|
1
|
Guo S, Zheng S, Liu M, Wang G. Novel Anti-Cancer Stem Cell Compounds: A Comprehensive Review. Pharmaceutics 2024; 16:1024. [PMID: 39204369 PMCID: PMC11360402 DOI: 10.3390/pharmaceutics16081024] [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: 05/30/2024] [Revised: 07/24/2024] [Accepted: 07/26/2024] [Indexed: 09/04/2024] Open
Abstract
Cancer stem cells (CSCs) possess a significant ability to renew themselves, which gives them a strong capacity to form tumors and expand to encompass additional body areas. In addition, they possess inherent resistance to chemotherapy and radiation therapies used to treat many forms of cancer. Scientists have focused on investigating the signaling pathways that are highly linked to the ability of CSCs to renew themselves and maintain their stem cell properties. The pathways encompassed are Notch, Wnt/β-catenin, hedgehog, STAT3, NF-κB, PI-3K/Akt/mTOR, sirtuin, ALDH, MDM2, and ROS. Recent studies indicate that directing efforts towards CSC cells is essential in eradicating the overall cancer cell population and reducing the likelihood of tumor metastasis. As our comprehension of the mechanisms that stimulate CSC activity, growth, and resistance to chemotherapy advances, the discovery of therapeutic drugs specifically targeting CSCs, such as small-molecule compounds, holds the potential to revolutionize cancer therapy. This review article examines and analyzes the novel anti-CSC compounds that have demonstrated effective and selective targeting of pathways associated with the renewal and stemness of CSCs. We also discussed their special drug metabolism and absorption mechanisms. CSCs have been the subject of much study in cancer biology. As a possible treatment for malignancies, small-molecule drugs that target CSCs are gaining more and more attention. This article provides a comprehensive review of the current state of key small-molecule compounds, summarizes their recent developments, and anticipates the future discovery of even more potent and targeted compounds, opening up new avenues for cancer treatment.
Collapse
Affiliation(s)
- Shanchun Guo
- RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA;
| | - Shilong Zheng
- RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA;
| | - Mingli Liu
- Department of Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA;
| | - Guangdi Wang
- RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA;
| |
Collapse
|
|
2
|
Lee JS, Lee HY. Ginseng-derived compounds as potential anticancer agents targeting cancer stem cells. J Ginseng Res 2024; 48:266-275. [PMID: 38707642 PMCID: PMC11068999 DOI: 10.1016/j.jgr.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 01/31/2024] [Accepted: 03/07/2024] [Indexed: 05/07/2024] Open
Abstract
Cancer stem cells (CSCs) are a rare subpopulation of cancer cells that exhibit stem cell-like characteristics, including self-renewal and differentiation in a multi-stage lineage state via symmetric or asymmetric division, causing tumor initiation, heterogeneity, progression, and recurrence and posing a major challenge to current anticancer therapy. Despite the importance of CSCs in carcinogenesis and cancer progression, currently available anticancer therapeutics have limitations for eradicating CSCs. Moreover, the efficacy and therapeutic windows of currently available anti-CSC agents are limited, suggesting the necessity to optimize and develop a novel anticancer agent targeting CSCs. Ginseng has been traditionally used for enhancing immunity and relieving fatigue. As ginseng's long history of use has demonstrated its safety, it has gained attention for its potential pharmacological properties, including anticancer effects. Several studies have identified the bioactive principles of ginseng, such as ginseng saponin (ginsenosides) and non-saponin compounds (e.g., polysaccharides, polyacetylenes, and phenolic compounds), and their pharmacological activities, including antioxidant, anticancer, antidiabetic, antifatigue, and neuroprotective effects. Notably, recent reports have shown the potential of ginseng-derived compounds as anti-CSC agents. This review investigates the biology of CSCs and efforts to utilize ginseng-derived components for cancer treatment targeting CSCs, highlighting their role in overcoming current therapeutic limitations.
Collapse
Affiliation(s)
- Ji-Sun Lee
- Department of Molecular, Cell & Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Ho-Young Lee
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Republic of Korea
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| |
Collapse
|
|
3
|
Potes Y, Bermejo-Millo JC, Mendes C, Castelão-Baptista JP, Díaz-Luis A, Pérez-Martínez Z, Solano JJ, Sardão VA, Oliveira PJ, Caballero B, Coto-Montes A, Vega-Naredo I. p66Shc signaling and autophagy impact on C2C12 myoblast differentiation during senescence. Cell Death Dis 2024; 15:200. [PMID: 38459002 PMCID: PMC10923948 DOI: 10.1038/s41419-024-06582-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 02/23/2024] [Accepted: 03/01/2024] [Indexed: 03/10/2024]
Abstract
During aging, muscle regenerative capacities decline, which is concomitant with the loss of satellite cells that enter in a state of irreversible senescence. However, what mechanisms are involved in myogenic senescence and differentiation are largely unknown. Here, we showed that early-passage or "young" C2C12 myoblasts activated the redox-sensitive p66Shc signaling pathway, exhibited a strong antioxidant protection and a bioenergetic profile relying predominantly on OXPHOS, responses that decrease progressively during differentiation. Furthermore, autophagy was increased in myotubes. Otherwise, late-passage or "senescent" myoblasts led to a highly metabolic profile, relying on both OXPHOS and glycolysis, that may be influenced by the loss of SQSTM1/p62 which tightly regulates the metabolic shift from aerobic glycolysis to OXPHOS. Furthermore, during differentiation of late-passage C2C12 cells, both p66Shc signaling and autophagy were impaired and this coincides with reduced myogenic capacity. Our findings recognized that the lack of p66Shc compromises the proliferation and the onset of the differentiation of C2C12 myoblasts. Moreover, the Atg7 silencing favored myoblasts growth, whereas interfered in the viability of differentiated myotubes. Then, our work demonstrates that the p66Shc signaling pathway, which highly influences cellular metabolic status and oxidative environment, is critical for the myogenic commitment and differentiation of C2C12 cells. Our findings also support that autophagy is essential for the metabolic switch observed during the differentiation of C2C12 myoblasts, confirming how its regulation determines cell fate. The regulatory roles of p66Shc and autophagy mechanisms on myogenesis require future attention as possible tools that could predict and measure the aging-related state of frailty and disability.
Collapse
Affiliation(s)
- Yaiza Potes
- Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain.
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
- Institute of Neurosciences of the Principality of Asturias (INEUROPA), Oviedo, Spain.
| | - Juan C Bermejo-Millo
- Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Institute of Neurosciences of the Principality of Asturias (INEUROPA), Oviedo, Spain
| | - Catarina Mendes
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- CIBB, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - José P Castelão-Baptista
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- CIBB, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- PDBEB - Doctoral Program in Experimental Biology and Biomedicine, Institute of Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
| | - Andrea Díaz-Luis
- Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
| | - Zulema Pérez-Martínez
- Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Microbiology service, University Central Hospital of Asturias, Oviedo, Spain
| | - Juan J Solano
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Geriatric Service, Monte Naranco Hospital, Av. Doctores Fernández Vega, Oviedo, Spain
| | - Vilma A Sardão
- CIBB, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- MIA-Portugal - Multidisciplinary Institute of Ageing, University of Coimbra, Coimbra, Portugal
| | - Paulo J Oliveira
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- CIBB, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Beatriz Caballero
- Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Institute of Neurosciences of the Principality of Asturias (INEUROPA), Oviedo, Spain
| | - Ana Coto-Montes
- Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Institute of Neurosciences of the Principality of Asturias (INEUROPA), Oviedo, Spain
| | - Ignacio Vega-Naredo
- Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain.
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
- Institute of Neurosciences of the Principality of Asturias (INEUROPA), Oviedo, Spain.
| |
Collapse
|
|
4
|
Liao Y, Luo Z, Liu Y, Xue W, He S, Chen X, Ren H, Yang X, Zhu D, Su Z, Huang Q, Guo H. Total flavonoids of Litchi seed attenuate stem cell-like properties in breast cancer by regulating Notch3 signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2023; 305:116133. [PMID: 36603788 DOI: 10.1016/j.jep.2023.116133] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/09/2022] [Accepted: 01/01/2023] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Breast cancer has been the most commonly-diagnosed cancer worldwide, and the treatment and prognosis of which are often limited by breast cancer stem cells (BCSCs). Litchi seeds have shown good anti-cancer activity in various cancers including prostate cancer, lung cancer and breast cancer. However, the activity and underlying mechanism of Litchi seeds against BCSCs remain unknown. AIM OF THE STUDY To investigate the activity and mechanism of total flavonoids of litchi seed (TFLS) against BCSCs in vitro and in vivo. MATERIALS AND METHODS Two orthotopic xenograft mouse models were established using HCC1806 cells pretreated or untreated with TFLS to determine whether TFLS could target BCSCs in vivo. Mammosphere formation and flow cytometry assays were employed to evaluate the effect of TFLS on BCSCs in vitro. The underlying mechanism was investigated using RT-qPCR, Western blot, immunohistochemistry and immunofluorescence experiments. RESULTS TFLS could significantly inhibit the viability of HCC1806, MCF-7 and HCC1937 cells in vitro and suppress the growth of HCC1806 cells in vivo. TFLS attenuated stem cell-like properties of breast cancer through reducing the percentage of CD44+CD24-/low cells, inhibiting the mammospheres formation and down-regulating the mRNA and protein levels of cancer stem cells related markers (Oct4, Nanog, Sox2) in MCF-7 and HCC1806 cells. Meanwhile, TFLS suppressed the tumor-initiating ability of BCSCs via reducing the percentage of CD44+CD24-/low cells in tumor and lowering tumor incidence rate in orthotopic xenograft mice. In addition, TFLS treatments restricted the expression and nuclear translocation of Notch3, subsequently down-regulated Hes1 and Runx2 expressions. CONCLUSIONS TFLS could suppress the growth of breast cancer and eliminate breast cancer stem cells by inhibiting the Notch3 signaling pathway.
Collapse
Affiliation(s)
- Yunnuo Liao
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation & Pharmaceutical College, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, China; Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, China
| | - Zhuo Luo
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation & Pharmaceutical College, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, China
| | - Ying Liu
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, China; Pharmaceutical College, Guangxi University of Chinese Medicine, 179 Mingxiu Dong Road, Nanning, 530001, China
| | - Wei Xue
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation & Pharmaceutical College, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, China; Department of Pharmacy, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, 530011, China
| | - Songhua He
- Guangxi Institute for Food and Drug Control, 9 Qinghu Road, Nanning, 530021, China
| | - Xin Chen
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation & Pharmaceutical College, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, China; Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, China
| | - Hong Ren
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, China; The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, China
| | - Xin Yang
- Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, China
| | - Dan Zhu
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation & Pharmaceutical College, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, China
| | - Zhiheng Su
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation & Pharmaceutical College, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, China.
| | - Qiuju Huang
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation & Pharmaceutical College, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, China.
| | - Hongwei Guo
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation & Pharmaceutical College, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, China; Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education, Guangxi Medical University, 22 Shuangyong Road, Nanning, 530021, China.
| |
Collapse
|
|
5
|
Guo M, Niu Y, Xie M, Liu X, Li X. Notch signaling, hypoxia, and cancer. Front Oncol 2023; 13:1078768. [PMID: 36798826 PMCID: PMC9927648 DOI: 10.3389/fonc.2023.1078768] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/19/2023] [Indexed: 02/04/2023] Open
Abstract
Notch signaling is involved in cell fate determination and deregulated in human solid tumors. Hypoxia is an important feature in many solid tumors, which activates hypoxia-induced factors (HIFs) and their downstream targets to promote tumorigenesis and cancer development. Recently, HIFs have been shown to trigger the Notch signaling pathway in a variety of organisms and tissues. In this review, we focus on the pro- and anti-tumorigenic functions of Notch signaling and discuss the crosstalk between Notch signaling and cellular hypoxic response in cancer pathogenesis, including epithelia-mesenchymal transition, angiogenesis, and the maintenance of cancer stem cells. The pharmacological strategies targeting Notch signaling and hypoxia in cancer are also discussed in this review.
Collapse
Affiliation(s)
- Mingzhou Guo
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Yang Niu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Min Xie
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Xiansheng Liu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Xiaochen Li
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Key Laboratory of Pulmonary Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China,*Correspondence: Xiaochen Li,
| |
Collapse
|
|
6
|
Cui G, Wang Z, Liu H, Pang Z. Cytokine-mediated crosstalk between cancer stem cells and their inflammatory niche from the colorectal precancerous adenoma stage to the cancerous stage: Mechanisms and clinical implications. Front Immunol 2022; 13:1057181. [PMID: 36466926 PMCID: PMC9714270 DOI: 10.3389/fimmu.2022.1057181] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 11/03/2022] [Indexed: 10/15/2023] Open
Abstract
The majority of colorectal cancers (CRCs) are thought to arise from precancerous adenomas. Upon exposure to diverse microenvironmental factors, precancerous stem cells (pCSCs) undergo complex genetic/molecular changes and gradually progress to form cancer stem cells (CSCs). Accumulative evidence suggests that the pCSC/CSC niche is an inflammatory dominated milieu that contains different cytokines that function as the key communicators between pCSCs/CSCs and their niche and have a decisive role in promoting CRC development, progression, and metastasis. In view of the importance and increasing data about cytokines in modulating pCSCs/CSC stemness properties and their significance in CRC, this review summarizes current new insights of cytokines, such as interleukin (IL)-4, IL-6, IL-8, IL-17A, IL-22, IL-23, IL-33 and interferon (IFN)-γ, involving in the modulation of pCSC/CSC properties and features in precancerous and cancerous lesions and discusses the possible mechanisms of adenoma progression to CRCs and their therapeutic potential.
