poorly understood component of human hepatocellular carcinoma (HCC). Herein, we unveil a novel mechanism by which metabolic switching in monocytes promotes the accumulation of neutrophils in the tumors of patients with HCC. Both monocyte-produced chemokines and signals from the tumor microenvironment promote the production of the pro-metastatic factor OSM by neutrophils. These data identify potential targets for immune-based anticancer therapies for HCC.
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Affiliation(s)
- Zhi-Peng Peng
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Ze-Zhou Jiang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Hao-Fan Guo
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China
| | - Meng-Meng Zhou
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China
| | - Yu-Fan Huang
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China
| | - Wan-Ru Ning
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China
| | - Jin-Hua Huang
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Limin Zheng
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Yan Wu
- MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China.
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The Role of Adipokines and Bone Marrow Adipocytes in Breast Cancer Bone Metastasis. Int J Mol Sci 2020; 21:ijms21144967. [PMID: 32674405 PMCID: PMC7404398 DOI: 10.3390/ijms21144967] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 02/07/2023] Open
Abstract
The morbidity and mortality of breast cancer is mostly due to a distant metastasis, especially to the bone. Many factors may be responsible for bone metastasis in breast cancer, but interactions between tumor cells and other surrounding types of cells, and cytokines secreted by both, are expected to play the most important role. Bone marrow adipocyte (BMA) is one of the cell types comprising the bone, and adipokine is one of the cytokines secreted by both breast cancer cells and BMAs. These BMAs and adipokines are known to be responsible for cancer progression, and this review is focused on how BMAs and adipokines work in the process of breast cancer bone metastasis. Their potential as suppressive targets for bone metastasis is also explored in this review.
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25
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Simões BM, Santiago-Gómez A, Chiodo C, Moreira T, Conole D, Lovell S, Alferez D, Eyre R, Spence K, Sarmiento-Castro A, Kohler B, Morisset L, Lanzino M, Andò S, Marangoni E, Sims AH, Tate EW, Howell SJ, Clarke RB. Targeting STAT3 signaling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer. Oncogene 2020; 39:4896-4908. [PMID: 32472077 PMCID: PMC7299846 DOI: 10.1038/s41388-020-1335-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 05/13/2020] [Accepted: 05/15/2020] [Indexed: 01/05/2023]
Abstract
Estrogen receptor (ER) positive breast cancer is frequently sensitive to endocrine therapy. Multiple mechanisms of endocrine therapy resistance have been identified, including cancer stem-like cell (CSC) activity. Here we investigate SFX-01, a stabilised formulation of sulforaphane (SFN), for its effects on breast CSC activity in ER+ preclinical models. SFX-01 reduced mammosphere formation efficiency (MFE) of ER+ primary and metastatic patient samples. Both tamoxifen and fulvestrant increased MFE and aldehyde dehydrogenase (ALDH) activity of patient-derived xenograft (PDX) tumors, which was reversed by combination with SFX-01. SFX-01 significantly reduced tumor-initiating cell frequency in secondary transplants and reduced the formation of spontaneous lung micrometastases by PDX tumors in mice. Mechanistically, we establish that both tamoxifen and fulvestrant induce STAT3 phosphorylation. SFX-01 suppressed phospho-STAT3 and SFN directly bound STAT3 in patient and PDX samples. Analysis of ALDH+ cells from endocrine-resistant patient samples revealed activation of STAT3 target genes MUC1 and OSMR, which were inhibited by SFX-01 in patient samples. Increased expression of these genes after 3 months' endocrine treatment of ER+ patients (n = 68) predicted poor prognosis. Our data establish the importance of STAT3 signaling in CSC-mediated resistance to endocrine therapy and the potential of SFX-01 for improving clinical outcomes in ER+ breast cancer.
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Affiliation(s)
- Bruno M Simões
- Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
| | - Angélica Santiago-Gómez
- Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Chiara Chiodo
- Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Department of Pharmacy, University of Calabria, Arcavacata di Rende, Italy
| | - Tiago Moreira
- Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Daniel Conole
- Molecular Sciences Research Hub, Imperial College, London, UK
| | - Scott Lovell
- Molecular Sciences Research Hub, Imperial College, London, UK
| | - Denis Alferez
- Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Rachel Eyre
- Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Katherine Spence
- Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Aida Sarmiento-Castro
- Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Bertram Kohler
- Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Ludivine Morisset
- Institut Curie, PSL Research University, Translational Research Department, Paris, France
| | - Marilena Lanzino
- Department of Pharmacy, University of Calabria, Arcavacata di Rende, Italy
| | - Sebastiano Andò
- Department of Pharmacy, University of Calabria, Arcavacata di Rende, Italy
| | - Elisabetta Marangoni
- Institut Curie, PSL Research University, Translational Research Department, Paris, France
| | - Andrew H Sims
- Applied Bioinformatics of Cancer Group, University of Edinburgh Cancer Research UK Centre, Edinburgh, UK
| | - Edward W Tate
- Molecular Sciences Research Hub, Imperial College, London, UK
| | - Sacha J Howell
- Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
| | - Robert B Clarke
- Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
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Kong D, Hughes CJ, Ford HL. Cellular Plasticity in Breast Cancer Progression and Therapy. Front Mol Biosci 2020; 7:72. [PMID: 32391382 PMCID: PMC7194153 DOI: 10.3389/fmolb.2020.00072] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 03/31/2020] [Indexed: 12/24/2022] Open
Abstract
With the exception of non-melanoma skin cancer, breast cancer is the most frequently diagnosed malignant disease among women, with the majority of mortality being attributable to metastatic disease. Thus, even with improved early screening and more targeted treatments which may enable better detection and control of early disease progression, metastatic disease remains a significant problem. While targeted therapies exist for breast cancer patients with particular subtypes of the disease (Her2+ and ER/PR+), even in these subtypes the therapies are often not efficacious once the patient's tumor metastasizes. Increases in stemness or epithelial-to-mesenchymal transition (EMT) in primary breast cancer cells lead to enhanced plasticity, enabling tumor progression, therapeutic resistance, and distant metastatic spread. Numerous signaling pathways, including MAPK, PI3K, STAT3, Wnt, Hedgehog, and Notch, amongst others, play a critical role in maintaining cell plasticity in breast cancer. Understanding the cellular and molecular mechanisms that regulate breast cancer cell plasticity is essential for understanding the biology of breast cancer progression and for developing novel and more effective therapeutic strategies for targeting metastatic disease. In this review we summarize relevant literature on mechanisms associated with breast cancer plasticity, tumor progression, and drug resistance.
