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Modak S, Aktar T, Majumder D, Singha AK, Maiti D. A systematic review on leptin's role in defining cancer: special emphasis on immunomodulation, inflammation, and therapeutic interventions. Genes Immun 2025:10.1038/s41435-025-00333-7. [PMID: 40374921 DOI: 10.1038/s41435-025-00333-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 04/22/2025] [Accepted: 04/30/2025] [Indexed: 05/18/2025]
Abstract
Leptin, an adipokine related to obesity, is mainly known for its role in regulating energy homeostasis and appetite by working via the leptin receptor. Recently, different groups have demonstrated that apart from adipocytes, specific cell types associated with cancer and tumor microenvironments express leptin and leptin receptors. This tumor microenvironment-associated leptin-leptin receptor signaling contributes to the different hallmarks of cancer, ranging from inflammatory changes to metastasis. Eventually, it has also been reported that high serum level of leptin, a characteristic of obese people, is linked to enhanced tumor growth. On the other hand, leptin can influence both innate as well as adaptive immunity related to cancer. Overall, leptin's role in modulating cancer is controversial. So, in this review, we summarized the role of leptin in shaping different forms of cancer that are influenced by leptin-leptin receptor signaling with special emphasis on immunomodulation and inflammatory events and also discussed the possible therapeutic interventions to date. As this review work, with the collection of different updated knowledge, has summarized the role of leptin on cancer, it would be useful material to have on hand for both beginners as well as pioneers of these and related fields.
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Affiliation(s)
- Snehashish Modak
- Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India
| | - Tamanna Aktar
- Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India
| | - Debabrata Majumder
- Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India
- Department of Integrative Immunobiology, Duke University Medical Center, Durham, NC, USA
| | - Ashish Kr Singha
- Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India
- Department of Human Physiology, Holy Cross College, Agartala, West Tripura, India
| | - Debasish Maiti
- Immunology Microbiology Lab, Tripura University, Suryamaninagar, Tripura, India.
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Yuan J, Yang L, Zhang H, Beeraka NM, Zhang D, Wang Q, Wang M, Pr HV, Sethi G, Wang G. Decoding tumor microenvironment: EMT modulation in breast cancer metastasis and therapeutic resistance, and implications of novel immune checkpoint blockers. Biomed Pharmacother 2024; 181:117714. [PMID: 39615165 DOI: 10.1016/j.biopha.2024.117714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 11/15/2024] [Accepted: 11/25/2024] [Indexed: 12/21/2024] Open
Abstract
Tumor microenvironment (TME) and epithelial-mesenchymal transition (EMT) play crucial roles in the initiation and progression of tumors. TME is composed of various cell types, such as immune cells, fibroblasts, and endothelial cells, as well as non-cellular components like extracellular matrix (ECM) proteins and soluble factors. These elements interact with tumor cells through a complex network of signaling pathways involving cytokines, growth factors, metabolites, and non-coding RNA-carrying exosomes. Hypoxic conditions within the TME further modulate these interactions, collectively influencing tumor growth, metastatic potential, and response to therapy. EMT represents a dynamic and reversible process where epithelial cells undergo phenotypic changes to adopt mesenchymal characteristics in several cancers, including breast cancers. This transformation enhances cell motility and imparts stem cell-like properties, which are closely associated with increased metastatic capability and resistance to conventional cancer treatments. Thus, understanding the crosstalk between the TME and EMT is essential for unraveling the underlying mechanisms of breast cancer metastasis and therapeutic resistance. This review uniquely examines the intricate interplay between the tumor TME and epithelial-mesenchymal transition EMT in driving breast cancer metastasis and treatment resistance. It explores the therapeutic potential of targeting the TME-EMT axis, specifically through CD73-TGF-β dual-blockade, to improve outcomes in triple-negative breast cancer. Additionally, it underscores new strategies to enhance immune checkpoint blockade (ICB) responses by modulating EMT, thereby offering innovative insights for more effective cancer treatment.
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Affiliation(s)
- Jie Yuan
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Li Yang
- Department of Clinical Laboratory Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Hua Zhang
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Narasimha M Beeraka
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str., Moscow 119991, Russia; Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Chiyyedu, Anantapuramu, Andhra Pradesh 515721, India; Department of Studies in Molecular Biology, Faculty of Science and Technology, University of Mysore, Mysore, Karnataka, 570006, India.
| | - Danfeng Zhang
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Qun Wang
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Minghua Wang
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
| | - Hemanth Vikram Pr
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| | - Geng Wang
- Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China.