Collapse
Affiliation(s)
- Guanglin Cui
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Faculty of Health Science, Nord University, Levanger, Norway
| | - Ziqi Wang
- College of Medical Imaging, Mudanjiang Medical University, Mudanjiang, China
| | - Hanzhe Liu
- School of Stomatology, Wuhan University, Wuhan, China
| | - Zhigang Pang
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| |
Collapse
|
|
7
|
Resistance to Trastuzumab. Cancers (Basel) 2022; 14:cancers14205115. [PMID: 36291900 PMCID: PMC9600208 DOI: 10.3390/cancers14205115] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 10/12/2022] [Accepted: 10/17/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Trastuzumab is a humanized antibody that has significantly improved the management and treatment outcomes of patients with cancers that overexpress HER2. Many research groups, both in academia and industry, have contributed towards understanding the various mechanisms engaged by trastuzumab to mediate its anti-tumor effects. Nevertheless, data from several clinical studies have indicated that a significant proportion of patients exhibit primary or acquired resistance to trastuzumab therapy. In this article, we discuss underlying mechanisms that contribute towards to resistance. Furthermore, we discuss the potential strategies to overcome some of the mechanisms of resistance to enhance the therapeutic efficacy of trastuzumab and other therapies based on it. Abstract One of the most impactful biologics for the treatment of breast cancer is the humanized monoclonal antibody, trastuzumab, which specifically recognizes the HER2/neu (HER2) protein encoded by the ERBB2 gene. Useful for both advanced and early breast cancers, trastuzumab has multiple mechanisms of action. Classical mechanisms attributed to trastuzumab action include cell cycle arrest, induction of apoptosis, and antibody-dependent cell-mediated cytotoxicity (ADCC). Recent studies have identified the role of the adaptive immune system in the clinical actions of trastuzumab. Despite the multiple mechanisms of action, many patients demonstrate resistance, primary or adaptive. Newly identified molecular and cellular mechanisms of trastuzumab resistance include induction of immune suppression, vascular mimicry, generation of breast cancer stem cells, deregulation of long non-coding RNAs, and metabolic escape. These newly identified mechanisms of resistance are discussed in detail in this review, particularly considering how they may lead to the development of well-rationalized, patient-tailored combinations that improve patient survival.
Collapse
|
|
8
|
Herbal Ingredients in the Prevention of Breast Cancer: Comprehensive Review of Potential Molecular Targets and Role of Natural Products. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:6044640. [PMID: 36017236 PMCID: PMC9398845 DOI: 10.1155/2022/6044640] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/06/2022] [Accepted: 07/26/2022] [Indexed: 11/17/2022]
Abstract
Among various cancers, breast cancer is the most prevalent type in women throughout the world. Breast cancer treatment is challenging due to complex nature of the etiology of disease. Cell division cycle alterations are often encountered in a variety of cancer types including breast cancer. Common treatments include chemotherapy, surgery, radiotherapy, and hormonal therapy; however, adverse effects and multidrug resistance lead to complications and noncompliance. Accordingly, there is an increasing demand for natural products from medicinal plants and foods. This review summarizes molecular mechanisms of signaling pathways in breast cancer and identifies mechanisms by which natural compounds may exert their efficacy in the treatment of breast cancer.
Collapse
|
|
9
|
Zhdanovskaya N, Firrincieli M, Lazzari S, Pace E, Scribani Rossi P, Felli MP, Talora C, Screpanti I, Palermo R. Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives. Cancers (Basel) 2021; 13:cancers13205106. [PMID: 34680255 PMCID: PMC8533696 DOI: 10.3390/cancers13205106] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/03/2021] [Accepted: 10/06/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary The Notch signaling pathway regulates cell proliferation, apoptosis, stem cell self-renewal, and differentiation in a context-dependent fashion both during embryonic development and in adult tissue homeostasis. Consistent with its pleiotropic physiological role, unproper activation of the signaling promotes or counteracts tumor pathogenesis and therapy response in distinct tissues. In the last twenty years, a wide number of studies have highlighted the anti-cancer potential of Notch-modulating agents as single treatment and in combination with the existent therapies. However, most of these strategies have failed in the clinical exploration due to dose-limiting toxicity and low efficacy, encouraging the development of novel agents and the design of more appropriate combinations between Notch signaling inhibitors and chemotherapeutic drugs with improved safety and effectiveness for distinct types of cancer. Abstract Notch signaling guides cell fate decisions by affecting proliferation, apoptosis, stem cell self-renewal, and differentiation depending on cell and tissue context. Given its multifaceted function during tissue development, both overactivation and loss of Notch signaling have been linked to tumorigenesis in ways that are either oncogenic or oncosuppressive, but always context-dependent. Notch signaling is critical for several mechanisms of chemoresistance including cancer stem cell maintenance, epithelial-mesenchymal transition, tumor-stroma interaction, and malignant neovascularization that makes its targeting an appealing strategy against tumor growth and recurrence. During the last decades, numerous Notch-interfering agents have been developed, and the abundant preclinical evidence has been transformed in orphan drug approval for few rare diseases. However, the majority of Notch-dependent malignancies remain untargeted, even if the application of Notch inhibitors alone or in combination with common chemotherapeutic drugs is being evaluated in clinical trials. The modest clinical success of current Notch-targeting strategies is mostly due to their limited efficacy and severe on-target toxicity in Notch-controlled healthy tissues. Here, we review the available preclinical and clinical evidence on combinatorial treatment between different Notch signaling inhibitors and existent chemotherapeutic drugs, providing a comprehensive picture of molecular mechanisms explaining the potential or lacking success of these combinations.
Collapse
Affiliation(s)
- Nadezda Zhdanovskaya
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Mariarosaria Firrincieli
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Center for Life Nano Science, Istituto Italiano di Tecnologia, 00161 Rome, Italy
| | - Sara Lazzari
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Eleonora Pace
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Pietro Scribani Rossi
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Maria Pia Felli
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;
| | - Claudio Talora
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
| | - Isabella Screpanti
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Correspondence: (I.S.); (R.P.)
| | - Rocco Palermo
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (N.Z.); (M.F.); (S.L.); (E.P.); (P.S.R.); (C.T.)
- Center for Life Nano Science, Istituto Italiano di Tecnologia, 00161 Rome, Italy
- Correspondence: (I.S.); (R.P.)
| |
Collapse
|
|
10
|
Luo H, Chen CY, Li X, Zhang X, Su CW, Liu Y, Cao T, Hao L, Wang M, Kang JX. Increased lipogenesis is critical for self-renewal and growth of breast cancer stem cells: Impact of omega-3 fatty acids. Stem Cells 2021; 39:1660-1670. [PMID: 34486791 PMCID: PMC9292025 DOI: 10.1002/stem.3452] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 08/10/2021] [Indexed: 12/22/2022]
Abstract
Aberrant lipid metabolism has recently been recognized as a new hallmark of malignancy, but the characteristics of fatty acid metabolism in breast cancer stem cells (BCSC) and potential interventions targeting this pathway remain to be addressed. Here, by using the in vitro BCSC models, mammosphere‐derived MCF‐7 cells and HMLE‐Twist‐ER cells, we found that the cells with stem cell‐like properties exhibited a very distinct profile of fatty acid metabolism compared with that of their parental cancer cells, characterized by increased lipogenesis, especially the activity of stearoyl‐CoA desaturase 1 (SCD1) responsible for the production of monounsaturated fatty acids, and augmented synthesis and utilization of the omega‐6 arachidonic acid (AA). Suppression of SCD1 activity by either enzyme inhibitors or small interfering RNA (siRNA) knockdown strikingly limited self‐renewal and growth of the BCSC, suggesting a key role for SCD1 in BCSC proliferation. Furthermore, elevated levels of SCD1 and other lipogenic enzymes were observed in human breast cancer tissues relative to the noncancer tissues from the same patients and correlated with the pathological grades. Interestingly, treatment of BCSC with omega‐3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, effectively downregulated the expression of the lipogenic enzymes and markedly suppressed BCSC self‐renewal and growth. Dietary supplementation of nude mice bearing BCSC‐derived tumors with omega‐3 fatty acids also significantly reduced their tumor load. These findings have demonstrated that increased lipogenesis is critical for self‐renewal and growth of BCSC, and that omega‐3 fatty acids are effective in targeting this pathway to exert their anticancer effect.
Collapse
Affiliation(s)
- Haiqing Luo
- Center of Oncology, The Affiliated Hospital of Guangdong Medical University, Guangdong, People's Republic of China.,Laboratory for Lipid Medicine and Technology (LLMT), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Chih-Yu Chen
- Laboratory for Lipid Medicine and Technology (LLMT), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Xiangyong Li
- Laboratory for Lipid Medicine and Technology (LLMT), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang, People's Republic of China
| | - Xin Zhang
- Department of Pathology, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen, People's Republic of China
| | - Chien-Wen Su
- Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
| | - Yinghua Liu
- Laboratory for Lipid Medicine and Technology (LLMT), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Tinglan Cao
- Laboratory for Lipid Medicine and Technology (LLMT), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Lei Hao
- Laboratory for Lipid Medicine and Technology (LLMT), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Meng Wang
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
| | - Jing X Kang
- Laboratory for Lipid Medicine and Technology (LLMT), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
11
|
Chen W, Wei W, Yu L, Ye Z, Huang F, Zhang L, Hu S, Cai C. Mammary Development and Breast Cancer: a Notch Perspective. J Mammary Gland Biol Neoplasia 2021; 26:309-320. [PMID: 34374886 PMCID: PMC8566423 DOI: 10.1007/s10911-021-09496-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 07/21/2021] [Indexed: 12/16/2022] Open
Abstract
Mammary gland development primarily occurs postnatally, and this unique process is complex and regulated by systemic hormones and local growth factors. The mammary gland is also a highly dynamic organ that undergoes profound changes at puberty and during the reproductive cycle. These changes are driven by mammary stem cells (MaSCs). Breast cancer is one of the most common causes of cancer-related death in women. Cancer stem cells (CSCs) play prominent roles in tumor initiation, drug resistance, tumor recurrence, and metastasis. The highly conserved Notch signaling pathway functions as a key regulator of the niche mediating mammary organogenesis and breast neoplasia. In this review, we discuss mechanisms by which Notch contributes to breast carcinoma pathology and suggest potentials for therapeutic targeting of Notch in breast cancer. In summary, we provide a comprehensive overview of Notch functions in regulating MaSCs, mammary development, and breast cancer.
Collapse
Affiliation(s)
- Weizhen Chen
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Wei Wei
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Liya Yu
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Zi Ye
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Fujing Huang
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Liyan Zhang
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China
| | - Shiqi Hu
- DU-ANU Joint Science College, Shandong University, Weihai, 264200, China
| | - Cheguo Cai
- Department of Orthopaedics, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
| |
Collapse
|
|
12
|
Waza AA, Tarfeen N, Majid S, Hassan Y, Mir R, Rather MY, Shah NUD. Metastatic Breast Cancer, Organotropism and Therapeutics: A Review. Curr Cancer Drug Targets 2021; 21:813-828. [PMID: 34365922 DOI: 10.2174/1568009621666210806094410] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 05/21/2021] [Accepted: 05/24/2021] [Indexed: 11/22/2022]
Abstract
The final stage of breast cancer involves spreading breast cancer cells to the vital organs like the brain, liver lungs and bones in the process called metastasis. Once the target organ is overtaken by the metastatic breast cancer cells, its usual function is compromised causing organ dysfunction and death. Despite the significant research on breast cancer metastasis, it's still the main culprit of breast cancer-related deaths. Exploring the complex molecular pathways associated with the initiation and progression of breast cancer metastasis could lead to the discovery of more effective ways of treating the devastating phenomenon. The present review article highlights the recent advances to understand the complexity associated with breast cancer metastases, organotropism and therapeutic advances.
Collapse
Affiliation(s)
- Ajaz Ahmad Waza
- Multidisciplinary Research Unit (MRU), Government Medical College (GMC) Srinagar, J & K, 190010. India
| | - Najeebul Tarfeen
- Centre of Research for Development, University of Kashmir, Srinagar 190006 . India
| | - Sabhiya Majid
- Department of Biochemistry, Government Medical College (GMC) Srinagar, J & K, 190010. India
| | - Yasmeena Hassan
- Division of Nursing, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Soura, Srinagar, J & K. India
| | - Rashid Mir
- Department of Medical Lab Technology, Faculty of Applied Medical Sciences, University of Tabuk, Kingdom of Saudi Arabia, Tabuk. Saudi Arabia
| | - Mohd Younis Rather
- Multidisciplinary Research Unit (MRU), Government Medical College (GMC) Srinagar, J & K, 190010. India
| | - Naseer Ue Din Shah
- Centre of Research for Development, University of Kashmir, Srinagar 190006 . India
| |
Collapse
|
|
13
|
Edwards A, Brennan K. Notch Signalling in Breast Development and Cancer. Front Cell Dev Biol 2021; 9:692173. [PMID: 34295896 PMCID: PMC8290365 DOI: 10.3389/fcell.2021.692173] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/07/2021] [Indexed: 12/22/2022] Open
Abstract
The Notch signalling pathway is a highly conserved developmental signalling pathway, with vital roles in determining cell fate during embryonic development and tissue homeostasis. Aberrant Notch signalling has been implicated in many disease pathologies, including cancer. In this review, we will outline the mechanism and regulation of the Notch signalling pathway. We will also outline the role Notch signalling plays in normal mammary gland development and how Notch signalling is implicated in breast cancer tumorigenesis and progression. We will cover how Notch signalling controls several different hallmarks of cancer within epithelial cells with sections focussed on its roles in proliferation, apoptosis, invasion, and metastasis. We will provide evidence for Notch signalling in the breast cancer stem cell phenotype, which also has implications for therapy resistance and disease relapse in breast cancer patients. Finally, we will summarise the developments in therapeutic targeting of Notch signalling, and the pros and cons of this approach for the treatment of breast cancer.
Collapse
Affiliation(s)
- Abigail Edwards
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| | - Keith Brennan
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| |
Collapse
|
|
14
|
Ludikhuize MC, Rodríguez Colman MJ. Metabolic Regulation of Stem Cells and Differentiation: A Forkhead Box O Transcription Factor Perspective. Antioxid Redox Signal 2021; 34:1004-1024. [PMID: 32847377 DOI: 10.1089/ars.2020.8126] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Stem cell activation and differentiation occur along changes in cellular metabolism. Metabolic transitions translate into changes in redox balance, cell signaling, and epigenetics, thereby regulating these processes. Metabolic transitions are key regulators of cell fate and exemplify the moonlighting nature of many metabolic enzymes and their associated metabolites. Recent Advances: Forkhead box O transcription factors (FOXOs) are bona fide regulators of cellular homeostasis. FOXOs are multitasking proteins able to regulate cell cycle, cellular metabolism, and redox state. Recent and ongoing research poses FOXOs as key factors in stem cell maintenance and differentiation in several tissues. Critical Issues: The multitasking nature of FOXOs and their tissue-specific expression patterns hinders to disclose a possible conserved mechanism of regulation of stem cell maintenance and differentiation. Moreover, cellular metabolism, cell signaling, and epigenetics establish complex regulatory interactions, which challenge the establishment of the causal/temporal nature of metabolic changes and stem cell activation and differentiation. Future Directions: The development of single-cell technologies and in vitro models able to reproduce the dynamics of stem cell differentiation are actively contributing to define the role of metabolism in this process. This knowledge is key to understanding and designing therapies for those pathologies where the balance between proliferation and differentiation is lost. Importantly, metabolic interventions could be applied to optimize stem cell cultures meant for therapeutical applications, such as transplantations, to treat autoimmune and degenerative disorders. Antioxid. Redox Signal. 34, 1004-1024.