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Affiliation(s)
- Deguang Kong
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Connor J. Hughes
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Pharmacology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Heide L. Ford
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Pharmacology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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Matsumoto Y, Ichikawa T, Kurozumi K, Otani Y, Fujimura A, Fujii K, Tomita Y, Hattori Y, Uneda A, Tsuboi N, Kaneda K, Makino K, Date I. Annexin A2-STAT3-Oncostatin M receptor axis drives phenotypic and mesenchymal changes in glioblastoma. Acta Neuropathol Commun 2020; 8:42. [PMID: 32248843 PMCID: PMC7132881 DOI: 10.1186/s40478-020-00916-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 03/13/2020] [Indexed: 12/14/2022] Open
Abstract
Glioblastoma (GBM) is characterized by extensive tumor cell invasion, angiogenesis, and proliferation. We previously established subclones of GBM cells with distinct invasive phenotypes and identified annexin A2 (ANXA2) as an activator of angiogenesis and perivascular invasion. Here, we further explored the role of ANXA2 in regulating phenotypic transition in GBM. We identified oncostatin M receptor (OSMR) as a key ANXA2 target gene in GBM utilizing microarray analysis and hierarchical clustering analysis of the Ivy Glioblastoma Atlas Project and The Cancer Genome Atlas datasets. Overexpression of ANXA2 in GBM cells increased the expression of OSMR and phosphorylated signal transducer and activator of transcription 3 (STAT3) and enhanced cell invasion, angiogenesis, proliferation, and mesenchymal transition. Silencing of OSMR reversed the ANXA2-induced phenotype, and STAT3 knockdown reduced OSMR protein expression. Exposure of GBM cells to hypoxic conditions activated the ANXA2–STAT3–OSMR signaling axis. Mice bearing ANXA2-overexpressing GBM exhibited shorter survival times compared with control tumor-bearing mice, whereas OSMR knockdown increased the survival time and diminished ANXA2-mediated tumor invasion, angiogenesis, and growth. Further, we uncovered a significant relationship between ANXA2 and OSMR expression in clinical GBM specimens, and demonstrated their correlation with tumor histopathology and patient prognosis. Our results indicate that the ANXA2–STAT3–OSMR axis regulates malignant phenotypic changes and mesenchymal transition in GBM, suggesting that this axis is a promising therapeutic target to treat GBM aggressiveness.
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Omokehinde T, Johnson RW. GP130 Cytokines in Breast Cancer and Bone. Cancers (Basel) 2020; 12:cancers12020326. [PMID: 32023849 PMCID: PMC7072680 DOI: 10.3390/cancers12020326] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 01/24/2020] [Accepted: 01/29/2020] [Indexed: 12/14/2022] Open
Abstract
Breast cancer cells have a high predilection for skeletal homing, where they may either induce osteolytic bone destruction or enter a latency period in which they remain quiescent. Breast cancer cells produce and encounter autocrine and paracrine cytokine signals in the bone microenvironment, which can influence their behavior in multiple ways. For example, these signals can promote the survival and dormancy of bone-disseminated cancer cells or stimulate proliferation. The interleukin-6 (IL-6) cytokine family, defined by its use of the glycoprotein 130 (gp130) co-receptor, includes interleukin-11 (IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1), among others. These cytokines are known to have overlapping pleiotropic functions in different cell types and are important for cross-talk between bone-resident cells. IL-6 cytokines have also been implicated in the progression and metastasis of breast, prostate, lung, and cervical cancer, highlighting the importance of these cytokines in the tumor–bone microenvironment. This review will describe the role of these cytokines in skeletal remodeling and cancer progression both within and outside of the bone microenvironment.
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Affiliation(s)
- Tolu Omokehinde
- Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Rachelle W. Johnson
- Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Correspondence: ; Tel.: +1-615-875-8965
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Song K, Chen J, Ding J, Xu H, Xu H, Qin Z. Hyperbaric oxygen suppresses stemness-associated properties and Nanog and oncostatin M expression, but upregulates β-catenin in orthotopic glioma models. J Int Med Res 2019; 48:300060519872898. [PMID: 31813325 PMCID: PMC7607208 DOI: 10.1177/0300060519872898] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Objective This study aimed to explore whether initial hyperbaric oxygen treatment
affects the stemness of glioma stem cells using an in vivo
basal ganglia glioma model. Methods A basal ganglia glioma rat model was established. Rats were exposed to normal
oxygen or hyperbaric oxygen on days 2, 4, 6, 8, 10, and 12. After 16 days of
glioma cell inoculation, western blot, ELISA, and flow cytometry were
performed to examine stemness-associated properties by examining the
expression of CD133, A2B5, Nanog, oncostatin M, β-catenin, Oct-3/4, Sox2,
and Nestin. Results Initial hyperbaric oxygen treatment began to affect glioma
stemness-associated properties. The proportion of
CD133+A2B5+ cells was significantly reduced after
initial hyperbaric oxygen treatment. Additionally, the expression of
stemness-related genes such as Nanog and oncostatin M was reduced, while
TGF-β and β-catenin were increased. Conclusions Initial hyperbaric oxygen treatment not only alters the hypoxic
microenvironment but also affects the stemness-associated properties of
cancer stem cells.
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Affiliation(s)
- Kun Song
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Junrui Chen
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jianbo Ding
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hao Xu
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hongzhi Xu
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhiyong Qin
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
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Christodoulatos GS, Spyrou N, Kadillari J, Psallida S, Dalamaga M. The Role of Adipokines in Breast Cancer: Current Evidence and Perspectives. Curr Obes Rep 2019; 8:413-433. [PMID: 31637624 DOI: 10.1007/s13679-019-00364-y] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE The current review shows evidence for the role of adipokines in breast cancer (BC) pathogenesis summarizing the mechanisms underlying the association between adipokines and breast malignancy. Special emphasis is given also on intriguing insights into the relationship between obesity and BC as well as on the role of novel adipokines in BC development. RECENT FINDINGS Recent evidence has underscored the role of the triad of obesity, insulin resistance, and adipokines in postmenopausal BC. Adipokines exert independent and joint effects on activation of major intracellular signal networks implicated in BC cell proliferation, growth, survival, invasion, and metastasis, particularly in the context of obesity, considered a systemic endocrine dysfunction characterized by chronic inflammation. To date, more than 10 adipokines have been linked to BC, and this catalog is continuously increasing. The majority of circulating adipokines, such as leptin, resistin, visfatin, apelin, lipocalin 2, osteopontin, and oncostatin M, is elevated in BC, while some adipokines such as adiponectin and irisin (adipo-myokine) are generally decreased in BC and considered protective against breast carcinogenesis. Further evidence from basic and translational research is necessary to delineate the ontological role of adipokines and their interplay in BC pathogenesis. More large-scale clinical and longitudinal studies are awaited to assess their clinical utility in BC prognosis and follow-up. Finally, novel more effective and safer adipokine-centered therapeutic strategies could pave the way for targeted oncotherapy.
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Affiliation(s)
- Gerasimos Socrates Christodoulatos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias, Goudi, 11527, Athens, Greece
- Laboratory of Microbiology, KAT Hospital, 2 Nikis, Kifisia, 14561, Athens, Greece
| | - Nikolaos Spyrou
- 251 Airforce General Hospital, 3 Kanellopoulou, 11525, Athens, Greece
| | - Jona Kadillari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias, Goudi, 11527, Athens, Greece
| | - Sotiria Psallida
- Laboratory of Microbiology, KAT Hospital, 2 Nikis, Kifisia, 14561, Athens, Greece
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias, Goudi, 11527, Athens, Greece.