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3
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Eldehna WM, Habib YA, Mahmoud AE, Barghash MF, Elsayed ZM, Elsawi AE, Maklad RM, Rashed M, Khalil A, Hammad SF, Ali MM, El Kerdawy AM. Design, synthesis, and in silico insights of novel N'-(2-oxoindolin-3-ylidene)piperidine-4-carbohydrazide derivatives as VEGFR-2 inhibitors. Bioorg Chem 2024; 153:107829. [PMID: 39317037 DOI: 10.1016/j.bioorg.2024.107829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/09/2024] [Accepted: 09/16/2024] [Indexed: 09/26/2024]
Abstract
Vascular endothelial growth factor (VEGF) is a crucial key factor in breast tumorigenesis. VEGF plays an important role in angiogenesis, tumor proliferation, and metastasis. Herein, we report the design and synthesis of twenty-one novel piperidine/oxindole derivatives as potential VEGFR-2 inhibitors. The designed compound library aimed to occupy the binding site of VEGFR-2 in a similar binding pattern to that of the reference VEGFR-2 inhibitor Sorafenib. The synthesized compounds were biologically evaluated for their cytotoxic effects against two breast cancer cell lines (MCF-7 and MDA-MB-468). Compounds 12e and 6n were the most potent cytotoxic derivatives against the former and the latter cell lines, showing IC50 values of 8.00 and 0.60 µM, respectively. Furthermore, all the synthesized compounds were evaluated for their inhibitory activities towards VEGFR-2, with compound 12e showing the most potent activity with an IC50 value of 45.9 nM, surpassing the reference standard Sorafenib (IC50 = 48.6 nM). Additionally, compound 6n emerged as the top performer when tested with the other most promising compounds for their cytotoxic effects on HUVEC (IC50 = 28.77 nM). The designed library of compounds was subjected to molecular docking and molecular dynamic simulations, which revealed key binding interactions within the VEGFR-2 active site, including hydrogen bonding with Cys919, Glu885, and Asp1046 residues. Moreover, in silico predictions of physicochemical and pharmacokinetic properties for the target compounds indicated favorable drug-like characteristics.
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Affiliation(s)
- Wagdy M Eldehna
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh P.O. Box 33516, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Canal El Mahmoudia St., Alexandria 21648, Egypt.
| | - Youmna A Habib
- Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Abeer E Mahmoud
- Biochemistry Department, Biotechnology Research Institute, National Research Centre, Dokki 12622, Giza, Egypt
| | - Mohamed F Barghash
- Biochemistry Department, Biotechnology Research Institute, National Research Centre, Dokki 12622, Giza, Egypt
| | - Zainab M Elsayed
- Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Ahmed E Elsawi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh P.O. Box 33516, Egypt
| | - Raed M Maklad
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh P.O. Box 33516, Egypt
| | - Mahmoud Rashed
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt
| | - Amira Khalil
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt
| | - Sherif F Hammad
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Ain Helwan, Egypt; PharmD Program, Egypt-Japan University of Science and Technology, New Borg El-Arab, Alexandria, Egypt
| | - Mamdouh M Ali
- Biochemistry Department, Biotechnology Research Institute, National Research Centre, Dokki 12622, Giza, Egypt
| | - Ahmed M El Kerdawy
- School of Pharmacy, College of Health and Science, University of Lincoln, Joseph Banks Laboratories, Green Lane, Lincoln, Lincolnshire, United Kingdom; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562 Cairo, Egypt
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Li Y, Wang L, Wang J, Xin Y, Lyu X. Relationship between adipocytes and hematological tumors in the bone marrow microenvironment: a literature review. Transl Cancer Res 2024; 13:5691-5701. [PMID: 39525009 PMCID: PMC11543051 DOI: 10.21037/tcr-24-52] [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: 01/09/2024] [Accepted: 08/29/2024] [Indexed: 11/16/2024]
Abstract
Background and Objective The bone marrow microenvironment is closely related to normal hematopoiesis and hematologic tumors. Adipocytes are an important part of the bone marrow microenvironment, in which they can release free fatty acids (FFAs) through lipolysis and secrete adipocytokines, etc., and participate in normal hematopoiesis, which is closely related to the occurrence and treatment of hematological tumors. In this review, we aim to discuss how bone marrow adipocytes (BMAs) can influence the proliferation, apoptosis, and chemotherapy resistance of cancer cells by reprogramming lipid metabolism and the secretion of various adipocytokines. Methods Studies from 2000 to July 2024 were reviewed from PubMed, Springer Link, and the Web of Science using the keywords bone marrow microenvironment, adipocytes, lipid metabolism, adipocytokines, hematological tumor, cancer, and their combinations. Unreliable articles such as those that are old and have a low impact factor are excluded, and there is no restriction on language. Key Content and Findings Adipocytes can regulate the proliferation and differentiation of hematopoietic stem cells (HSCs) by secreting inflammatory factors and adipocytokines to maintain hematopoietic homeostasis. Adipocytes can also stimulate and accelerate the occurrence and progression of hematological tumors by secreting adipocytokines and mediating the reprogramming of lipid metabolism. Moreover, abundant adipocytes in bone marrow can protect tumor cells by physically blocking and/or secreting cytokines, leading to chemotherapy resistance. Conclusions Therefore, the targeted inhibition of related lipid metabolism pathways and adipocytokines might be a potential therapeutic target for hematological tumors, which would be helpful to inhibit tumor growth and correct chemotherapy resistance.