Collapse
Affiliation(s)
- Marlies Corine Ludikhuize
- Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - María José Rodríguez Colman
- Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| |
Collapse
|
|
15
|
Wang Y, Li W, Huang F, Wu X, Chen W, Dong M, Zhou J. Synthesis of sophocarpine triflorohydrazone and its proliferation inhibition and apoptosis induction activity in myeloma cells through Notch3-p53 signaling activation. ENVIRONMENTAL TOXICOLOGY 2021; 36:484-490. [PMID: 33156571 DOI: 10.1002/tox.23053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 10/04/2020] [Accepted: 10/18/2020] [Indexed: 06/11/2023]
Abstract
Multiple myeloma is indicated by the presence of excessive monoclonal plasma cells in bone marrow, which result in the formation of osteolytic lesions. The present study investigated SCA as anti-proliferative agent for myeloma cells and explored the mechanism associated. Effect of SCA on viabilities of KRASA12 and AMO-1 cells was evaluated by MTT assay and apoptotic ratio using flow cytometry. Protein expression was investigated by western blotting and expression of genes related to Notch3-p53 signaling axis using RT-PCR assay. Increase in SCA concentration caused a significant (P < .01) reduction in KRASA12 and AMO-1 cell viability. The KRASA12 and AMO-1 cell viabilities were reduced to 29% and 21%, respectively on treatment with 21 μM doses of SCA. SCA treatment of KRASA12 and AMO-1 cells significantly (P < .05) increased apoptosis compared with untreated cells. The Bcl-2 (26 kDa) protein expression was reduced whereas the Bax (21 kDa) and cleaved caspase-3 levels elevated in SCA treated KRASA12 and AMO-1 cells. Treatment with SCA significantly promoted Hes1, p53 (53 kDa) and Hey1 mRNA expression in KRASA12 and AMO-1 cells. Treatment of KRASA12 and AMO-1 cells with SCA led to a marked reduction in Notch3 protein expression. SCA inhibits KRASA12 and AMO-1 myeloma cell proliferation by promoting pro-apoptotic proteins. Moreover, SCA treatment suppressed Hes1 and Hey1 mRNA expression and targeted Notch3 expression. Therefore, SCA may be studied further for development of treatment for myeloma.
Collapse
Affiliation(s)
- Yong Wang
- Department of Hematology, Affiliated Hospital of Jiujiang University, Jiujiang, China
- Key Laboratory of System Bio-medicine of Jiangxi Province, Jiujiang University, Jiujiang, China
- Clinical Research Center for Precision Medicine and Translational Medicine, Jiujiang University, Jiujiang, China
| | - Wen Li
- Department of Hematology, Affiliated Hospital of Jiujiang University, Jiujiang, China
- Key Laboratory of System Bio-medicine of Jiangxi Province, Jiujiang University, Jiujiang, China
- Clinical Research Center for Precision Medicine and Translational Medicine, Jiujiang University, Jiujiang, China
| | - Fangmei Huang
- Department of Hematology, Affiliated Hospital of Jiujiang University, Jiujiang, China
| | - Xiaojian Wu
- Department of Hematology, Affiliated Hospital of Jiujiang University, Jiujiang, China
| | - Wenbin Chen
- Department of Hematology, Affiliated Hospital of Jiujiang University, Jiujiang, China
| | - Ming Dong
- Department of Hematology, Affiliated Hospital of Jiujiang University, Jiujiang, China
| | - Jie Zhou
- Department of Hematology, Affiliated Hospital of Jiujiang University, Jiujiang, China
| |
Collapse
|
|
16
|
Akil A, Gutiérrez-García AK, Guenter R, Rose JB, Beck AW, Chen H, Ren B. Notch Signaling in Vascular Endothelial Cells, Angiogenesis, and Tumor Progression: An Update and Prospective. Front Cell Dev Biol 2021; 9:642352. [PMID: 33681228 PMCID: PMC7928398 DOI: 10.3389/fcell.2021.642352] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 01/19/2021] [Indexed: 12/12/2022] Open
Abstract
The Notch signaling pathway plays an essential role in a wide variety of biological processes including cell fate determination of vascular endothelial cells and the regulation of arterial differentiation and angiogenesis. The Notch pathway is also an essential regulator of tumor growth and survival by functioning as either an oncogene or a tumor suppressor in a context-dependent manner. Crosstalk between the Notch and other signaling pathways is also pivotal in tumor progression by promoting cancer cell growth, migration, invasion, metastasis, tumor angiogenesis, and the expansion of cancer stem cells (CSCs). In this review, we provide an overview and update of Notch signaling in endothelial cell fate determination and functioning, angiogenesis, and tumor progression, particularly in the development of CSCs and therapeutic resistance. We further summarize recent studies on how endothelial signaling crosstalk with the Notch pathway contributes to tumor angiogenesis and the development of CSCs, thereby providing insights into vascular biology within the tumor microenvironment and tumor progression.
Collapse
Affiliation(s)
- Abdellah Akil
- Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Ana K. Gutiérrez-García
- Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Rachael Guenter
- Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - J. Bart Rose
- Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- O’Neal Comprehensive Cancer Center, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Adam W. Beck
- Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Herbert Chen
- Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- O’Neal Comprehensive Cancer Center, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Bin Ren
- Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- O’Neal Comprehensive Cancer Center, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| |
Collapse
|
|
17
|
Orzechowska M, Anusewicz D, Bednarek AK. Functional Gene Expression Differentiation of the Notch Signaling Pathway in Female Reproductive Tract Tissues-A Comprehensive Review With Analysis. Front Cell Dev Biol 2021; 8:592616. [PMID: 33384996 PMCID: PMC7770115 DOI: 10.3389/fcell.2020.592616] [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: 08/07/2020] [Accepted: 11/11/2020] [Indexed: 12/13/2022] Open
Abstract
The Notch pathway involves evolutionarily conserved signaling regulating the development of the female tract organs such as breast, ovary, cervix, and uterine endometrium. A great number of studies revealed Notch aberrancies in association with their carcinogenesis and disease progression, the management of which is still challenging. The present study is a comprehensive review of the available literature on Notch signaling during the normal development and carcinogenesis of the female tract organs. The review has been enriched with our analyses of the TCGA data including breast, cervical, ovarian, and endometrial carcinomas concerning the effects of Notch signaling at two levels: the core components and downstream effectors, hence filling the lack of global overview of Notch-driven carcinogenesis and disease progression. Phenotype heterogeneity regarding Notch signaling was projected in two uniform manifold approximation and projection algorithm dimensions, preceded by the principal component analysis step reducing the data burden. Additionally, overall and disease-free survival analyses were performed with the optimal cutpoint determination by Evaluate Cutpoints software to establish the character of particular Notch components in tumorigenesis. In addition to the review, we demonstrated separate models of the examined cancers of the Notch pathway and its targets, although expression profiles of all normal tissues were much more similar to each other than to its cancerous compartments. Such Notch-driven cancerous differentiation resulted in a case of opposite association with DFS and OS. As a consequence, target genes also show very distinct profiles including genes associated with cell proliferation and differentiation, energy metabolism, or the EMT. In conclusion, the observed Notch associations with the female tract malignancies resulted from differential expression of target genes. This may influence a future analysis to search for new therapeutic targets based on specific Notch pathway profiles.
Collapse
Affiliation(s)
| | - Dorota Anusewicz
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
| | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
| |
Collapse
|
|
18
|
Wang H, Cui G, Yu B, Sun M, Yang H. Cancer Stem Cell Niche in Colorectal Cancer and Targeted Therapies. Curr Pharm Des 2020; 26:1979-1993. [PMID: 32268862 DOI: 10.2174/1381612826666200408102305] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 03/06/2020] [Indexed: 12/11/2022]
Abstract
Cancer stem cells (CSCs), also known as tumor-initiating cells, are a sub-population of tumor cells found in many human cancers that are endowed with self-renewal and pluripotency. CSCs may be more resistant to conventional anticancer therapies than average cancer cells, as they can easily escape the cytotoxic effects of standard chemotherapy, thereby resulting in tumor relapse. Despite significant progress in related research, effective elimination of CSCs remains an unmet clinical need. CSCs are localized in a specialized microenvironment termed the niche, which plays a pivotal role in cancer multidrug resistance. The niche components of CSCs, such as the extracellular matrix, also physically shelter CSCs from therapeutic agents. Colorectal cancer is the most common malignancy worldwide and presents a relatively transparent process of cancer initiation and development, making it an ideal model for CSC niche research. Here, we review recent advances in the field of CSCs using colorectal cancer as an example to illustrate the potential therapeutic value of targeting the CSC niche. These findings not only provide a novel theoretical basis for in-depth discussions on tumor occurrence, development, and prognosis evaluation, but also offer new strategies for the targeted treatment of cancer.
Collapse
Affiliation(s)
- Hao Wang
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Sciences, Liaoning Normal University, Dalian, China.,Laboratory medical college, Jilin Medical University, Jilin, China
| | - Guihua Cui
- School of Pharmacy, Jilin Medical University, Jilin, China
| | - Bo Yu
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Sciences, Liaoning Normal University, Dalian, China
| | - Meiyan Sun
- Laboratory medical college, Jilin Medical University, Jilin, China
| | - Hong Yang
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Sciences, Liaoning Normal University, Dalian, China
| |
Collapse
|
|
19
|
Shen Q, Reedijk M. Notch Signaling and the Breast Cancer Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1287:183-200. [PMID: 33034033 DOI: 10.1007/978-3-030-55031-8_12] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Notch promotes breast cancer progression through tumor initiating cell maintenance, tumor cell fate specification, proliferation, survival, and motility. In addition, Notch is recognized as a decisive mechanism in regulating various juxtacrine and paracrine communications in the tumor microenvironment (TME). In this chapter, we review recent studies on stress-mediated Notch activation within the TME and sequelae such as angiogenesis, extracellular matrix remodeling, changes in the innate and adaptive immunophenotype, and therapeutic perspectives.
Collapse
Affiliation(s)
- Qiang Shen
- Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Michael Reedijk
- Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
| |
Collapse
|
|
20
|
Strapcova S, Takacova M, Csaderova L, Martinelli P, Lukacikova L, Gal V, Kopacek J, Svastova E. Clinical and Pre-Clinical Evidence of Carbonic Anhydrase IX in Pancreatic Cancer and Its High Expression in Pre-Cancerous Lesions. Cancers (Basel) 2020; 12:E2005. [PMID: 32707920 PMCID: PMC7464147 DOI: 10.3390/cancers12082005] [Citation(s) in RCA: 17] [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: 06/22/2020] [Revised: 07/14/2020] [Accepted: 07/16/2020] [Indexed: 12/11/2022] Open
Abstract
Hypoxia is a common phenomenon that occurs in most solid tumors. Regardless of tumor origin, the evolution of a hypoxia-adapted phenotype is critical for invasive cancer development. Pancreatic ductal adenocarcinoma is also characterized by hypoxia, desmoplasia, and the presence of necrosis, predicting poor outcome. Carbonic anhydrase IX (CAIX) is one of the most strict hypoxia regulated genes which plays a key role in the adaptation of cancer cells to hypoxia and acidosis. Here, we summarize clinical data showing that CAIX expression is associated with tumor necrosis, vascularization, expression of Frizzled-1, mucins, or proteins involved in glycolysis, and inevitably, poor prognosis of pancreatic cancer patients. We also describe the transcriptional regulation of CAIX in relation to signaling pathways activated in pancreatic cancers. A large part deals with the preclinical evidence supporting the relevance of CAIX in processes leading to the aggressive behavior of pancreatic tumors. Furthermore, we focus on CAIX occurrence in pre-cancerous lesions, and for the first time, we describe CAIX expression within intraductal papillary mucinous neoplasia. Our review concludes with a detailed account of clinical trials implicating that treatment consisting of conventionally used therapies combined with CAIX targeting could result in an improved anti-cancer response in pancreatic cancer patients.
Collapse
Affiliation(s)
- Sabina Strapcova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia; (S.S.); (M.T.); (L.C.); (L.L.); (J.K.)
| | - Martina Takacova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia; (S.S.); (M.T.); (L.C.); (L.L.); (J.K.)
| | - Lucia Csaderova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia; (S.S.); (M.T.); (L.C.); (L.L.); (J.K.)
| | - Paola Martinelli
- Institute of Cancer Research, Clinic of Internal Medicine I, Medical University of Vienna, 1090 Vienna, Austria;
- Cancer Cell Signaling, Boehringer-Ingelheim RCV Vienna, A-1121 Vienna, Austria
| | - Lubomira Lukacikova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia; (S.S.); (M.T.); (L.C.); (L.L.); (J.K.)
| | - Viliam Gal
- Alpha Medical Pathology, Ruzinovska 6, 82606 Bratislava, Slovakia;
| | - Juraj Kopacek
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia; (S.S.); (M.T.); (L.C.); (L.L.); (J.K.)
| | - Eliska Svastova
- Department of Tumor Biology, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 84505 Bratislava, Slovakia; (S.S.); (M.T.); (L.C.); (L.L.); (J.K.)
| |
Collapse
|
|
21
|
Zhang F, Liu S. Mechanistic insights of adipocyte metabolism in regulating breast cancer progression. Pharmacol Res 2020; 155:104741. [PMID: 32151679 DOI: 10.1016/j.phrs.2020.104741] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 01/20/2020] [Accepted: 03/02/2020] [Indexed: 02/07/2023]
Abstract
Adipocyte account for the largest component in breast tissue. Dysfunctional adipocyte metabolism, such as metaflammation in metabolically abnormal obese patients, will cause hyperplasia and hypertrophy of its constituent adipocytes. Inflamed adipose tissue is one of the biggest risk factors causing breast cancer. Factors linking adipocyte metabolism to breast cancer include dysfunctional secretion of proinflammatory mediators, proangiogenic factors and estrogens. The accumulation of tumor supporting cells and systemic effects, such as insulin resistance, dyslipidemia and oxidative stress, which are caused by abnormal adipocyte metabolism, further contribute to a more aggressive tumor microenvironment and stimulate breast cancer stem cell to influence the development and progression of breast cancer. Here, in this review, we focus on the adipocyte metabolism in regulating breast cancer progression, and discuss the potential targets which can be used for breast cancer therapy.