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Polak KL, Chernosky NM, Smigiel JM, Tamagno I, Jackson MW. Balancing STAT Activity as a Therapeutic Strategy. Cancers (Basel) 2019; 11:cancers11111716. [PMID: 31684144 PMCID: PMC6895889 DOI: 10.3390/cancers11111716] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/23/2019] [Accepted: 10/31/2019] [Indexed: 12/13/2022] Open
Abstract
Driven by dysregulated IL-6 family member cytokine signaling in the tumor microenvironment (TME), aberrant signal transducer and activator of transcription (STAT3) and (STAT5) activation have been identified as key contributors to tumorigenesis. Following transformation, persistent STAT3 activation drives the emergence of mesenchymal/cancer-stem cell (CSC) properties, important determinants of metastatic potential and therapy failure. Moreover, STAT3 signaling within tumor-associated macrophages and neutrophils drives secretion of factors that facilitate metastasis and suppress immune cell function. Persistent STAT5 activation is responsible for cancer cell maintenance through suppression of apoptosis and tumor suppressor signaling. Furthermore, STAT5-mediated CD4+/CD25+ regulatory T cells (Tregs) have been implicated in suppression of immunosurveillance. We discuss these roles for STAT3 and STAT5, and weigh the attractiveness of different modes of targeting each cancer therapy. Moreover, we discuss how anti-tumorigenic STATs, including STAT1 and STAT2, may be leveraged to suppress the pro-tumorigenic functions of STAT3/STAT5 signaling.
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Affiliation(s)
- Kelsey L Polak
- Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
| | - Noah M Chernosky
- Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
| | - Jacob M Smigiel
- Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
| | - Ilaria Tamagno
- Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
| | - Mark W Jackson
- Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
- Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
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Smigiel JM, Taylor SE, Bryson BL, Tamagno I, Polak K, Jackson MW. Cellular plasticity and metastasis in breast cancer: a pre- and post-malignant problem. JOURNAL OF CANCER METASTASIS AND TREATMENT 2019; 5:47. [PMID: 32355893 PMCID: PMC7192216 DOI: 10.20517/2394-4722.2019.26] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
As a field we have made tremendous strides in treating breast cancer, with a decline in the past 30 years of overall breast cancer mortality. However, this progress is met with little affect once the disease spreads beyond the primary site. With a 5-year survival rate of 22%, 10-year of 13%, for those patients with metastatic breast cancer (mBC), our ability to effectively treat wide spread disease is minimal. A major contributing factor to this ineffectiveness is the complex make-up, or heterogeneity, of the primary site. Within a primary tumor, secreted factors, malignant and pre-malignant epithelial cells, immune cells, stromal fibroblasts and many others all reside alongside each other creating a dynamic environment contributing to metastasis. Furthermore, heterogeneity contributes to our lack of understanding regarding the cells' remarkable ability to undergo epithelial/non-cancer stem cell (CSC) to mesenchymal/CSC (E-M/CSC) plasticity. The enhanced invasion & motility, tumor-initiating potential, and acquired therapeutic resistance which accompanies E-M/CSC plasticity implicates a significant role in metastasis. While most work trying to understand E-M/CSC plasticity has been done on malignant cells, recent evidence is emerging concerning the ability for pre-malignant cells to undergo E-M/CSC plasticity and contribute to the metastatic process. Here we will discuss the importance of E-M/CSC plasticity within malignant and pre-malignant populations of the tumor. Moreover, we will discuss how one may potentially target these populations, ultimately disrupting the metastatic cascade and increasing patient survival for those with mBC.
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Affiliation(s)
- Jacob M. Smigiel
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Sarah E. Taylor
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Benjamin L. Bryson
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Ilaria Tamagno
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Kelsey Polak
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Mark W. Jackson
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
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Over-expression of miR-206 decreases the Euthyrox-resistance by targeting MAP4K3 in papillary thyroid carcinoma. Biomed Pharmacother 2019; 114:108605. [DOI: 10.1016/j.biopha.2019.108605] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 01/04/2019] [Accepted: 01/18/2019] [Indexed: 01/13/2023] Open
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Culig Z. Epithelial mesenchymal transition and resistance in endocrine-related cancers. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2019; 1866:1368-1375. [PMID: 31108117 DOI: 10.1016/j.bbamcr.2019.05.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 04/26/2019] [Accepted: 05/16/2019] [Indexed: 12/21/2022]
Abstract
Epithelial to mesencyhmal transition (EMT) has a central role in tumor metastasis and progression. EMT is regulated by several growth factors and pro-inflammatory cytokines. The most important role in this regulation could be attributed to transforming growth factor-β (TGF-β). In breast cancer, TGF-β effect on EMT could be potentiated by Fos-related antigen, oncogene HER2, epidermal growth factor, or mitogen-activated protein kinase kinase 5 - extracellular-regulated kinase signaling. Several microRNAs in breast cancer have a considerable role either in potentiation or in suppression of EMT thus acting as oncogenic or tumor suppressive modulators. At present, possibilities to target EMT are discussed but the results of clinical translation are still limited. In prostate cancer, many cellular events are regulated by androgenic hormones. Different experimental results on androgenic stimulation or inhibition of EMT have been reported in the literature. Thus, a possibility that androgen ablation therapy leads to EMT thus facilitating tumor progression has to be discussed. Novel therapy agents, such as the anti-diabetic drug metformin or selective estrogen receptor modulator ormeloxifene were used in pre-clinical studies to inhibit EMT in prostate cancer. Taken together, the results of pre-clinical and clinical studies in breast cancer may be helpful in the process of drug development and identify potential risk during the early stage of that process.
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Affiliation(s)
- Zoran Culig
- Experimental Urology, Department of Urology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
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Guo Q, Li VZ, Nichol JN, Huang F, Yang W, Preston SEJ, Talat Z, Lefrère H, Yu H, Zhang G, Basik M, Gonçalves C, Zhan Y, Plourde D, Su J, Torres J, Marques M, Habyan SA, Bijian K, Amant F, Witcher M, Behbod F, McCaffrey L, Alaoui-Jamali M, Giannakopoulos NV, Brackstone M, Postovit LM, Del Rincón SV, Miller WH. MNK1/NODAL Signaling Promotes Invasive Progression of Breast Ductal Carcinoma In Situ. Cancer Res 2019; 79:1646-1657. [PMID: 30659022 PMCID: PMC6513674 DOI: 10.1158/0008-5472.can-18-1602] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 11/02/2018] [Accepted: 01/10/2019] [Indexed: 12/11/2022]
Abstract
The mechanisms by which breast cancers progress from relatively indolent ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) are not well understood. However, this process is critical to the acquisition of metastatic potential. MAPK-interacting serine/threonine-protein kinase 1 (MNK1) signaling can promote cell invasion. NODAL, a morphogen essential for embryogenic patterning, is often reexpressed in breast cancer. Here we describe a MNK1/NODAL signaling axis that promotes DCIS progression to IDC. We generated MNK1 knockout (KO) or constitutively active MNK1 (caMNK1)-expressing human MCF-10A-derived DCIS cell lines, which were orthotopically injected into the mammary glands of mice. Loss of MNK1 repressed NODAL expression, inhibited DCIS to IDC conversion, and decreased tumor relapse and metastasis. Conversely, caMNK1 induced NODAL expression and promoted IDC. The MNK1/NODAL axis promoted cancer stem cell properties and invasion in vitro. The MNK1/2 inhibitor SEL201 blocked DCIS progression to invasive disease in vivo. In clinical samples, IDC and DCIS with microinvasion expressed higher levels of phospho-MNK1 and NODAL versus low-grade (invasion-free) DCIS. Cumulatively, our data support further development of MNK1 inhibitors as therapeutics for preventing invasive disease. SIGNIFICANCE: These findings provide new mechanistic insight into progression of ductal carcinoma and support clinical application of MNK1 inhibitors to delay progression of indolent ductal carcinoma in situ to invasive ductal carcinoma.