Collapse
Affiliation(s)
- Fuchuang Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, Key Laboratory of Medical Epigenetics and Metabolism, Innovation Center for Cell Signaling Network, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, Key Laboratory of Medical Epigenetics and Metabolism, Innovation Center for Cell Signaling Network, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| |
Collapse
|
|
22
|
Mansour FA, Al-Mazrou A, Al-Mohanna F, Al-Alwan M, Ghebeh H. PD-L1 is overexpressed on breast cancer stem cells through notch3/mTOR axis. Oncoimmunology 2020; 9:1729299. [PMID: 32313717 PMCID: PMC7153827 DOI: 10.1080/2162402x.2020.1729299] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Revised: 01/01/2020] [Accepted: 01/06/2020] [Indexed: 12/13/2022] Open
Abstract
The T-cell inhibitory molecule PD-L1 is expressed on a fraction of breast cancer cells. The distribution of PD-L1 on the different subpopulations of breast cancer cells is not well-defined. Our aim was to study the expression level of PD-L1 on breast cancer stem-like (CSC-like) cells and their differentiated-like counterparts. We used multi-parametric flow cytometry to measure PD-L1 expression in different subpopulations of breast cancer cells. Pathway inhibitors, quantitative immunofluorescence, cell sorting, and western blot were used to investigate the underlying mechanism of PD-L1 upregulation in CSC-like cells. Specifically, PD-L1 was overexpressed up to three folds on breast CSC-like cells compared with more differentiated-like cancer cells. Functional in vitro and in vivo assays show higher stemness of PD-L1hi as compared with PD-L1lo cells. Among different pathways examined, PD-L1 expression on CSCs was partly dependant on Notch, and/or PI3K/AKT pathway activation. The effect of Notch inhibitors on PD-L1 overexpression in CSCs was completely abrogated upon mTOR knockdown. Specific knockdown of different Notch receptors shows Notch3 as a mediator for PD-L1 overexpression on CSCs and important for maintaining their stemness. Indeed, Notch3 was found to be overexpressed on PD-L1hi cells and specific knockdown of Notch3 abolished the effect of notch inhibitors and ligands on PD-L1 expression as well as mTOR activation. Our data demonstrated that overexpression of PD-L1 on CSCs is partly mediated by the notch pathway through Notch3/mTOR axis. We propose that these findings will help in a better design of anti-PD-L1 combination therapies to treat breast cancer effectively.
Collapse
Affiliation(s)
- Fatmah A Mansour
- Stem Cell & Tissue Re-engineering Program, Research Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Amer Al-Mazrou
- Stem Cell & Tissue Re-engineering Program, Research Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Falah Al-Mohanna
- Department of Comparative Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Monther Al-Alwan
- Stem Cell & Tissue Re-engineering Program, Research Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.,College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia
| | - Hazem Ghebeh
- Stem Cell & Tissue Re-engineering Program, Research Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.,College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia
| |
Collapse
|
|
23
|
Piwarski SA, Thompson C, Chaudhry AR, Denvir J, Primerano DA, Fan J, Salisbury TB. The putative endogenous AHR ligand ITE reduces JAG1 and associated NOTCH1 signaling in triple negative breast cancer cells. Biochem Pharmacol 2020; 174:113845. [PMID: 32032581 DOI: 10.1016/j.bcp.2020.113845] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 02/03/2020] [Indexed: 12/21/2022]
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. TNBC expresses AHR and AHR ligands have anti-cancer activity in TNBC. The aggressiveness of TNBC is due in part to JAG1-NOTCH1 signaling. ITE is a putative endogenous AHR ligand. We show that ITE reduces the expression of JAG1 the amount of Notch 1 intracellular domain (NICD1) and the phosphorylation of STAT3 (at tyrosine 705) in TNBC MDA-MB-231 cells. The STAT3 inhibitor STATTIC also reduced JAG1. STAT3, thus, mediates regulation of JAG1 in MDA-MB-231 cells. Reducing the expression of JAG1 with short interfering RNA decreases the growth, migration and invasiveness of MDA-MB-231 cells. JAG1, therefore, has cellular effects in MDA-MB-231 cells under basal conditions. We consequently evaluated if exposing cells to greater amounts of JAG1 would counteract ITE cellular effects in MDA-MB-231 cells. The results show that JAG1 does not counteract the cellular effects of ITE. JAG1, thus, has no effect on growth or invasiveness in MDA-MB-231 cells treated with ITE. JAG1, therefore, has context dependent roles in MDA-MB-231 cells (basal versus ITE treatment). The results also show that other pathways, not inhibition of the JAG1-NOTCH1 pathway, are important for mediating the growth and invasive inhibitory effect of ITE on MDA-MB-231 cells.
Collapse
Affiliation(s)
- Sean A Piwarski
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA.
| | - Chelsea Thompson
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA.
| | - Ateeq R Chaudhry
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA.
| | - James Denvir
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA.
| | - Donald A Primerano
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA.
| | - Jun Fan
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA.
| | - Travis B Salisbury
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA.
| |
Collapse
|
|
24
|
Bissoli I, Muscari C. Doxorubicin and α-Mangostin oppositely affect luminal breast cancer cell stemness evaluated by a new retinaldehyde-dependent ALDH assay in MCF-7 tumor spheroids. Biomed Pharmacother 2020; 124:109927. [PMID: 31982725 DOI: 10.1016/j.biopha.2020.109927] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 12/29/2019] [Accepted: 12/29/2019] [Indexed: 02/08/2023] Open
Abstract
According to cancer stem cell theory, only a limited number of self-renewing and cloning cells are responsible for tumor relapse after a period of remittance. The aim of the present study was to investigate the effects of Doxorubicin and α-Mangostin, two antiproliferative drugs, on both tumor bulk and stem cells in multicellular tumor spheroids originated from the luminal MCF-7 breast cancer cell line. A new and original fluorimetric assay was used to selectively measure the activity of the retinaldehyde-dependent isoenzymes of aldehyde dehydrogenase (RALDH), which are markers of a subpopulation of breast cancer stem cells. The administration of 5 μg/ml (12.2 μM) α-Mangostin for 48 h provoked: i) a marked disaggregation of the spheroids, leading to a doubling of their volume (p < 0.01), ii) a 40 % decrease in cell viability (p < 0.01), evaluated by the acid phosphatase assay, and iii) a reduction by more than 90 % of RALDH activity. By contrast, Doxorubicin given for 48 h in the range of 0.1-40 μM did not significantly reduce cell viability and caused only a modest modification of the spheroid morphology. Moreover, 40 μM Doxorubicin increased RALDH activity 2.5-fold compared to the untreated sample. When the two drugs were administered together using 5 μg/ml α-Mangostin, the IC50 of Doxorubicin referred to cell viability decreased six-fold and the RALDH activity was further reduced. In conclusion, the combined administration of Doxorubicin and α-Mangostin provoked a significant cytotoxicity and a remarkable inhibition of RALDH activity in MCF-7 tumor spheroids, suggesting that these drugs could be effective in reducing cell stemness in luminal breast cancer.
Collapse
Affiliation(s)
- Irene Bissoli
- Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
| | - Claudio Muscari
- Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
| |
Collapse
|
|
25
|
Lewis K, Kiepas A, Hudson J, Senecal J, Ha JR, Voorand E, Annis MG, Sabourin V, Ahn R, La Selva R, Tabariès S, Hsu BE, Siegel MJ, Dankner M, Canedo EC, Lajoie M, Watson IR, Brown CM, Siegel PM, Ursini-Siegel J. p66ShcA functions as a contextual promoter of breast cancer metastasis. Breast Cancer Res 2020; 22:7. [PMID: 31941526 PMCID: PMC6964019 DOI: 10.1186/s13058-020-1245-6] [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: 03/13/2019] [Accepted: 01/05/2020] [Indexed: 01/25/2023] Open
Abstract
Background The p66ShcA redox protein is the longest isoform of the Shc1 gene and is variably expressed in breast cancers. In response to a variety of stress stimuli, p66ShcA becomes phosphorylated on serine 36, which allows it to translocate from the cytoplasm to the mitochondria where it stimulates the formation of reactive oxygen species (ROS). Conflicting studies suggest both pro- and anti-tumorigenic functions for p66ShcA, which prompted us to examine the contribution of tumor cell-intrinsic functions of p66ShcA during breast cancer metastasis. Methods We tested whether p66ShcA impacts the lung-metastatic ability of breast cancer cells. Breast cancer cells characteristic of the ErbB2+/luminal (NIC) or basal (4T1) subtypes were engineered to overexpress p66ShcA. In addition, lung-metastatic 4T1 variants (4T1-537) were engineered to lack endogenous p66ShcA via Crispr/Cas9 genomic editing. p66ShcA null cells were then reconstituted with wild-type p66ShcA or a mutant (S36A) that cannot translocate to the mitochondria, thereby lacking the ability to stimulate mitochondrial-dependent ROS production. These cells were tested for their ability to form spontaneous metastases from the primary site or seed and colonize the lung in experimental (tail vein) metastasis assays. These cells were further characterized with respect to their migration rates, focal adhesion dynamics, and resistance to anoikis in vitro. Finally, their ability to survive in circulation and seed the lungs of mice was assessed in vivo. Results We show that p66ShcA increases the lung-metastatic potential of breast cancer cells by augmenting their ability to navigate each stage of the metastatic cascade. A non-phosphorylatable p66ShcA-S36A mutant, which cannot translocate to the mitochondria, still potentiated breast cancer cell migration, lung colonization, and growth of secondary lung metastases. However, breast cancer cell survival in the circulation uniquely required an intact p66ShcA S36 phosphorylation site. Conclusion This study provides the first evidence that both mitochondrial and non-mitochondrial p66ShcA pools collaborate in breast cancer cells to promote their maximal metastatic fitness.
Collapse
Affiliation(s)
- Kyle Lewis
- Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, QC, H3T 1E2, Canada.,Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada
| | - Alex Kiepas
- Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada.,Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue, West, Room 513, Montreal, QC, H3A 1A3, Canada
| | - Jesse Hudson
- Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, QC, H3T 1E2, Canada.,Division of Experimental Medicine, McGill University, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada
| | - Julien Senecal
- Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue, West, Room 513, Montreal, QC, H3A 1A3, Canada.,Division of Experimental Medicine, McGill University, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada.,Department of Medicine, McGill University, 1001 Decarie Boulevard, Montreal, QC, H3G 1Y6, Canada
| | - Jacqueline R Ha
- Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, QC, H3T 1E2, Canada.,Division of Experimental Medicine, McGill University, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada
| | - Elena Voorand
- Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada.,Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue, West, Room 513, Montreal, QC, H3A 1A3, Canada
| | - Matthew G Annis
- Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue, West, Room 513, Montreal, QC, H3A 1A3, Canada.,Department of Medicine, McGill University, 1001 Decarie Boulevard, Montreal, QC, H3G 1Y6, Canada
| | - Valerie Sabourin
- Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, QC, H3T 1E2, Canada
| | - Ryuhjin Ahn
- Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, QC, H3T 1E2, Canada.,Division of Experimental Medicine, McGill University, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada
| | - Rachel La Selva
- Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, QC, H3T 1E2, Canada.,Division of Experimental Medicine, McGill University, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada
| | - Sébastien Tabariès
- Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue, West, Room 513, Montreal, QC, H3A 1A3, Canada.,Department of Medicine, McGill University, 1001 Decarie Boulevard, Montreal, QC, H3G 1Y6, Canada
| | - Brian E Hsu
- Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue, West, Room 513, Montreal, QC, H3A 1A3, Canada.,Division of Experimental Medicine, McGill University, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada
| | - Matthew J Siegel
- Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, QC, H3T 1E2, Canada
| | - Matthew Dankner
- Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue, West, Room 513, Montreal, QC, H3A 1A3, Canada.,Division of Experimental Medicine, McGill University, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada.,Department of Medicine, McGill University, 1001 Decarie Boulevard, Montreal, QC, H3G 1Y6, Canada
| | - Eduardo Cepeda Canedo
- Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, QC, H3T 1E2, Canada.,Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada
| | - Mathieu Lajoie
- Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue, West, Room 513, Montreal, QC, H3A 1A3, Canada
| | - Ian R Watson
- Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada.,Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue, West, Room 513, Montreal, QC, H3A 1A3, Canada
| | - Claire M Brown
- Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada
| | - Peter M Siegel
- Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada. .,Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue, West, Room 513, Montreal, QC, H3A 1A3, Canada. .,Department of Medicine, McGill University, 1001 Decarie Boulevard, Montreal, QC, H3G 1Y6, Canada.
| | - Josie Ursini-Siegel
- Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, QC, H3T 1E2, Canada. .,Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada. .,Division of Experimental Medicine, McGill University, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada. .,Gerald Bronfman Department of Oncology, McGill University, 5100 Maisonneuve Blvd West, Montreal, QC, H4A 3T2, Canada.
| |
Collapse
|
|
26
|
Diaz Bessone MI, Simón-Gracia L, Scodeller P, Ramirez MDLA, Lago Huvelle MA, Soler-Illia GJAA, Simian M. iRGD-guided tamoxifen polymersomes inhibit estrogen receptor transcriptional activity and decrease the number of breast cancer cells with self-renewing capacity. J Nanobiotechnology 2019; 17:120. [PMID: 31812165 PMCID: PMC6898937 DOI: 10.1186/s12951-019-0553-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 11/25/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Tamoxifen (Tam) is the most frequent treatment for estrogen receptor (ER) positive breast cancer. We recently showed that fibronectin (FN) leads to Tam resistance and selection of breast cancer stem cells. With the aim of developing a nanoformulation that would simultaneously tackle ER and FN/β1 integrin interactions, we designed polyethylene glycol-polycaprolactone polymersomes polymersomes (PS) that carry Tam and are functionalized with the tumor-penetrating iRGD peptide (iRGD-PS-Tam). RESULTS Polyethylene glycol-polycaprolactone PS were assembled and loaded with Tam using the hydration film method. The loading of encapsulated Tam, measured by UPLC, was 2.4 ± 0.5 mol Tam/mol polymer. Physicochemical characterization of the PS demonstrated that iRGD functionalization had no effect on morphology, and a minimal effect on the PS size and polydispersity (176 nm and Pdi 0.37 for iRGD-TAM-PS and 171 nm and Pdi 0.36 for TAM-PS). iRGD-PS-Tam were taken up by ER+ breast carcinoma cells in 2D-culture and exhibited increased penetration of 3D-spheroids. Treatment with iRGD-PS-Tam inhibited proliferation and sensitized cells cultured on FN to Tam. Mechanistically, treatment with iRGD-PS-Tam resulted in inhibition ER transcriptional activity as evaluated by a luciferase reporter assay. iRGD-PS-Tam reduced the number of cells with self-renewing capacity, a characteristic of breast cancer stem cells. In vivo, systemic iRGD-PS-Tam showed selective accumulation at the tumor site. CONCLUSIONS Our study suggests iRGD-guided delivery of PS-Tam as a potential novel therapeutic strategy for the management of breast tumors that express high levels of FN. Future studies in pre-clinical in vivo models are warranted.