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Affiliation(s)
- Qianyu Guo
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Vivian Z Li
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Jessica N Nichol
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Fan Huang
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - William Yang
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Samuel E J Preston
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Zahra Talat
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Hanne Lefrère
- Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Henry Yu
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Guihua Zhang
- Cancer Research Institute of Northern Alberta, Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - Mark Basik
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Christophe Gonçalves
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Yao Zhan
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Dany Plourde
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Jie Su
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Jose Torres
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Maud Marques
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Sara Al Habyan
- Goodman Cancer Centre, McGill University, Montréal, Québec, Canada
| | - Krikor Bijian
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Frédéric Amant
- Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Michael Witcher
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Fariba Behbod
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Centre, Kansas City, Kansas
| | - Luke McCaffrey
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Goodman Cancer Centre, McGill University, Montréal, Québec, Canada
| | - Moulay Alaoui-Jamali
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Nadia V Giannakopoulos
- Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Muriel Brackstone
- Departments of Surgery and Oncology, Western University, London, Ontario, Canada
| | - Lynne-Marie Postovit
- Cancer Research Institute of Northern Alberta, Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
- Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Sonia V Del Rincón
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
| | - Wilson H Miller
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.
- Department of Oncology, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada
- Rossy Cancer Network, McGill University, Montréal, Québec, Canada
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Browning L, Patel MR, Horvath EB, Tawara K, Jorcyk CL. IL-6 and ovarian cancer: inflammatory cytokines in promotion of metastasis. Cancer Manag Res 2018; 10:6685-6693. [PMID: 30584363 PMCID: PMC6287645 DOI: 10.2147/cmar.s179189] [Citation(s) in RCA: 186] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Ovarian cancer is the most fatal gynecological cancer in the USA and the fifth most common cancer-related cause of death in women. Inflammation has been shown to play many roles in ovarian cancer tumor growth, with the proinflammatory cytokine interleukin-6 (IL-6) having been established as a key immunoregulatory cytokine. Ovarian cancer cells continuously secrete cytokines that promote tumorigenicity in both autocrine and paracrine fashions while also receiving signals from the tumor microenvironment (TME). The TME contains many cells including leukocytes and fibroblasts, which respond to proinflammatory cytokines and secrete their own cytokines, which can produce many effects including promotion of chemoresistance, resistance to apoptosis, invasion, angiogenesis by way of overexpression of vascular endothelial growth factor, and promotion of metastatic growth at distant sites. IL-6 and its proinflammatory family members, including oncostatin M, have been found to directly stimulate enhanced invasion of cancer cells through basement membrane degradation caused by the overexpression of matrix metalloproteinases, stimulate promotion of cell cycle, enhance resistance to chemotherapy, and cause epithelial-to-mesenchymal transition (EMT). IL-6 has been shown to activate signaling pathways that lead to tumor proliferation, the most studied of which being the Janus kinase (JAK) and STAT3 pathway. IL-6-induced JAK/STAT activation leads to constitutive activation of STAT3, which has been correlated with enhanced tumor cell growth and resistance to chemotherapy. IL-6 has also been shown to act as a trigger of the EMT, the hypothesized first step in the metastatic cascade. Understanding the important role of IL-6 and its family members' effects on the pathogenesis of ovarian cancer tumor growth and metastasis may lead to more novel treatments, detection methods, and improvement of overall clinical outcomes.
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Affiliation(s)
- Landon Browning
- University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Megha R Patel
- University of California Riverside School of Medicine, Riverside, CA 92521, USA
| | - Eli Bring Horvath
- Department of Biological Sciences, Boise State University, Boise, ID 83725, USA,
| | - Ken Tawara
- Department of Biological Sciences, Boise State University, Boise, ID 83725, USA, .,Biomolecular Sciences Program, Boise State University, Boise, ID 83725, USA,
| | - Cheryl L Jorcyk
- Department of Biological Sciences, Boise State University, Boise, ID 83725, USA, .,Biomolecular Sciences Program, Boise State University, Boise, ID 83725, USA,
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West NR, Owens BMJ, Hegazy AN. The oncostatin M-stromal cell axis in health and disease. Scand J Immunol 2018; 88:e12694. [DOI: 10.1111/sji.12694] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Accepted: 06/15/2018] [Indexed: 12/17/2022]
Affiliation(s)
- Nathaniel R. West
- Department of Cancer Immunology; Genentech; South San Francisco California
| | - Benjamin M. J. Owens
- Somerville College; University of Oxford; Oxford UK
- EUSA Pharma; Hemel Hempstead UK
| | - Ahmed N. Hegazy
- Division of Gastroenterology, Infectiology, and Rheumatology; Charité Universitätsmedizin; Berlin Germany
- Deutsches Rheuma-Forschungszentrum; ein Institut der Leibniz-Gemeinschaft; Berlin Germany
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Bhattacharya A, Kumar J, Hermanson K, Sun Y, Qureshi H, Perley D, Scheidegger A, Singh BB, Dhasarathy A. The calcium channel proteins ORAI3 and STIM1 mediate TGF-β induced Snai1 expression. Oncotarget 2018; 9:29468-29483. [PMID: 30034631 PMCID: PMC6047677 DOI: 10.18632/oncotarget.25672] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 06/09/2018] [Indexed: 12/11/2022] Open
Abstract
Calcium influx into cells via plasma membrane protein channels is tightly regulated to maintain cellular homeostasis. Calcium channel proteins in the plasma membrane and endoplasmic reticulum have been linked to cancer, specifically during the epithelial-mesenchymal transition (EMT), a cell state transition process implicated in both cancer cell migration and drug resistance. The transcription factor SNAI1 (SNAIL) is upregulated during EMT and is responsible for gene expression changes associated with EMT, but the calcium channels required for Snai1 expression remain unknown. In this study, we show that blocking store-operated calcium entry (SOCE) with 2-aminoethoxydiphenylborane (2APB) reduces cell migration but, paradoxically, increases the level of TGF-β dependent Snai1 gene activation. We determined that this increased Snai1 transcription involves signaling through the AKT pathway and subsequent binding of NF-κB (p65) at the Snai1 promoter in response to TGF-β. We also demonstrated that the calcium channel protein ORAI3 and the stromal interaction molecule 1 (STIM1) are required for TGF-β dependent Snai1 transcription. These results suggest that calcium channels differentially regulate cell migration and Snai1 transcription, indicating that each of these steps could be targeted to ensure complete blockade of cancer progression.
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Affiliation(s)
- Atrayee Bhattacharya
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
| | - Janani Kumar
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
- Present address: MD Anderson Cancer Center, Mitchell Basic Sciences Research Building, TX, USA
| | - Kole Hermanson
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
| | - Yuyang Sun
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
- Present address: UT Health Science Center, San Antonio, San Antonio, TX, USA
| | - Humaira Qureshi
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
- Present address: Habib University, University Avenue, Gulistan-e-Jauhar, Karachi, Pakistan
| | - Danielle Perley
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
| | - Adam Scheidegger
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
| | - Brij B. Singh
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
- Present address: UT Health Science Center, San Antonio, San Antonio, TX, USA
| | - Archana Dhasarathy
- Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
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Tawara K, Bolin C, Koncinsky J, Kadaba S, Covert H, Sutherland C, Bond L, Kronz J, Garbow JR, Jorcyk CL. OSM potentiates preintravasation events, increases CTC counts, and promotes breast cancer metastasis to the lung. Breast Cancer Res 2018; 20:53. [PMID: 29898744 PMCID: PMC6001163 DOI: 10.1186/s13058-018-0971-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 04/21/2018] [Indexed: 02/08/2023] Open
Abstract
Background Systemic and chronic inflammatory conditions in patients with breast cancer have been associated with reduced patient survival and increased breast cancer aggressiveness. This paper characterizes the role of an inflammatory cytokine, oncostatin M (OSM), in the preintravasation aspects of breast cancer metastasis. Methods OSM expression levels in human breast cancer tissue samples were assessed using tissue microarrays, and expression patterns based on clinical stage were assessed. To determine the in vivo role of OSM in breast cancer metastasis to the lung, we used three orthotopic breast cancer mouse models, including a syngeneic 4T1.2 mouse mammary cancer model, the MDA-MB-231 human breast cancer xenograft model, and an OSM-knockout (OSM-KO) mouse model. Progression of metastatic disease was tracked by magnetic resonance imaging and bioluminescence imaging. Endpoint analysis included circulating tumor cell (CTC) counts, lung metastatic burden analysis by qPCR, and ex vivo bioluminescence imaging. Results Using tissue microarrays, we found that tumor cell OSM was expressed at the highest levels in ductal carcinoma in situ. This finding suggests that OSM may function during the earlier steps of breast cancer metastasis. In mice bearing MDA-MB-231-Luc2 xenograft tumors, peritumoral injection of recombinant human OSM not only increased metastases to the lung and decreased survival but also increased CTC numbers. To our knowledge, this is the first time that a gp130 family inflammatory cytokine has been shown to directly affect CTC numbers. Using a 4T1.2 syngeneic mouse model of breast cancer, we found that mice bearing 4T1.2-shOSM tumors with knocked down tumor expression of OSM had reduced CTCs, decreased lung metastatic burden, and increased survival compared with mice bearing control tumors. CTC numbers were further reduced in OSM-KO mice bearing the same tumors, demonstrating the importance of both paracrine- and autocrine-produced OSM in this process. In vitro studies further supported the hypothesis that OSM promotes preintravasation aspects of cancer metastasis, because OSM induced both 4T1.2 tumor cell detachment and migration. Conclusions Collectively, our findings suggest that OSM plays a crucial role in the early steps of metastatic breast cancer progression, resulting in increased CTCs and lung metastases as well as reduced survival. Therefore, early therapeutic inhibition of OSM in patients with breast cancer may prevent breast cancer metastasis. Electronic supplementary material The online version of this article (10.1186/s13058-018-0971-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ken Tawara
- Department of Biological Sciences, Biomolecular Sciences Program, Boise State University, 1910 University Drive, Boise, ID, 83725, USA
| | - Celeste Bolin
- Department of Biological Sciences, Biomolecular Sciences Program, Boise State University, 1910 University Drive, Boise, ID, 83725, USA
| | - Jordan Koncinsky
- Department of Biological Sciences, Biomolecular Sciences Program, Boise State University, 1910 University Drive, Boise, ID, 83725, USA
| | - Sujatha Kadaba
- Department of Biological Sciences, Biomolecular Sciences Program, Boise State University, 1910 University Drive, Boise, ID, 83725, USA
| | - Hunter Covert
- Department of Biological Sciences, Biomolecular Sciences Program, Boise State University, 1910 University Drive, Boise, ID, 83725, USA
| | - Caleb Sutherland
- Department of Biological Sciences, Biomolecular Sciences Program, Boise State University, 1910 University Drive, Boise, ID, 83725, USA
| | - Laura Bond
- Department of Biological Sciences, Biomolecular Sciences Program, Boise State University, 1910 University Drive, Boise, ID, 83725, USA
| | | | - Joel R Garbow
- Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, 63110, USA
| | - Cheryl L Jorcyk
- Department of Biological Sciences, Biomolecular Sciences Program, Boise State University, 1910 University Drive, Boise, ID, 83725, USA.
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Shrivastava R, Asif M, Singh V, Dubey P, Ahmad Malik S, Lone MUD, Tewari BN, Baghel KS, Pal S, Nagar GK, Chattopadhyay N, Bhadauria S. M2 polarization of macrophages by Oncostatin M in hypoxic tumor microenvironment is mediated by mTORC2 and promotes tumor growth and metastasis. Cytokine 2018; 118:130-143. [PMID: 29625858 DOI: 10.1016/j.cyto.2018.03.032] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2017] [Revised: 03/19/2018] [Accepted: 03/21/2018] [Indexed: 12/16/2022]
Abstract
Oncostatin M (OSM), an inflammatory cytokine belonging to the interleukin-6 (IL-6) superfamily, plays a vital role in multitude of physiological and pathological processes. Its role in breast tumor progression and metastasis to distant organs is well documented. Recent reports implicate OSM in macrophage M2 polarization, a key pro-tumoral phenomenon. M2 polarization of macrophages is believed to promote tumor progression by potentiating metastasis and angiogenesis. In the current study, we delineated the mechanism underlying OSM induced macrophage M2 polarization. The findings revealed that OSM skews macrophages towards an M2 polarized phenotype via mTOR signaling complex 2 (mTORC2). mTORC2 relays signals through two effector kinases i.e. PKC-α and Akt. Our results indicated that mTORC2 mediated M2 polarization of macrophages is not dependent on PKC-α and is primarily affected via Akt, particularly Akt1. In vivo studies conducted on 4T1/BALB/c mouse orthotropic model of breast cancer further corroborated these observations wherein i.v. reintroduction of mTORC2 abrogated monocytes into orthotropic mouse model resulted in diminished acquisition of M2 specific attributes by tumor associated macrophages. Metastasis to distant organs like lung, liver and bone was reduced as evident by decrease in formation of focal metastatic lesions in mTORC2 abrogated monocytes mice. Our study pinpoints key role of mTORC2-Akt1 axis in OSM induced macrophage polarization and suggests for possible usage of Oncostatin-M blockade and/or selective mTORC2 inhibition as a potential anti-cancer strategy particularly with reference to metastasis of breast cancer to distant organs such as lung, liver and bone.
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Affiliation(s)
- Richa Shrivastava
- Division of Toxicology and Experimental Medicine, Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India
| | - Mohammad Asif
- Division of Toxicology and Experimental Medicine, Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh 226031, India
| | - Varsha Singh
- Division of Toxicology and Experimental Medicine, Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh 226031, India
| | - Parul Dubey
- Department of Surgical Oncology, King George Medical University, Lucknow, Uttar Pradesh 226003, India
| | - Showkat Ahmad Malik
- Division of Toxicology and Experimental Medicine, Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh 226031, India
| | - Mehraj-U-Din Lone
- Division of Toxicology and Experimental Medicine, Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh 226031, India
| | - Brij Nath Tewari
- Department of Surgical Oncology, King George Medical University, Lucknow, Uttar Pradesh 226003, India
| | - Khemraj Singh Baghel
- Division of Toxicology and Experimental Medicine, Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh 226031, India
| | - Subhashis Pal
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Target in Health and Illness (ASTHI), Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh 226031, India
| | - Geet Kumar Nagar
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Target in Health and Illness (ASTHI), Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh 226031, India
| | - Naibedya Chattopadhyay
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Target in Health and Illness (ASTHI), Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh 226031, India
| | - Smrati Bhadauria
- Division of Toxicology and Experimental Medicine, Central Drug Research Institute (CSIR), Lucknow, Uttar Pradesh 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India.