Collapse
Affiliation(s)
- María Inés Diaz Bessone
- Instituto de Nanosistemas, Universidad Nacional de San Martín, 25 de Mayo 1021, San Martín, 1650 Buenos Aires, Argentina
| | - Lorena Simón-Gracia
- Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14b, 50411 Tartu, Estonia
| | - Pablo Scodeller
- Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14b, 50411 Tartu, Estonia
| | - María de los Angeles Ramirez
- Instituto de Nanosistemas, Universidad Nacional de San Martín, 25 de Mayo 1021, San Martín, 1650 Buenos Aires, Argentina
| | - María Amparo Lago Huvelle
- Instituto de Nanosistemas, Universidad Nacional de San Martín, 25 de Mayo 1021, San Martín, 1650 Buenos Aires, Argentina
| | - Galo J. A. A. Soler-Illia
- Instituto de Nanosistemas, Universidad Nacional de San Martín, 25 de Mayo 1021, San Martín, 1650 Buenos Aires, Argentina
| | - Marina Simian
- Instituto de Nanosistemas, Universidad Nacional de San Martín, 25 de Mayo 1021, San Martín, 1650 Buenos Aires, Argentina
| |
Collapse
|
|
27
|
Zheng D, Tao M, Liang X, Li Y, Jin J, He Q. p66Shc regulates podocyte autophagy in high glucose environment through the Notch-PTEN-PI3K/Akt/mTOR pathway. Histol Histopathol 2019; 35:405-415. [PMID: 31650524 DOI: 10.14670/hh-18-178] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Autophagy has been found to be involved in podocyte injury, which is a key factor in the progression of diabetic kidney disease (DKD). p66Shc is an important protein adaptor that regulates production of reactive oxygen species (ROS) and induction of apoptosis, and is a novel biomarker for oxidative damage of renal tubules. Our preliminary studies showed that p66Shc expression in podocytes of DKD patients is increased, while autophagic flux and podocyte number is decreased in DKD patients. The mechanism by which p66Shc may regulate podocyte autophagy and injury remains unknown. The present study aimed to investigate the molecular function of p66Shc under high glucose condition and its possible therapeutic utility in DKD. METHODS We histologically evaluated kidney injury in a streptozocin (STZ)-induced mouse model of diabetes using HE, PAS, PASM, and Masson staining and assessed glomerular structure by transmission electron microscopy. The apoptosis rate of high glucose-treated podocytes was assessed by TUNEL and Annexin V/PI staining. Markers of podocyte autophagy were measured by immunofluorescence and western blotting. DHE/ET fluorescence quantification was used for ROS detection and quantification. RESULTS Urine creatinine, serum creatinine, urinary microalbumin, and p66Shc expression were significantly increased in STZ-induced diabetic mice. Cultured MPC5 podocytes subjected to high glucose showed reduced viability, and p66Shc overexpression further accelerated apoptosis. p66Shc knockdown enhanced HG-induced autophagy, while p66Shc overexpression reduced the expression of PTEN and increased the expression of mTOR and phospho-mTOR. LC3 protein expression was higher in cells with p66Shc knockdown, indicating that activation of p66Shc inhibits podocyte autophagy. DAPT, an inhibitor of the Notch pathway, downregulated the expression of p66Shc. CONCLUSION These findings indicate that p66Shc inhibits podocyte autophagy and induces apoptosis through the Notch -PTEN-PI3K/Akt/ mTOR signaling pathway in high glucose environment, providing novel evidence for its potential role in DKD treatment.
Collapse
Affiliation(s)
- Danna Zheng
- Zhejiang Chinese Medical University, Zhejiang, PR China.,Department of Nephrology, Zhejiang Provincial People's Hospital, Zhejiang, PR China.,People's Hospital of Hangzhou Medical College, Zhejiang, PR China.,Chinese Medical Nephrology Key Laboratory of Zhejiang Province, Zhejiang, PR China
| | - Mei Tao
- Department of Nephrology, Zhejiang Provincial People's Hospital, Zhejiang, PR China.,People's Hospital of Hangzhou Medical College, Zhejiang, PR China.,Chinese Medical Nephrology Key Laboratory of Zhejiang Province, Zhejiang, PR China
| | - Xudong Liang
- Department of Nephrology, Zhejiang Provincial People's Hospital, Zhejiang, PR China.,People's Hospital of Hangzhou Medical College, Zhejiang, PR China.,Chinese Medical Nephrology Key Laboratory of Zhejiang Province, Zhejiang, PR China
| | - Yiwen Li
- Department of Nephrology, Zhejiang Provincial People's Hospital, Zhejiang, PR China.,People's Hospital of Hangzhou Medical College, Zhejiang, PR China.,Chinese Medical Nephrology Key Laboratory of Zhejiang Province, Zhejiang, PR China
| | - Juan Jin
- Department of Nephrology, Zhejiang Provincial People's Hospital, Zhejiang, PR China.,People's Hospital of Hangzhou Medical College, Zhejiang, PR China.,Chinese Medical Nephrology Key Laboratory of Zhejiang Province, Zhejiang, PR China
| | - Qiang He
- Department of Nephrology, Zhejiang Provincial People's Hospital, Zhejiang, PR China.,People's Hospital of Hangzhou Medical College, Zhejiang, PR China.,Chinese Medical Nephrology Key Laboratory of Zhejiang Province, Zhejiang, PR China
| |
Collapse
|
|
28
|
Huang P, Feng X, Zhao Z, Yang B, Fang T, Guo M, Xia J. p66Shc promotes HCC progression in the tumor microenvironment via STAT3 signaling. Exp Cell Res 2019; 383:111550. [DOI: 10.1016/j.yexcr.2019.111550] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 08/05/2019] [Accepted: 08/06/2019] [Indexed: 12/19/2022]
|
|
29
|
Magalhães-Novais S, Bermejo-Millo JC, Loureiro R, Mesquita KA, Domingues MR, Maciel E, Melo T, Baldeiras I, Erickson JR, Holy J, Potes Y, Coto-Montes A, Oliveira PJ, Vega-Naredo I. Cell quality control mechanisms maintain stemness and differentiation potential of P19 embryonic carcinoma cells. Autophagy 2019; 16:313-333. [PMID: 30990357 DOI: 10.1080/15548627.2019.1607694] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Given the relatively long life of stem cells (SCs), efficient mechanisms of quality control to balance cell survival and resistance to external and internal stress are required. Our objective was to test the relevance of cell quality control mechanisms for SCs maintenance, differentiation and resistance to cell death. We compared cell quality control in P19 stem cells (P19SCs) before and after differentiation (P19dCs). Differentiation of P19SCs resulted in alterations in parameters involved in cell survival and protein homeostasis, including the redox system, cardiolipin and lipid profiles, unfolded protein response, ubiquitin-proteasome and lysosomal systems, and signaling pathways controlling cell growth. In addition, P19SCs pluripotency was correlated with stronger antioxidant protection, modulation of apoptosis, and activation of macroautophagy, which all contributed to preserve SCs quality by increasing the threshold for cell death activation. Furthermore, our findings identify critical roles for the PI3K-AKT-MTOR pathway, as well as autophagic flux and apoptosis regulation in the maintenance of P19SCs pluripotency and differentiation potential.Abbreviations: 3-MA: 3-methyladenine; AKT/protein kinase B: thymoma viral proto-oncogene; AKT1: thymoma viral proto-oncogene 1; ATG: AuTophaGy-related; ATF6: activating transcription factor 6; BAX: BCL2-associated X protein; BBC3/PUMA: BCL2 binding component 3; BCL2: B cell leukemia/lymphoma 2; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CASP3: caspase 3; CASP8: caspase 8; CASP9: caspase 9; CL: cardiolipin; CTSB: cathepsin B; CTSD: cathepsin D; DDIT3/CHOP: DNA-damage inducible transcript 3; DNM1L/DRP1: dynamin 1-like; DRAM1: DNA-damage regulated autophagy modulator 1; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; EIF2S1/eIF2α: eukaryotic translation initiation factor 2, subunit alpha; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; ESCs: embryonic stem cells; KRT8/TROMA-1: cytokeratin 8; LAMP2A: lysosomal-associated membrane protein 2A; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NANOG: Nanog homeobox; NAO: 10-N-nonyl acridine orange; NFE2L2/NRF2: nuclear factor, erythroid derived 2, like 2; OPA1: OPA1, mitochondrial dynamin like GTPase; P19dCs: P19 differentiated cells; P19SCs: P19 stem cells; POU5F1/OCT4: POU domain, class 5, transcription factor 1; PtdIns3K: phosphatidylinositol 3-kinase; RA: retinoic acid; ROS: reactive oxygen species; RPS6KB1/p70S6K: ribosomal protein S6 kinase, polypeptide 1; SCs: stem cells; SOD: superoxide dismutase; SHC1-1/p66SHC: src homology 2 domain-containing transforming protein C1, 66 kDa isoform; SOX2: SRY (sex determining region Y)-box 2; SQSTM1/p62: sequestosome 1; SPTAN1/αII-spectrin: spectrin alpha, non-erythrocytic 1; TOMM20: translocase of outer mitochondrial membrane 20; TRP53/p53: transformation related protein 53; TUBB3/betaIII-tubulin: tubulin, beta 3 class III; UPR: unfolded protein response; UPS: ubiquitin-proteasome system.
Collapse
Affiliation(s)
| | - Juan C Bermejo-Millo
- Department of Morphology and Cell Biology, University of Oviedo, Oviedo, Spain.,Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Rute Loureiro
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Cantanhede, Portugal
| | - Katia A Mesquita
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Cantanhede, Portugal
| | - M Rosário Domingues
- Mass Spectrometry Centre, Department of Chemistry & QOPNA, University of Aveiro, Aveiro, Portugal
| | - Elisabete Maciel
- Mass Spectrometry Centre, Department of Chemistry & QOPNA, University of Aveiro, Aveiro, Portugal.,Department of Biology & CESAM, University of Aveiro, Aveiro, Portugal
| | - Tânia Melo
- Mass Spectrometry Centre, Department of Chemistry & QOPNA, University of Aveiro, Aveiro, Portugal
| | - Inês Baldeiras
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Cantanhede, Portugal.,School of Medicine, University of Coimbra, Coimbra, Portugal
| | - Jenna R Erickson
- Department of Biomedical Sciences, University of Minnesota-Duluth, Duluth, MN, USA
| | - Jon Holy
- Department of Biomedical Sciences, University of Minnesota-Duluth, Duluth, MN, USA
| | - Yaiza Potes
- Department of Morphology and Cell Biology, University of Oviedo, Oviedo, Spain.,Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Ana Coto-Montes
- Department of Morphology and Cell Biology, University of Oviedo, Oviedo, Spain.,Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Paulo J Oliveira
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Cantanhede, Portugal
| | - Ignacio Vega-Naredo
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Cantanhede, Portugal.,Department of Morphology and Cell Biology, University of Oviedo, Oviedo, Spain.,Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| |
Collapse
|
|
30
|
Porcheri C, Meisel CT, Mitsiadis T. Multifactorial Contribution of Notch Signaling in Head and Neck Squamous Cell Carcinoma. Int J Mol Sci 2019; 20:E1520. [PMID: 30917608 PMCID: PMC6471940 DOI: 10.3390/ijms20061520] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 03/21/2019] [Accepted: 03/22/2019] [Indexed: 12/20/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) defines a group of solid tumors originating from the mucosa of the upper aerodigestive tract, pharynx, larynx, mouth, and nasal cavity. It has a metastatic evolution and poor prognosis and is the sixth most common cancer in the world, with 600,000 new cases reported every year. HNSCC heterogeneity and complexity is reflected in a multistep progression, involving crosstalk between several molecular pathways. The Notch pathway is associated with major events supporting cancerogenic evolution: cell proliferation, self-renewal, angiogenesis, and preservation of a pro-oncogenic microenvironment. Additionally, Notch is pivotal in tumor development and plays a dual role acting as both oncogene and tumor suppressor. In this review, we summarize the role of the Notch pathway in HNSCC, with a special focus on its compelling role in major events of tumor initiation and growth.
Collapse
Affiliation(s)
- Cristina Porcheri
- University of Zurich, Institute of Oral Biology, Plattenstrasse 11, CH-8032 Zurich, Switzerland.
| | - Christian Thomas Meisel
- University of Zurich, Institute of Oral Biology, Plattenstrasse 11, CH-8032 Zurich, Switzerland.
| | - Thimios Mitsiadis
- University of Zurich, Institute of Oral Biology, Plattenstrasse 11, CH-8032 Zurich, Switzerland.
| |
Collapse
|
|
31
|
Modulation of Obesity and Insulin Resistance by the Redox Enzyme and Adaptor Protein p66 Shc. Int J Mol Sci 2019; 20:ijms20040985. [PMID: 30813483 PMCID: PMC6412263 DOI: 10.3390/ijms20040985] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 02/15/2019] [Accepted: 02/21/2019] [Indexed: 12/27/2022] Open
Abstract
Initially reported as a longevity-related protein, the 66 kDa isoform of the mammalian Shc1 locus has been implicated in several metabolic pathways, being able to act both as an adaptor protein and as a redox enzyme capable of generating reactive oxygen species (ROS) when it localizes to the mitochondrion. Ablation of p66Shc has been shown to be protective against obesity and the insurgence of insulin resistance, but not all the studies available in the literature agree on these points. This review will focus in particular on the role of p66Shc in the modulation of glucose homeostasis, obesity, body temperature, and respiration/energy expenditure. In view of the obesity and diabetes epidemic, p66Shc may represent a promising therapeutic target with enormous implications for human health.
Collapse
|
|
32
|
Giovannini C, Salzano AM, Baglioni M, Vitale M, Scaloni A, Zambrano N, Giannone FA, Vasuri F, D'Errico A, Svegliati Baroni G, Bolondi L, Gramantieri L. Brivanib in combination with Notch3 silencing shows potent activity in tumour models. Br J Cancer 2019; 120:601-611. [PMID: 30765875 PMCID: PMC6461893 DOI: 10.1038/s41416-018-0375-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 12/03/2018] [Accepted: 12/14/2018] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Sorafenib is the first targeted agent proven to improve survival of patients with advanced hepatocellular carcinoma (HCC) and it has been used in first line treatments with heterogeneous response across patients. Most of the promising agents evaluated in first-line or second-line phase III trials for HCC failed to improve patient survival. The absence of molecular characterisation, including the identification of pathways driving resistance might be responsible for these disappointing results. METHODS 2D DIGE and MS analyses were used to reveal proteomic signatures resulting from Notch3 inhibition in HepG2 cells, combined with brivanib treatment. The therapeutic potential of Notch3 inhibition combined with brivanib treatment was also demonstrated in a rat model of HCC and in cell lines derived from different human cancers. RESULTS Using a proteomic approach, we have shown that Notch3 is strongly involved in brivanib resistance through a p53-dependent regulation of enzymes of the tricarboxylic acid (TCA), both in vitro and in vivo. CONCLUSION We have demonstrated that regulation of the TCA cycle is a common mechanism in different human cancers, suggesting that Notch3 inhibitors combined with brivanib treatment may represent a strong formulation for the treatment of HCC as well as Notch3-driven cancers.
Collapse
Affiliation(s)
- Catia Giovannini
- Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi University Hospital, Bologna, Italy. .,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
| | - Anna Maria Salzano
- Proteomics & Mass Spectrometry Laboratory, ISPAAM, National Research Council, 80147, Napoli, Italy
| | - Michele Baglioni
- Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi University Hospital, Bologna, Italy
| | - Monica Vitale
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy.,CEINGE Biotecnologie Avanzate S.C.aR.L, Napoli, Italy
| | - Andrea Scaloni
- Proteomics & Mass Spectrometry Laboratory, ISPAAM, National Research Council, 80147, Napoli, Italy
| | - Nicola Zambrano
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy.,CEINGE Biotecnologie Avanzate S.C.aR.L, Napoli, Italy
| | | | - Francesco Vasuri
- Pathology Unit, St. Orsola-Malpighi University Hospital, 40138, Bologna, Italy
| | - Antonia D'Errico
- Pathology Unit, St. Orsola-Malpighi University Hospital, 40138, Bologna, Italy
| | | | - Luigi Bolondi
- Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi University Hospital, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Laura Gramantieri
- Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi University Hospital, Bologna, Italy
| |
Collapse
|
|
33
|
Zhang Y, Lin XY, Zhang JH, Xie ZL, Deng H, Huang YF, Huang XH. Apoptosis of mouse myeloma cells induced by curcumin via the Notch3-p53 signaling axis. Oncol Lett 2019; 17:127-134. [PMID: 30655747 PMCID: PMC6313093 DOI: 10.3892/ol.2018.9591] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 08/15/2018] [Indexed: 12/19/2022] Open
Abstract
Resistance to apoptosis is a characteristic of cancer. Curcumin has become a potential anticancer drug for its pro-apoptotic effects, but the underlying mechanisms remain unclear. Furthermore, the Notch3-p53 signaling axis serves an important role in cell fate. The present study was designed to investigate the antitumor effect of curcumin by the Notch3-p53 axis in mouse myeloma P3X63Ag8 cells. The effects of curcumin on the viability of P3X63Ag8 cells were evaluated using an MTT assay. Quantitative expression of the Notch3-p53 signaling axis-associated genes was measured by reverse transcription-quantitative polymerase chain reaction, and western blot analysis was used to investigate the expression of proteins. Additionally, flow cytometry was used to measure the ratio of apoptosis. The results demonstrated that curcumin could significantly inhibit cell viability. No significant pro-apoptotic effect was observed when the concentration of curcumin was <30 µM. At 30 µM, curcumin-treated cells exhibited an apoptotic phenomenon, and the ratio of late apoptosis increased with the concentration of curcumin, and reached 28.4 and 51.8% in the medium- and high-dose groups, respectively. Curcumin inhibited the expression of Notch3, while the middle- and high-dose groups promoted p53. The expression of Notch3-responsive genes Hes family BHLH transcription factor 1 and Hes-related family transcription factor with YRPW motif 1 were notably promoted. Curcumin treatment significantly downregulated B-cell lymphoma-2 (Bcl-2) at the mRNA and protein levels, but upregulated Bcl-2-associated X. These data indicated that curcumin exhibited antitumor effects in mouse myeloma cells with induction of apoptosis by affecting the Notch3-p53 signaling axis.
Collapse
Affiliation(s)
- Ying Zhang
- Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, P.R. China
| | - Xin-Yu Lin
- Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, P.R. China
- Department of Zoology, College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, P.R. China
| | - Jiao-Hui Zhang
- Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, P.R. China
| | - Zheng-Lu Xie
- Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, P.R. China
| | - Hui Deng
- Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, P.R. China
| | - Yi-Fang Huang
- Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, P.R. China
| | - Xiao-Hong Huang
- Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou, Fujian 350002, P.R. China
| |
Collapse
|
|
34
|
Mollen EWJ, Ient J, Tjan-Heijnen VCG, Boersma LJ, Miele L, Smidt ML, Vooijs MAGG. Moving Breast Cancer Therapy up a Notch. Front Oncol 2018; 8:518. [PMID: 30515368 PMCID: PMC6256059 DOI: 10.3389/fonc.2018.00518] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 10/22/2018] [Indexed: 12/11/2022] Open
Abstract
Breast cancer is the second most common malignancy, worldwide. Treatment decisions are based on tumor stage, histological subtype, and receptor expression and include combinations of surgery, radiotherapy, and systemic treatment. These, together with earlier diagnosis, have resulted in increased survival. However, initial treatment efficacy cannot be guaranteed upfront, and these treatments may come with (long-term) serious adverse effects, negatively affecting a patient's quality of life. Gene expression-based tests can accurately estimate the risk of recurrence in early stage breast cancers. Disease recurrence correlates with treatment resistance, creating a major need to resensitize tumors to treatment. Notch signaling is frequently deregulated in cancer and is involved in treatment resistance. Preclinical research has already identified many combinatory therapeutic options where Notch involvement enhances the effectiveness of radiotherapy, chemotherapy or targeted therapies for breast cancer. However, the benefit of targeting Notch has remained clinically inconclusive. In this review, we summarize the current knowledge on targeting the Notch pathway to enhance current treatments for breast cancer and to combat treatment resistance. Furthermore, we propose mechanisms to further exploit Notch-based therapeutics in the treatment of breast cancer.
Collapse
Affiliation(s)
- Erik W J Mollen
- Department of Radiotherapy, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands.,Department of Radiation Oncology (MAASTRO), Maastricht University Medical Centre+, Maastricht, Netherlands.,Division of Medical Oncology, Department of Surgery, Maastricht University Medical Centre+, Maastricht, Netherlands
| | - Jonathan Ient
- Department of Radiotherapy, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Vivianne C G Tjan-Heijnen
- Department of Radiotherapy, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands.,Division of Medical Oncology, Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, Netherlands
| | - Liesbeth J Boersma
- Department of Radiotherapy, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands.,Department of Radiation Oncology (MAASTRO), Maastricht University Medical Centre+, Maastricht, Netherlands
| | - Lucio Miele
- Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, United States.,Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Marjolein L Smidt
- Department of Radiotherapy, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands.,Division of Medical Oncology, Department of Surgery, Maastricht University Medical Centre+, Maastricht, Netherlands
| | - Marc A G G Vooijs
- Department of Radiotherapy, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands.,Department of Radiation Oncology (MAASTRO), Maastricht University Medical Centre+, Maastricht, Netherlands
| |
Collapse
|
|
35
|
Soltanian S, Dehghani H. BORIS: a key regulator of cancer stemness. Cancer Cell Int 2018; 18:154. [PMID: 30323717 PMCID: PMC6173857 DOI: 10.1186/s12935-018-0650-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 09/27/2018] [Indexed: 02/07/2023] Open
Abstract
BORIS (CTCFL) is a DNA binding protein which is involved in tumorigenesis. Although, there are different opinions on the level of gene expression and function of BORIS in normal and cancer tissues, the results of many studies have classified BORIS as a protein belonging to cancer/testis (CT) genes, which are identified as a group of genes that are expressed normally in testis, and abnormally in various types of cancers. In testis, BORIS induces the expression of some male germ cell/testis specific genes, and plays crucial roles during spermatogenesis and production of sperm. In tumorigenesis, the role of BORIS in the expression induction of some CT genes and oncogenes, as well as increasing proliferation/viability of cancer cells has been demonstrated in many researches. In addition to cancer cells, some believe that BORIS is also expressed in normal conditions and plays a universal function in cell division and regulation of genes. The following is a comprehensive review on contradictory views on the expression pattern and biological function of BORIS in normal, as well as cancer cells/tissues, and presents some evidence that support the expression of BORIS in cancer stem cells (CSCs) and advanced stage/poorer differentiation grade of cancers. Boris is involved in the regulation of CSC cellular and molecular features such as self-renewal, chemo-resistance, tumorigenicity, sphere-forming ability, and migration capacity. Finally, the role of BORIS in regulating two important signaling pathways including Wnt/β-catenin and Notch in CSCs, and its ability in recruiting transcription factors or chromatin-remodeling proteins to induce tumorigenesis is discussed.
Collapse
Affiliation(s)
- Sara Soltanian
- Department of Biology, Faculty of Sciences, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Hesam Dehghani
- Department of Basic Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Azadi Square, Mashhad, 91775-1793 Iran
- Division of Biotechnology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
- Stem Cells and Regenerative Medicine Research Group, Research Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| |
Collapse
|
|
36
|
Varghese E, Samuel SM, Abotaleb M, Cheema S, Mamtani R, Büsselberg D. The "Yin and Yang" of Natural Compounds in Anticancer Therapy of Triple-Negative Breast Cancers. Cancers (Basel) 2018; 10:E346. [PMID: 30248941 PMCID: PMC6209965 DOI: 10.3390/cancers10100346] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 09/18/2018] [Accepted: 09/19/2018] [Indexed: 02/07/2023] Open
Abstract
Among the different types of breast cancers, triple-negative breast cancers (TNBCs) are highly aggressive, do not respond to conventional hormonal/human epidermal growth factor receptor 2 (HER2)-targeted interventions due to the lack of the respective receptor targets, have chances of early recurrence, metastasize, tend to be more invasive in nature, and develop drug resistance. The global burden of TNBCs is increasing regardless of the number of cytotoxic drugs being introduced into the market each year as they have only moderate efficacy and/or unforeseen side effects. Therefore, the demand for more efficient therapeutic interventions, with reduced side effects, for the treatment of TNBCs is rising. While some plant metabolites/derivatives actually induce the risk of cancers, many plant-derived active principles have gained attention as efficient anticancer agents against TNBCs, with fewer adverse side effects. Here we discuss the possible oncogenic molecular pathways in TNBCs and how the purified plant-derived natural compounds specifically target and modulate the genes and/or proteins involved in these aberrant pathways to exhibit their anticancer potential. We have linked the anticancer potential of plant-derived natural compounds (luteolin, chalcones, piperine, deguelin, quercetin, rutin, fisetin, curcumin, resveratrol, and others) to their ability to target multiple dysregulated signaling pathways (such as the Wnt/β-catenin, Notch, NF-κB, PI3K/Akt/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and Hedgehog) leading to suppression of cell growth, proliferation, migration, inflammation, angiogenesis, epithelial-mesenchymal transition (EMT) and metastasis, and activation of apoptosis in TNBCs. Plant-derived compounds in combination with classical chemotherapeutic agents were more efficient in the treatment of TNBCs, possibly with lesser side effects.
Collapse
Affiliation(s)
- Elizabeth Varghese
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar.
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar.
| | - Mariam Abotaleb
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar.
| | - Sohaila Cheema
- Institute for Population Health, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar.
| | - Ravinder Mamtani
- Institute for Population Health, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar.
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar.
| |
Collapse
|
|
37
|
Colombo M, Mirandola L, Chiriva-Internati M, Basile A, Locati M, Lesma E, Chiaramonte R, Platonova N. Cancer Cells Exploit Notch Signaling to Redefine a Supportive Cytokine Milieu. Front Immunol 2018; 9:1823. [PMID: 30154786 PMCID: PMC6102368 DOI: 10.3389/fimmu.2018.01823] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Accepted: 07/24/2018] [Indexed: 12/19/2022] Open
Abstract
Notch signaling is a well-known key player in the communication between adjacent cells during organ development, when it controls several processes involved in cell differentiation. Notch-mediated communication may occur through the interaction of Notch receptors with ligands on adjacent cells or by a paracrine/endocrine fashion, through soluble molecules that can mediate the communication between cells at distant sites. Dysregulation of Notch pathway causes a number of disorders, including cancer. Notch hyperactivation may be caused by mutations of Notch-related genes, dysregulated upstream pathways, or microenvironment signals. Cancer cells may exploit this aberrant signaling to "educate" the surrounding microenvironment cells toward a pro-tumoral behavior. This may occur because of key cytokines secreted by tumor cells or it may involve the microenvironment through the activation of Notch signaling in stromal cells, an event mediated by a direct cell-to-cell contact and resulting in the increased secretion of several pro-tumorigenic cytokines. Up to now, review articles were mainly focused on Notch contribution in a specific tumor context or immune cell populations. Here, we provide a comprehensive overview on the outcomes of Notch-mediated pathological interactions in different tumor settings and on the molecular and cellular mediators involved in this process. We describe how Notch dysregulation in cancer may alter the cytokine network and its outcomes on tumor progression and antitumor immune response.