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Oncostatin M induces tumorigenic properties in non-transformed human prostate epithelial cells, in part through activation of signal transducer and activator of transcription 3 (STAT3). Biochem Biophys Res Commun 2018. [PMID: 29526757 DOI: 10.1016/j.bbrc.2018.03.056] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Prostate cancer is one of the most common types of cancer in men in Western countries. Chronic inflammation in the prostate, regulated by a complex network of factors including inflammatory cytokines, is one of the established risk factors for development of prostate cancer. Interleukin-6 (IL-6) is a well-known promoter of inflammation-induced carcinogenesis and disease progression in prostate cancer. Presence in the prostate and possible roles in tumor development by other members of the IL-6 family of cytokines have, however, been less studied. Here we show that the IL-6-type cytokine oncostatin M (OSM) indeed induce cellular properties associated with tumorigenesis and disease progression in non-transformed human prostate epithelial cells, including morphological changes, epithelial-to-mesenchymal transition (EMT), enhanced migration and pro-invasive growth patterns. The effects by OSM were partly mediated by activation of signal transducer and activator of transcription 3 (STAT3), a transcription factor established as driver of cancer progression and treatment resistance in numerous types of cancer. The findings presented here further consolidate IL-6-type cytokines and STAT3 as promising future treatment targets for prostate cancer.
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Yang HF, Yu M, Jin HD, Yao JQ, Lu ZL, Yabasin IB, Yan Q, Wen QP. Fentanyl Promotes Breast Cancer Cell Stemness and Epithelial-Mesenchymal Transition by Upregulating α1, 6-Fucosylation via Wnt/β-Catenin Signaling Pathway. Front Physiol 2017; 8:510. [PMID: 28798691 PMCID: PMC5526971 DOI: 10.3389/fphys.2017.00510] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 07/04/2017] [Indexed: 01/14/2023] Open
Abstract
Cancer pain is a common and severe complication of human breast cancer, and relieving pain is fundamental strategy in the treatment. Fentanyl, as an opioid analgesic, is widely used in breast cancer patients. However, little is known about its effects on stemness and epithelial-mesenchymal transition (EMT) of breast cancer cells. Aberrant protein glycosylation is involved in cancer malignancy. The α1, 6-fucosylation is an important type of glycosylation, and the elevated α1, 6-fucosylation catalyzed by fucosyltransferase VIII (FUT8) is found in many tumors. However, whether 1, 6-fucosylation is involved in regulating stemness and EMT, and stimulated by fentanyl is not clear. In this study, we found that fentanyl induced stemness and EMT in MCF-7 and MDA-MB-231 breast cancer cells by analysis of sphere formation, expression of stemness markers (Sox2, Oct4) and EMT markers (N-cadherin, E-cadherin and Vimentin). Results also showed that fentanyl upregulated FUT8 gene and protein expression by qPCR, Western blot and immunofluorescent staining, as well as α1, 6-fucosylation level by Lectin blot and Lectin fluorescent staining. Furthermore, decreased or blocked α1, 6-fucosylation by FUT8 siRNA transfection or LCA Lectin blockage reduced stemness and EMT. Additionally, fentanyl activated the key molecules and target genes in Wnt/β-catenin signaling pathway. LGK-974 (an inhibitor of Wnt ligands) suppressed fentanyl-mediated upregulation of α1, 6-fucosylation, stemness and EMT. The results of tumor xenograft demonstrated that fentanyl enhanced tumor growth, α1, 6-fucosylation, stemness and EMT. Taken together, our study reveals that fentanyl upregulated FUT8 expression, which increased α1, 6-fucosylation level through activation of Wnt/β-catenin signaling pathway, thereby, induce stemness and EMT of breast cancer cells. This study suggest a potential side effect of fentanyl in the treatment of cancer, which may guide the safety of fentanyl in the clinical application.
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Affiliation(s)
- Hong-Fang Yang
- Department of Anesthesiology, First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Ming Yu
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Department of Biochemistry and Molecular Biology, Dalian Medical UniversityDalian, China
| | - Hui-Dan Jin
- Department of Anesthesiology, First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Jia-Qi Yao
- Department of Anesthesiology, Affiliated Xinhua Hospital of Dalian UniversityDalian, China
| | - Zhi-Li Lu
- Department of Anesthesiology, First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Iddrisu B Yabasin
- Department of Anesthesiology, First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Qiu Yan
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Department of Biochemistry and Molecular Biology, Dalian Medical UniversityDalian, China
| | - Qing-Ping Wen
- Department of Anesthesiology, First Affiliated Hospital of Dalian Medical UniversityDalian, China
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Shien K, Papadimitrakopoulou VA, Ruder D, Behrens C, Shen L, Kalhor N, Song J, Lee JJ, Wang J, Tang X, Herbst RS, Toyooka S, Girard L, Minna JD, Kurie JM, Wistuba II, Izzo JG. JAK1/STAT3 Activation through a Proinflammatory Cytokine Pathway Leads to Resistance to Molecularly Targeted Therapy in Non-Small Cell Lung Cancer. Mol Cancer Ther 2017; 16:2234-2245. [PMID: 28729401 DOI: 10.1158/1535-7163.mct-17-0148] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 06/24/2017] [Accepted: 07/05/2017] [Indexed: 12/11/2022]
Abstract
Molecularly targeted drugs have yielded significant therapeutic advances in oncogene-driven non-small cell lung cancer (NSCLC), but a majority of patients eventually develop acquired resistance. Recently, the relation between proinflammatory cytokine IL6 and resistance to targeted drugs has been reported. We investigated the functional contribution of IL6 and the other members of IL6 family proinflammatory cytokine pathway to resistance to targeted drugs in NSCLC cells. In addition, we examined the production of these cytokines by cancer cells and cancer-associated fibroblasts (CAF). We also analyzed the prognostic significance of these molecule expressions in clinical NSCLC samples. In NSCLC cells with acquired resistance to targeted drugs, we observed activation of the IL6-cytokine pathway and STAT3 along with epithelial-to-mesenchymal transition (EMT) features. In particular, IL6 family cytokine oncostatin-M (OSM) induced a switch to the EMT phenotype and protected cells from targeted drug-induced apoptosis in OSM receptors (OSMRs)/JAK1/STAT3-dependent manner. The cross-talk between NSCLC cells and CAFs also preferentially activated the OSM/STAT3 pathway via a paracrine mechanism and decreased sensitivity to targeted drugs. The selective JAK1 inhibitor filgotinib effectively suppressed STAT3 activation and OSMR expression, and cotargeting inhibition of the oncogenic pathway and JAK1 reversed resistance to targeted drugs. In the analysis of clinical samples, OSMR gene expression appeared to be associated with worse prognosis in patients with surgically resected lung adenocarcinoma. Our data suggest that the OSMRs/JAK1/STAT3 axis contributes to resistance to targeted drugs in oncogene-driven NSCLC cells, implying that this pathway could be a therapeutic target. Mol Cancer Ther; 16(10); 2234-45. ©2017 AACR.
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Affiliation(s)
- Kazuhiko Shien
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Dennis Ruder
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Carmen Behrens
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Li Shen
- Department of Bioinformatics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Neda Kalhor
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Juhee Song
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - J Jack Lee
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jing Wang
- Department of Bioinformatics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ximing Tang
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Roy S Herbst
- Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut
| | - Shinichi Toyooka
- Department of General Thoracic Surgery, Okayama University Hospital, Okayama, Japan
| | - Luc Girard
- Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - John D Minna
- Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jonathan M Kurie
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Julie G Izzo
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Pothoven KL, Schleimer RP. The barrier hypothesis and Oncostatin M: Restoration of epithelial barrier function as a novel therapeutic strategy for the treatment of type 2 inflammatory disease. Tissue Barriers 2017; 5:e1341367. [PMID: 28665760 DOI: 10.1080/21688370.2017.1341367] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Mucosal epithelium maintains tissue homeostasis through many processes, including epithelial barrier function, which separates the environment from the tissue. The barrier hypothesis of type 2 inflammatory disease postulates that epithelial and epidermal barrier dysfunction, which cause inappropriate exposure to the environment, can result in allergic sensitization and development of type 2 inflammatory disease. The restoration of barrier dysfunction once it's lost, or the prevention of barrier dysfunction, have the potential to be exciting new therapeutic strategies for the treatment of type 2 inflammatory disease. Neutrophil-derived Oncostatin M has been shown to be a potent disrupter of epithelial barrier function through the induction of epithelial-mesenchymal transition (EMT). This review will discuss these events and outline several points along this axis at which therapeutic intervention could be beneficial for the treatment of type 2 inflammatory diseases.
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Affiliation(s)
- Kathryn L Pothoven
- a Division of Allergy-Immunology, Department of Medicine , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.,b Driskill Graduate Program , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.,c Immunology Program, Benaroya Research Institute at Virginia Mason , Seattle , WA , USA
| | - Robert P Schleimer
- a Division of Allergy-Immunology, Department of Medicine , Northwestern University Feinberg School of Medicine , Chicago , IL , USA.,d Departments of Otolaryngology and Microbiology-Immunology , Northwestern University Feinberg School of Medicine , Chicago , IL , USA
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45
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Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Nat Chem 2017; 9:1025-1033. [PMID: 28937680 DOI: 10.1038/nchem.2778] [Citation(s) in RCA: 445] [Impact Index Per Article: 55.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 04/03/2017] [Indexed: 12/30/2022]
Abstract
Cancer stem cells (CSCs) represent a subset of cells within tumours that exhibit self-renewal properties and the capacity to seed tumours. CSCs are typically refractory to conventional treatments and have been associated to metastasis and relapse. Salinomycin operates as a selective agent against CSCs through mechanisms that remain elusive. Here, we provide evidence that a synthetic derivative of salinomycin, which we named ironomycin (AM5), exhibits a more potent and selective activity against breast CSCs in vitro and in vivo, by accumulating and sequestering iron in lysosomes. In response to the ensuing cytoplasmic depletion of iron, cells triggered the degradation of ferritin in lysosomes, leading to further iron loading in this organelle. Iron-mediated production of reactive oxygen species promoted lysosomal membrane permeabilization, activating a cell death pathway consistent with ferroptosis. These findings reveal the prevalence of iron homeostasis in breast CSCs, pointing towards iron and iron-mediated processes as potential targets against these cells.
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West NR, Hegazy AN, Owens BMJ, Bullers SJ, Linggi B, Buonocore S, Coccia M, Görtz D, This S, Stockenhuber K, Pott J, Friedrich M, Ryzhakov G, Baribaud F, Brodmerkel C, Cieluch C, Rahman N, Müller-Newen G, Owens RJ, Kühl AA, Maloy KJ, Plevy SE, Keshav S, Travis SPL, Powrie F. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med 2017; 23:579-589. [PMID: 28368383 PMCID: PMC5420447 DOI: 10.1038/nm.4307] [Citation(s) in RCA: 536] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 02/17/2017] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are mainstay therapies for IBD. However, up to 40% of patients are nonresponsive to anti-TNF agents, which makes the identification of alternative therapeutic targets a priority. Here we show that, relative to healthy controls, inflamed intestinal tissues from patients with IBD express high amounts of the cytokine oncostatin M (OSM) and its receptor (OSMR), which correlate closely with histopathological disease severity. The OSMR is expressed in nonhematopoietic, nonepithelial intestinal stromal cells, which respond to OSM by producing various proinflammatory molecules, including interleukin (IL)-6, the leukocyte adhesion factor ICAM1, and chemokines that attract neutrophils, monocytes, and T cells. In an animal model of anti-TNF-resistant intestinal inflammation, genetic deletion or pharmacological blockade of OSM significantly attenuates colitis. Furthermore, according to an analysis of more than 200 patients with IBD, including two cohorts from phase 3 clinical trials of infliximab and golimumab, high pretreatment expression of OSM is strongly associated with failure of anti-TNF therapy. OSM is thus a potential biomarker and therapeutic target for IBD, and has particular relevance for anti-TNF-resistant patients.
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Affiliation(s)
- Nathaniel R. West
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Ahmed N. Hegazy
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | | | | | - Bryan Linggi
- Janssen Research and Development LLC, Raritan, NJ, USA
| | - Sofia Buonocore
- Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
| | - Margherita Coccia
- Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
| | - Dieter Görtz
- Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany
| | - Sébastien This
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Krista Stockenhuber
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Johanna Pott
- Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
| | | | - Grigory Ryzhakov
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | | | | | - Constanze Cieluch
- Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité–Universitätsmedizin Berlin, Germany
| | - Nahid Rahman
- OPPF-UK, The Research Complex at Harwell, Rutherford Appleton Laboratory, Harwell, Oxford, UK
| | - Gerhard Müller-Newen
- Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany
| | - Raymond J. Owens
- OPPF-UK, The Research Complex at Harwell, Rutherford Appleton Laboratory, Harwell, Oxford, UK
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Anja A. Kühl
- Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité–Universitätsmedizin Berlin, Germany
| | - Kevin J. Maloy
- Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
| | | | | | - Satish Keshav
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Simon P. L. Travis
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Fiona Powrie
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
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47
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Lehtinen L, Vainio P, Wikman H, Huhtala H, Mueller V, Kallioniemi A, Pantel K, Kronqvist P, Kallioniemi O, Carpèn O, Iljin K. PLA2G7 associates with hormone receptor negativity in clinical breast cancer samples and regulates epithelial-mesenchymal transition in cultured breast cancer cells. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2017; 3:123-138. [PMID: 28451461 PMCID: PMC5402179 DOI: 10.1002/cjp2.69] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 03/10/2017] [Indexed: 12/12/2022]
Abstract
Breast cancer is the leading cause of cancer‐related deaths in women due to distinct cancer subtypes associated with early recurrence and aggressive metastatic progression. High lipoprotein‐associated phospholipase A2 (PLA2G7) expression has previously been associated with aggressive disease and metastasis in prostate cancer. Here, we explore the expression pattern and functional role of PLA2G7 in breast cancer. First, a bioinformatic analysis of genome‐wide gene expression data from 970 breast samples was carried out to evaluate the expression pattern of PLA2G7 mRNA in breast cancer. Second, the expression profile of PLA2G7 was studied in 1042 breast cancer samples including 89 matched lymph node metastasis samples using immunohistochemistry. Third, the effect of PLA2G7 silencing on genome‐wide gene expression profile was studied and validated in cultured breast cancer cells expressing PLA2G7 at high level. Last, the expression pattern of PLA2G7 mRNA was investigated in 24 nonmalignant tissue samples and 65 primary and 7 metastatic tumour samples derived from various organs using qRT‐PCR. The results from clinical breast cancer samples indicated that PLA2G7 is overexpressed in a subset of breast cancer samples compared to its expression in benign breast tissue samples and that high PLA2G7 expression associated with hormone receptor negativity as well as with poor prognosis in a subset of breast cancer samples. In vitro functional studies highlighted the putative role of PLA2G7 in the regulation of epithelial‐mesenchymal transition (EMT)‐related signalling pathways, vimentin and E‐cadherin protein expression as well as cell migration in cultured breast cancer cells. Furthermore, supporting the findings in breast and prostate cancer, high PLA2G7 mRNA expression was associated with metastatic cancer in four additional organs of origin. In conclusion, our results indicate that PLA2G7 is highly expressed in a subset of metastatic and aggressive breast cancers and in metastatic samples of various tissues of origin and promotes EMT and migration in cultured breast cancer cells.