Collapse
Affiliation(s)
- Michela Colombo
- Department of Health Sciences, Università degli Studi di Milano, Milano, Italy
| | | | - Maurizio Chiriva-Internati
- Kiromic Biopharma Inc., Houston, TX, United States.,Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.,Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Andrea Basile
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milano, Italy
| | - Massimo Locati
- Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Milano, Italy.,Humanitas Clinical and Research Center, Rozzano, Italy
| | - Elena Lesma
- Department of Health Sciences, Università degli Studi di Milano, Milano, Italy
| | | | - Natalia Platonova
- Department of Health Sciences, Università degli Studi di Milano, Milano, Italy
| |
Collapse
|
|
38
|
Guarnieri AL, Towers CG, Drasin DJ, Oliphant MUJ, Andrysik Z, Hotz TJ, Vartuli RL, Linklater ES, Pandey A, Khanal S, Espinosa JM, Ford HL. The miR-106b-25 cluster mediates breast tumor initiation through activation of NOTCH1 via direct repression of NEDD4L. Oncogene 2018; 37:3879-3893. [PMID: 29662198 PMCID: PMC6043359 DOI: 10.1038/s41388-018-0239-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Revised: 02/01/2018] [Accepted: 03/03/2018] [Indexed: 01/07/2023]
Abstract
Tumor-initiating cells (TIC) represent a subset of tumor cells with increased self-renewal capability. TICs display resistance to frontline cancer treatment and retain the ability to repopulate a tumor after therapy, leading to cancer relapse. NOTCH signaling has been identified as an important driver of the TIC population, yet mechanisms governing regulation of this pathway in cancer remain to be fully elucidated. Here we identify a novel mechanism of NOTCH regulation and TIC induction in breast cancer via the miR-106b-25 miRNA cluster. We show that the miR-106b-25 cluster upregulates NOTCH1 in multiple breast cancer cell lines, representing both estrogen receptor (ER+) and triple negative breast cancer (TNBC) through direct repression of the E3 ubiquitin ligase, NEDD4L. We further show that upregulation of NOTCH1 is necessary for TIC induction downstream of miR-106b-25 in both ER + and TNBC breast cancer cells, and that re-expression of NEDD4L is sufficient to reverse miR106b-25-mediated NOTCH1 upregulation and TIC induction. Importantly, we demonstrate a significant positive correlation between miR-106b-25 and NOTCH1 protein, yet a significant inverse correlation between miR-106b-25 and NEDD4L mRNA in human breast cancer, suggesting a critical role for the miR106b-25/NEDD4L/NOTCH1 axis in the disease. Further, we show for the first time that NEDD4L expression alone is significantly associated with a better relapse-free prognosis for breast cancer patients. These data expand our knowledge of the mechanisms underlying NOTCH activation and TIC induction in breast cancer, and may provide new avenues for the development of therapies targeting this resistant subset of tumor cells.
Collapse
Affiliation(s)
- A L Guarnieri
- Program in Molecular Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - C G Towers
- Program in Molecular Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - D J Drasin
- Program in Molecular Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - M U J Oliphant
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Integrated Physiology Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Z Andrysik
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - T J Hotz
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - R L Vartuli
- Program in Molecular Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - E S Linklater
- Program in Molecular Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - A Pandey
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - S Khanal
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - J M Espinosa
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
- Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Boulder, CO, 80309, USA
| | - H L Ford
- Program in Molecular Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
- Integrated Physiology Program, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
| |
Collapse
|
|
39
|
Shah D, Wyatt D, Baker AT, Simms P, Peiffer DS, Fernandez M, Rakha E, Green A, Filipovic A, Miele L, Osipo C. Inhibition of HER2 Increases JAGGED1-dependent Breast Cancer Stem Cells: Role for Membrane JAGGED1. Clin Cancer Res 2018; 24:4566-4578. [PMID: 29895705 DOI: 10.1158/1078-0432.ccr-17-1952] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 04/19/2018] [Accepted: 06/04/2018] [Indexed: 12/21/2022]
Abstract
Purpose: HER2-positive breast cancer is driven by cells possessing stem-like properties of self-renewal and differentiation, referred to as cancer stem cells (CSC). CSCs are implicated in radiotherapy, chemotherapy resistance, and tumor recurrence. NOTCH promotes breast CSC survival and self-renewal, and overexpression of NOTCH1 and the NOTCH ligand JAGGED1 predict poor outcome. Resistance to anti-HER2 therapy in HER2+ breast cancer requires NOTCH1, and that combination of trastuzumab and a gamma secretase inhibitor (GSI) prevents tumor relapse in xenograft models.Experimental Design: The current study investigates mechanisms by which HER2 tyrosine kinase activity regulates NOTCH-dependent CSC survival and tumor initiation.Results: Lapatinib-mediated HER2 inhibition shifts the population of HER2+ breast cancer cells from low membrane JAGGED1 expression to higher levels, independent of sensitivity to anti-HER2 treatment within the bulk cell population. This increase in membrane JAGGED1 is associated with higher NOTCH receptor expression, activation, and enrichment of CSCs in vitro and in vivo Importantly, lapatinib treatment results in growth arrest and cell death of JAGGED1 low-expressing cells while the JAGGED1 high-expressing cells continue to cycle. High membrane JAGGED1 protein expression predicts poor overall cumulative survival in women with HER2+ breast cancer.Conclusions: These results indicate that higher membrane JAGGED1 expression may be used to either predict response to anti-HER2 therapy or for detection of NOTCH-sensitive CSCs posttherapy. Sequential blockade of HER2 followed by JAGGED1 or NOTCH could be more effective than simultaneous blockade to prevent drug resistance and tumor progression. Clin Cancer Res; 24(18); 4566-78. ©2018 AACR.
Collapse
Affiliation(s)
- Deep Shah
- Molecular Pharmacology and Therapeutics Program, Loyola University Chicago: Health Sciences Division, Maywood, Illinois
| | - Debra Wyatt
- Oncology Research Institute, Loyola University Chicago: Health Sciences Division, Maywood, Illinois
| | - Andrew T Baker
- Integrated Cell Biology Program, Loyola University Chicago: Health Sciences Division, Maywood, Illinois
| | - Patricia Simms
- FACS Core Facility, Office of Research Services, Loyola University Chicago: Health Sciences Division, Maywood, Illinois
| | - Daniel S Peiffer
- Integrated Cell Biology Program, Loyola University Chicago: Health Sciences Division, Maywood, Illinois.,MD/PhD Program, Loyola University Chicago: Health Sciences Division, Maywood, Illinois
| | - Michelle Fernandez
- Department of Microbiology and Immunology, Loyola University Chicago: Health Sciences Division, Maywood, Illinois
| | - Emad Rakha
- Departments of Histopathology and Medicine, University of Nottingham and University Hospital NHS Trust, Nottingham, United Kingdom
| | - Andrew Green
- Departments of Histopathology and Medicine, University of Nottingham and University Hospital NHS Trust, Nottingham, United Kingdom
| | | | - Lucio Miele
- Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Los Angeles
| | - Clodia Osipo
- Oncology Research Institute, Loyola University Chicago: Health Sciences Division, Maywood, Illinois. .,Department of Microbiology and Immunology, Loyola University Chicago: Health Sciences Division, Maywood, Illinois
| |
Collapse
|
|
40
|
Feng Y, Spezia M, Huang S, Yuan C, Zeng Z, Zhang L, Ji X, Liu W, Huang B, Luo W, Liu B, Lei Y, Du S, Vuppalapati A, Luu HH, Haydon RC, He TC, Ren G. Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes Dis 2018; 5:77-106. [PMID: 30258937 PMCID: PMC6147049 DOI: 10.1016/j.gendis.2018.05.001] [Citation(s) in RCA: 739] [Impact Index Per Article: 105.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 05/08/2018] [Indexed: 12/14/2022] Open
Abstract
As the most commonly occurring cancer in women worldwide, breast cancer poses a formidable public health challenge on a global scale. Breast cancer consists of a group of biologically and molecularly heterogeneous diseases originated from the breast. While the risk factors associated with this cancer varies with respect to other cancers, genetic predisposition, most notably mutations in BRCA1 or BRCA2 gene, is an important causative factor for this malignancy. Breast cancers can begin in different areas of the breast, such as the ducts, the lobules, or the tissue in between. Within the large group of diverse breast carcinomas, there are various denoted types of breast cancer based on their invasiveness relative to the primary tumor sites. It is important to distinguish between the various subtypes because they have different prognoses and treatment implications. As there are remarkable parallels between normal development and breast cancer progression at the molecular level, it has been postulated that breast cancer may be derived from mammary cancer stem cells. Normal breast development and mammary stem cells are regulated by several signaling pathways, such as estrogen receptors (ERs), HER2, and Wnt/β-catenin signaling pathways, which control stem cell proliferation, cell death, cell differentiation, and cell motility. Furthermore, emerging evidence indicates that epigenetic regulations and noncoding RNAs may play important roles in breast cancer development and may contribute to the heterogeneity and metastatic aspects of breast cancer, especially for triple-negative breast cancer. This review provides a comprehensive survey of the molecular, cellular and genetic aspects of breast cancer.
Collapse
Affiliation(s)
- Yixiao Feng
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Departments of General Surgery, Clinical Laboratory Medicine, Orthopaedic Surgery, Plastic Surgery and Burn, and Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Mia Spezia
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Shifeng Huang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Departments of General Surgery, Clinical Laboratory Medicine, Orthopaedic Surgery, Plastic Surgery and Burn, and Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Chengfu Yuan
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Biochemistry and Molecular Biology, China Three Gorges University School of Medicine, Yichang 443002, China
| | - Zongyue Zeng
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine and School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Linghuan Zhang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Xiaojuan Ji
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Wei Liu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Departments of General Surgery, Clinical Laboratory Medicine, Orthopaedic Surgery, Plastic Surgery and Burn, and Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Bo Huang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine and School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
- Department of Clinical Laboratory Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Wenping Luo
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, The Affiliated Hospital of Stomatology, Chongqing Medical University, Chongqing 401147, China
| | - Bo Liu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Departments of General Surgery, Clinical Laboratory Medicine, Orthopaedic Surgery, Plastic Surgery and Burn, and Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Yan Lei
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Departments of General Surgery, Clinical Laboratory Medicine, Orthopaedic Surgery, Plastic Surgery and Burn, and Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Scott Du
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Student Inquiry Research Program, Illinois Mathematics and Science Academy (IMSA), Aurora, IL 60506, USA
| | - Akhila Vuppalapati
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Student Inquiry Research Program, Illinois Mathematics and Science Academy (IMSA), Aurora, IL 60506, USA
| | - Hue H. Luu
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Rex C. Haydon
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Guosheng Ren
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Departments of General Surgery, Clinical Laboratory Medicine, Orthopaedic Surgery, Plastic Surgery and Burn, and Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| |
Collapse
|
|
41
|
Marie-Egyptienne DT, Chaudary N, Kalliomäki T, Hedley DW, Hill RP. Cancer initiating-cells are enriched in the CA9 positive fraction of primary cervix cancer xenografts. Oncotarget 2018; 8:1392-1404. [PMID: 27901496 PMCID: PMC5352063 DOI: 10.18632/oncotarget.13625] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 11/07/2016] [Indexed: 12/27/2022] Open
Abstract
Numerous studies have suggested that Cancer Initiating Cells (CIC) can be identified/enriched in cell populations obtained from solid tumors based on the expression of cell surface marker proteins. We used early passage primary cervix cancer xenografts to sort cells based on the expression of the intrinsic hypoxia marker Carbonic Anhydrase 9 (CA9) and tested their cancer initiation potential by limiting dilution assay. We demonstrated that CICs are significantly enriched in the CA9+ fraction in 5/6 models studied. Analyses of the expression of the stem cell markers Oct4, Notch1, Sca-1 & Bmi1 showed a trend toward an increase in the CA9+ populations, albeit not significant. We present evidence that enhanced autophagy does not play a role in the enhanced growth of the CA9+ cells. Our study suggests a direct in vivo functional link between hypoxic cells and CICs in primary cervix cancer xenografts.
Collapse
Affiliation(s)
- Delphine Tamara Marie-Egyptienne
- Ontario Cancer Institute/Princess Margaret Cancer Centre, University Health Network and Campbell Family Institute for Cancer Research, Toronto, Ontario, M5G2M9, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Naz Chaudary
- Ontario Cancer Institute/Princess Margaret Cancer Centre, University Health Network and Campbell Family Institute for Cancer Research, Toronto, Ontario, M5G2M9, Canada
| | - Tuula Kalliomäki
- Ontario Cancer Institute/Princess Margaret Cancer Centre, University Health Network and Campbell Family Institute for Cancer Research, Toronto, Ontario, M5G2M9, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - David William Hedley
- Ontario Cancer Institute/Princess Margaret Cancer Centre, University Health Network and Campbell Family Institute for Cancer Research, Toronto, Ontario, M5G2M9, Canada.,Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, M5G2M9, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada
| | - Richard Peter Hill
- Ontario Cancer Institute/Princess Margaret Cancer Centre, University Health Network and Campbell Family Institute for Cancer Research, Toronto, Ontario, M5G2M9, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.,Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
42
|
Carbonic Anhydrase IX (CAIX), Cancer, and Radiation Responsiveness. Metabolites 2018; 8:metabo8010013. [PMID: 29439394 PMCID: PMC5874614 DOI: 10.3390/metabo8010013] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 02/06/2018] [Accepted: 02/07/2018] [Indexed: 12/23/2022] Open
Abstract
Carbonic anhydrase IX has been under intensive investigation as a therapeutic target in cancer. Studies demonstrate that this enzyme has a key role in pH regulation in cancer cells, allowing these cells to adapt to the adverse conditions of the tumour microenviroment. Novel CAIX inhibitors have shown efficacy in both in vitro and in vivo pre-clinical cancer models, adversely affecting cell viability, tumour formation, migration, invasion, and metastatic growth when used alone. In co-treatments, CAIX inhibitors may enhance the effects of anti-angiogenic drugs or chemotherapy agents. Research suggests that these inhibitors may also increase the response of tumours to radiotherapy. Although many of the anti-tumour effects of CAIX inhibition may be dependent on its role in pH regulation, recent work has shown that CAIX interacts with several of the signalling pathways involved in the cellular response to radiation, suggesting that pH-independent mechanisms may also be an important basis of its role in tumour progression. Here, we discuss these pH-independent interactions in the context of the ability of CAIX to modulate the responsiveness of cancer to radiation.
Collapse
|
|
43
|
Jin L, Han B, Siegel E, Cui Y, Giuliano A, Cui X. Breast cancer lung metastasis: Molecular biology and therapeutic implications. Cancer Biol Ther 2018; 19:858-868. [PMID: 29580128 PMCID: PMC6300341 DOI: 10.1080/15384047.2018.1456599] [Citation(s) in RCA: 196] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 03/18/2018] [Accepted: 03/19/2018] [Indexed: 02/05/2023] Open
Abstract
Distant metastasis accounts for the vast majority of deaths in patients with cancer. Breast cancer exhibits a distinct metastatic pattern commonly involving bone, liver, lung, and brain. Breast cancer can be divided into different subtypes based on gene expression profiles, and different breast cancer subtypes show preference to distinct organ sites of metastasis. Luminal breast tumors tend to metastasize to bone while basal-like breast cancer (BLBC) displays a lung tropism of metastasis. However, the mechanisms underlying this organ-specific pattern of metastasis still remain to be elucidated. In this review, we will summarize the recent advances regarding the molecular signaling pathways as well as the therapeutic strategies for treating breast cancer lung metastasis.
Collapse
Affiliation(s)
- Liting Jin
- Department of Breast Surgery, Hubei Cancer Hospital, Wuhan, China
| | - Bingchen Han
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Emily Siegel
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yukun Cui
- Laboratory for Breast Cancer Diagnosis and Treatment, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Armando Giuliano
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Xiaojiang Cui
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- CONTACT Xiaojiang Cui Cedars-Sinai Medical Center, 8700 Beverly Blvd, Davis Building 2065, Los Angeles, CA 90048
| |
Collapse
|
|
44
|
Del Barco Barrantes I, Stephan-Otto Attolini C, Slobodnyuk K, Igea A, Gregorio S, Gawrzak S, Gomis RR, Nebreda AR. Regulation of Mammary Luminal Cell Fate and Tumorigenesis by p38α. Stem Cell Reports 2017; 10:257-271. [PMID: 29290625 PMCID: PMC5768988 DOI: 10.1016/j.stemcr.2017.11.021] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 11/28/2017] [Accepted: 11/29/2017] [Indexed: 12/18/2022] Open
Abstract
Mammary stem and progenitor cells are essential for mammary gland homeostasis and are also candidates for cells of origin of mammary tumors. Here, we have investigated the function of the protein kinase p38α in the mammary gland using mice that delete this protein in the luminal epithelial cells. We show that p38α regulates the fate of luminal progenitor cells through modulation of the transcription factor RUNX1, an important controller of the estrogen receptor-positive cell lineage. We also provide evidence that the regulation of RUNX1 by p38α probably involves the kinase MSK1, which phosphorylates histone H3 at the RUNX1 promoter. Moreover, using a mouse model for breast cancer initiated by luminal cells, we show that p38α downregulation in mammary epithelial cells reduces tumor burden, which correlates with decreased numbers of tumor-initiating cells. Collectively, our results define a key role for p38α in luminal progenitor cell fate that affects mammary tumor formation.
Luminal progenitor cell fate in the mammary gland is regulated by p38α p38α controls the ER transcriptional program by modulating RUNX1 p38α regulates H3 phosphorylation at the RUNX1 promoter through the kinase MSK1 p38α promotes mammary tumorigenesis by maintaining luminal tumor-initiating cells
Collapse
Affiliation(s)
- Ivan Del Barco Barrantes
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.
| | - Camille Stephan-Otto Attolini
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
| | - Konstantin Slobodnyuk
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
| | - Ana Igea
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
| | - Sara Gregorio
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
| | - Sylwia Gawrzak
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
| | - Roger R Gomis
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain; ICREA, Passeig de Lluís Companys 23, 08010 Barcelona, Spain; CIBERONC, 08028 Barcelona, Spain
| | - Angel R Nebreda
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain; ICREA, Passeig de Lluís Companys 23, 08010 Barcelona, Spain.
| |
Collapse
|
|
45
|
Loureiro R, Mesquita KA, Magalhães-Novais S, Oliveira PJ, Vega-Naredo I. Mitochondrial biology in cancer stem cells. Semin Cancer Biol 2017; 47:18-28. [DOI: 10.1016/j.semcancer.2017.06.012] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Revised: 06/24/2017] [Accepted: 06/27/2017] [Indexed: 02/06/2023]
|
|
46
|
Li L, Liu CC, Chen X, Xu S, Hernandez Cortes-Manno S, Cheng SH. Mechanistic Study of Bakuchiol-Induced Anti-breast Cancer Stem Cell and in Vivo Anti-metastasis Effects. Front Pharmacol 2017; 8:746. [PMID: 29093680 PMCID: PMC5651275 DOI: 10.3389/fphar.2017.00746] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 10/03/2017] [Indexed: 12/21/2022] Open
Abstract
Cancer stem cells are involved in cancer establishment, progression, and resistance to current treatments. We demonstrated the in vitro and in vivo anti-breast cancer effect of bakuchiol in a previous study. However, the ability of bakuchiol to target breast cancer stem cells (BCSCs) and inhibit breast cancer metastasis remains unknown. In the current study, we used the cell surface markers CD44 and CD24 to distinguish BCSCs from MCF-7 cells. Bakuchiol inhibited mammosphere formation and aldehyde dehydrogenase activity in BCSCs. Moreover, bakuchiol induced apoptosis and suppressed the mitochondrial membrane potential of BCSCs. Bakuchiol upregulated the expression levels of pro-apoptotic genes, BNIP3 and DAPK2. Bakuchiol induced oxidative stress and altered lipogenesis in BCSCs. In zebrafish xenografts, bakuchiol inhibited breast cancer cell metastasis in vivo. In addition, bakuchiol altered the expression levels of metastasis-related genes through upregulating CK18 and downregulating Notch3, FASN, TGFBR1, and ACVR1B. Our study provides evidence for the anti-breast cancer potential of bakuchiol.
Collapse
Affiliation(s)
- Li Li
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong
| | - Chi C Liu
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong
| | - Xueping Chen
- Vitargent (International) Biotechnology Limited, Sha Tin, Hong Kong
| | - Shisan Xu
- Department of Infectious Diseases and Public Health, City University of Hong Kong, Kowloon, Hong Kong
| | | | - Shuk H Cheng
- Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong
| |
Collapse
|
|
47
|
Chung WC, Zhang S, Challagundla L, Zhou Y, Xu K. Lunatic Fringe and p53 Cooperatively Suppress Mesenchymal Stem-Like Breast Cancer. Neoplasia 2017; 19:885-895. [PMID: 28938159 PMCID: PMC5608590 DOI: 10.1016/j.neo.2017.08.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 08/03/2017] [Accepted: 08/07/2017] [Indexed: 12/05/2022]
Abstract
Claudin-low breast cancer (CLBC) is a poor prognosis molecular subtype showing stemness and mesenchymal features. We previously discovered that deletion of a Notch signaling modulator, Lunatic Fringe (Lfng), in the mouse mammary gland induced a subset of tumors resembling CLBC. Here we report that deletion of one copy of p53 on this background not only accelerated mammary tumor development but also led to a complete penetrance of the mesenchymal stem-like phenotype. All mammary tumors examined in the Lfng/p53 compound mutant mice displayed a mesenchymal/spindloid pathology. These tumors showed high level expressions of epithelial-to-mesenchymal transition (EMT) markers including Vimentin, Twist, and PDGFRα, a gene known to be enriched in CLBC. Prior to tumor onset, Lfng/p53 mutant mammary glands exhibited increased levels of Vimentin and E-cadherin, but decreased expressions of cytokeratin 14 and cytokeratin 8, accompanied by elevated basal cell proliferation and an expanded mammary stem cell-enriched population. Lfng/p53 mutant glands displayed increased accumulation of Notch3 intracellular fragment, up-regulation of Hes5 and down-regulation of Hes1. Analysis in human breast cancer datasets found the lowest HES1 and second lowest LFNG expressions in CLBC among molecular subtypes, and low level of LFNG is associated with poor survival. Immunostaining of human breast cancer tissue array found correlation between survival and LFNG immunoreactivity. Finally, patients carrying TP53 mutations express lower LFNG than patients with wild type TP53. Taken together, these data revealed genetic interaction between Lfng and p53 in mammary tumorigenesis, established a new mouse model resembling CLBC, and may suggest targeting strategy for this disease.
Collapse
Affiliation(s)
- Wen-Cheng Chung
- Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
| | - Shubing Zhang
- Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
| | - Lavanya Challagundla
- Department of Data Science, University of Mississippi Medical Center, Jackson, MS, USA
| | - Yunyun Zhou
- Department of Data Science, University of Mississippi Medical Center, Jackson, MS, USA
| | - Keli Xu
- Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA; Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS, USA.
| |
Collapse
|
|
48
|
Inder S, O'Rourke S, McDermott N, Manecksha R, Finn S, Lynch T, Marignol L. The Notch-3 receptor: A molecular switch to tumorigenesis? Cancer Treat Rev 2017; 60:69-76. [PMID: 28889086 DOI: 10.1016/j.ctrv.2017.08.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 08/25/2017] [Accepted: 08/26/2017] [Indexed: 01/03/2023]
Abstract
The Notch pathway is a highly conserved pathway increasingly implicated with the progression of human cancers. Of the four existing receptors associated with the pathway, the deregulation in the expression of the Notch-3 receptor is associated with more aggressive disease and poor prognosis. Selective targeting of this receptor has the potential to enhance current anti-cancer treatments. Molecular profiling strategies are increasingly incorporated into clinical decision making. This review aims to evaluate the clinical potential of Notch-3 within this new era of personalised medicine.
Collapse
Affiliation(s)
- Shakeel Inder
- Translational Radiobiology and Molecular Oncology, Applied Radiation Therapy Trinity, Trinity College Dublin, Dublin, Ireland; Department of Urology, St James's Hospital, Dublin, Ireland
| | - Sinead O'Rourke
- Translational Radiobiology and Molecular Oncology, Applied Radiation Therapy Trinity, Trinity College Dublin, Dublin, Ireland
| | - Niamh McDermott
- Translational Radiobiology and Molecular Oncology, Applied Radiation Therapy Trinity, Trinity College Dublin, Dublin, Ireland
| | | | - Stephen Finn
- Department of Histopathology, St James's Hospital, Dublin, Ireland
| | - Thomas Lynch
- Department of Urology, St James's Hospital, Dublin, Ireland
| | - Laure Marignol
- Translational Radiobiology and Molecular Oncology, Applied Radiation Therapy Trinity, Trinity College Dublin, Dublin, Ireland.
| |
Collapse
|
|
49
|
Asgharzadeh MR, Barar J, Pourseif MM, Eskandani M, Jafari Niya M, Mashayekhi MR, Omidi Y. Molecular machineries of pH dysregulation in tumor microenvironment: potential targets for cancer therapy. BIOIMPACTS : BI 2017; 7:115-133. [PMID: 28752076 PMCID: PMC5524986 DOI: 10.15171/bi.2017.15] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 05/28/2017] [Accepted: 06/06/2017] [Indexed: 12/30/2022]
Abstract
Introduction: Cancer is an intricate disorder/dysfunction of cells that can be defined as a genetic heterogeneity in human disease. Therefore, it is characterized by several adaptive complex hallmarks. Among them, the pH dysregulation appears as a symbol of aberrant functions within the tumor microenvironment (TME). In comparison with normal tissues, in the solid tumors, we face with an irregular acidification and alkalinization of the extracellular and intracellular fluids. Methods: In this study, we comprehensively discussed the most recent reports on the hallmarks of solid tumors to provide deep insights upon the molecular machineries involved in the pH dysregulation of solid tumors and their impacts on the initiation and progression of cancer. Results: The dysregulation of pH in solid tumors is fundamentally related to the Warburg effect and hypoxia, leading to expression of a number of molecular machineries, including: NHE1, H+ pump V-ATPase, CA-9, CA-12, MCT-1, GLUT-1. Activation of proton exchangers and transporters (PETs) gives rise to formation of TME. This condition favors the cancer cells to evade from the anoikis and apoptosis, granting them aggressive and metastasis phenotype, as well as resistance to chemotherapy and radiation therapy. This review aimed to discuss the key molecular changes of tumor cells in terms of bio-energetics and cancer metabolism in relation with pH dysregulation. During this phenomenon, the intra- and extracellular metabolites are altered and/or disrupted. Such molecular alterations provide molecular hallmarks for direct targeting of the PETs by potent relevant inhibitors in combination with conventional cancer therapies as ultimate therapy against solid tumors. Conclusion: Taken all, along with other treatment strategies, targeting the key molecular machineries related to intra- and extracellular metabolisms within the TME is proposed as a novel strategy to inhibit or block PETs that are involved in the pH dysregulation of solid tumors.
Collapse
Affiliation(s)
- Mohammad Reza Asgharzadeh
- Department of Biology, Fars Science and Research Branch, Islamic Azad University, Marvdasht, Iran
- Department of Biology, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran
| | - Jaleh Barar
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad M. Pourseif
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Eskandani
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mojtaba Jafari Niya
- Department of Biology, Fars Science and Research Branch, Islamic Azad University, Marvdasht, Iran
- Department of Biology, Marvdasht Branch, Islamic Azad University, Marvdasht, Iran
| | | | - Yadollah Omidi
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
50
|
HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance. Cancers (Basel) 2017; 9:cancers9050040. [PMID: 28445439 PMCID: PMC5447950 DOI: 10.3390/cancers9050040] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 04/10/2017] [Accepted: 04/21/2017] [Indexed: 12/19/2022] Open
Abstract
HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs) is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs). HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2), which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT) of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab.
Collapse
|