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Affiliation(s)
- Laura Lehtinen
- Department of PathologyTurku University and Turku University HospitalTurkuFinland
| | - Paula Vainio
- Department of PathologyTurku University and Turku University HospitalTurkuFinland
| | - Harriet Wikman
- Institute of Tumour Biology, Centre of Experimental MedicineUniversity Medical Centre Hamburg-EppendorfGermany
| | - Heini Huhtala
- School of Health SciencesUniversity of TampereTampereFinland
| | - Volkmar Mueller
- Department of GynecologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
| | | | - Klaus Pantel
- Institute of Tumour Biology, Centre of Experimental MedicineUniversity Medical Centre Hamburg-EppendorfGermany
| | - Pauliina Kronqvist
- Department of PathologyTurku University and Turku University HospitalTurkuFinland
| | - Olli Kallioniemi
- FIMM, Institute for Molecular Medicine FinlandUniversity of HelsinkiFinland.,Present address: Department of Oncology-Pathology, Science for Life LaboratoryKarolinska InstitutetSolnaSweden
| | - Olli Carpèn
- Department of PathologyTurku University and Turku University HospitalTurkuFinland.,Present address: Department of PathologyUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
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48
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Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling. Oncogene 2017; 36:4001-4013. [PMID: 28288136 PMCID: PMC5509502 DOI: 10.1038/onc.2017.33] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Revised: 01/20/2017] [Accepted: 01/24/2017] [Indexed: 02/06/2023]
Abstract
Increasing evidence supports the idea that cancer cell plasticity promotes metastasis and tumor recurrence, resulting in patient mortality. While it is clear that the tumor microenvironment (TME) contributes to cancer cell plasticity, the specific TME factors most actively controlling plasticity remain largely unknown. Here, we performed a screen to identify TME cytokines and growth factors that promote epithelial–mesenchymal plasticity, and acquisition of cancer stem cell (CSC) properties. Of 28 TME cytokines and growth factors tested, we identified Oncostatin M (OSM) as the most potent inducer of mesenchymal/CSC properties. OSM-induced plasticity was Signal Transducer and Activator of Transcription 3 (STAT3)-dependent, and also required a novel intersection with transforming growth factor-β (TGF-β)/SMAD signaling. OSM/STAT3 activation promoted SMAD3 nuclear accumulation, DNA binding and induced SMAD3-dependent transcriptional activity. Suppression of TGF-β receptor activity or ablation of SMAD3 or SMAD4, but not SMAD2, strongly suppressed OSM/STAT3-mediated plasticity. Moreover, removal of OSM or inhibition of STAT3 or SMAD3 resulted in a marked reversion to a non-invasive, epithelial phenotype. We propose that targeted blockade of the STAT3/SMAD3 axis in tumor cells may represent a novel therapeutic approach to prevent the plasticity required for metastatic progression and tumor recurrence.
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49
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Integrated MicroRNA-mRNA Profiling Identifies Oncostatin M as a Marker of Mesenchymal-Like ER-Negative/HER2-Negative Breast Cancer. Int J Mol Sci 2017; 18:ijms18010194. [PMID: 28106823 PMCID: PMC5297825 DOI: 10.3390/ijms18010194] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 01/12/2017] [Accepted: 01/13/2017] [Indexed: 12/21/2022] Open
Abstract
MicroRNAs (miRNAs) simultaneously modulate different oncogenic networks, establishing a dynamic system of gene expression and pathway regulation. In this study, we analyzed global miRNA and messenger RNA (mRNA) expression profiles of 17 cell lines representing different molecular breast cancer subtypes. Spearman's rank correlation test was used to evaluate the correlation between miRNA and mRNA expression. Hierarchical clustering and pathway analysis were also performed. Publicly available gene expression profiles (n = 699) and tumor tissues (n = 80) were analyzed to assess the relevance of key miRNA-regulated pathways in human breast cancer. We identified 39 significantly deregulated miRNAs, and the integration between miRNA and mRNA data revealed the importance of immune-related pathways, particularly the Oncostatin M (OSM) signaling, associated with mesenchymal-like breast cancer cells. OSM levels correlated with genes involved in the inflammatory response, epithelial-to-mesenchymal transition (EMT), and epidermal growth factor (EGF) signaling in human estrogen receptor (ER)-negative/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Our results suggest that the deregulation of specific miRNAs may cooperatively impair immune and EMT pathways. The identification of the OSM inflammatory pathway as an important mediator of EMT in triple-negative breast cancer (TNBC) may provide a novel potential opportunity to improve therapeutic strategies.
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50
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Smigiel JM, Parameswaran N, Jackson MW. Potent EMT and CSC Phenotypes Are Induced By Oncostatin-M in Pancreatic Cancer. Mol Cancer Res 2017; 15:478-488. [PMID: 28053127 DOI: 10.1158/1541-7786.mcr-16-0337] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 11/21/2016] [Accepted: 11/30/2016] [Indexed: 12/19/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is referred to as a silent killer due to the lack of clear symptoms, a lack of early detection methods, and a high frequency of metastasis at diagnosis. In addition, pancreatic cancer is remarkably resistant to chemotherapy, and clinical treatment options remain limited. The tumor microenvironment (TME) and associated factors are important determinants of metastatic capacity and drug resistance. Here, oncostatin M (OSM), an IL6 cytokine family member, was identified as an important driver of mesenchymal and cancer stem cell (CSC) phenotypes. Furthermore, the generation of cells that harbor mesenchymal/CSC properties following OSM exposure resulted in enhanced tumorigenicity, increased metastasis, and resistance to gemcitabine. OSM induced the expression of ZEB1, Snail (SNAI1), and OSM receptor (OSMR), engaging a positive feedback loop to potentiate the mesenchymal/CSC program. Suppression of JAK1/2 by ruxolitinib prevented STAT3-mediated transcription of ZEB1, SNAI1 and OSMR, as well as the emergence of a mesenchymal/CSC phenotype. Likewise, ZEB1 silencing, by shRNA-mediated knockdown, in OSM-driven mesenchymal/CSC reverted the phenotype back to an epithelial/non-CSC state. Importantly, the generation of cells with mesenchymal/CSC properties was unique to OSM, and not observed following IL6 exposure, implicating OSMR and downstream effector signaling as a distinct target in PDAC. Overall, these data demonstrate the capacity of OSM to regulate an epithelial-mesenchymal transition (EMT)/CSC plasticity program that promotes tumorigenic properties.Implications: Therapeutic targeting the OSM/OSMR axis within the TME may prevent or reverse the aggressive mesenchymal and CSC phenotypes associated with poor outcomes in patients with PDAC. Mol Cancer Res; 15(4); 478-88. ©2017 AACR.
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Affiliation(s)
- Jacob M Smigiel
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio
| | | | - Mark W Jackson
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio. .,Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
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