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Affiliation(s)
- Yuchun Li
- Central Laboratory, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Linlin Wang
- Central Laboratory, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Jingyu Wang
- Central Laboratory, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Yaping Xin
- Department of Endocrinology and Metabolic Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaodong Lyu
- Central Laboratory, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
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Lagarde CB, Thapa K, Cullen NM, Hawes ML, Salim K, Benz MC, Dietrich SR, Burow BE, Bunnell BA, Martin EC, Collins-Burow BM, Lynch RM, Hoang VT, Burow ME, Fang JS. Obesity and leptin in breast cancer angiogenesis. Front Endocrinol (Lausanne) 2024; 15:1465727. [PMID: 39439572 PMCID: PMC11493622 DOI: 10.3389/fendo.2024.1465727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 09/04/2024] [Indexed: 10/25/2024] Open
Abstract
At the time of breast cancer diagnosis, most patients meet the diagnostic criteria to be classified as obese or overweight. This can significantly impact patient outcome: breast cancer patients with obesity (body mass index > 30) have a poorer prognosis compared to patients with a lean BMI. Obesity is associated with hyperleptinemia, and leptin is a well-established driver of metastasis in breast cancer. However, the effect of hyperleptinemia on angiogenesis in breast cancer is less well-known. Angiogenesis is an important process in breast cancer because it is essential for tumor growth beyond 1mm3 in size as well as cancer cell circulation and metastasis. This review investigates the role of leptin in regulating angiogenesis, specifically within the context of breast cancer and the associated tumor microenvironment in obese patients.
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Affiliation(s)
- Courtney B. Lagarde
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Kapil Thapa
- Department of Cell and Molecular Biology, Tulane University School of Science and Engineering, New Orleans, LA, United States
| | - Nicole M. Cullen
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Mackenzie L. Hawes
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Khudeja Salim
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Megan C. Benz
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Sophie R. Dietrich
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
- United States Department of Agriculture Southern Regional Research Center, New Orleans, LA, United States
| | - Brandon E. Burow
- Department of Cell and Molecular Biology, Tulane University School of Science and Engineering, New Orleans, LA, United States
| | - Bruce A. Bunnell
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Elizabeth C. Martin
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Bridgette M. Collins-Burow
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Ronald M. Lynch
- Department of Physiology, College of Medicine, University of Arizona, Tucson, AZ, United States
| | - Van T. Hoang
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Matthew E. Burow
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, United States
- Department of Surgery, Tulane University School of Medicine, New Orleans, LA, United States
| | - Jennifer S. Fang
- Department of Cell and Molecular Biology, Tulane University School of Science and Engineering, New Orleans, LA, United States
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
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Shokrollahi B, Zheng HY, Ma XY, Shang JH. The effects of apelin on IGF1/FSH-induced steroidogenesis, proliferation, Bax expression, and total antioxidant capacity in granulosa cells of buffalo ovarian follicles. Vet Res Commun 2023; 47:1523-1533. [PMID: 37036601 DOI: 10.1007/s11259-023-10107-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 03/15/2023] [Indexed: 04/11/2023]
Abstract
Apelin (APLN) was believed to be an adipokine secreted from adipose tissue. However, studies demonstrate that it is a pleiotropic peptide and has several effects on the female reproductive system. In this study, We examined the effects of different doses of IGF1 and FSH in the presence of APLN-13 on the production of progesterone in buffalo ovary granulosa cells. Furthermore, different doses of APLN isoforms (APLN-13 and APLN-17) were tested on proliferation, Bax protein expression, and antioxidant capacity in the same cells. Granulosa cells of buffalo ovaries were cultured in the presence of different doses of IGF1 and FSH with or without APLN-13 (10-9 M) to evaluate its effect on the secretion of progesterone tested by ELISA assay. The WST-1 method was used to survey the effect of APLN on granulosa cell proliferation and cytotoxicity. In addition, the antioxidant capacity of the cells in the presence of APLN was assessed using the FRAP method. mRNA and Bax protein levels were measured in granulosa cells treated with APLN using real-time PCR and western blot techniques. APLN-13 (10-9) stimulated the effect of IGF1 on the production of progesterone, and its levels were affected by APLN-13 dose-dependently. However, it did not significantly stimulate the effect of FSH on the secretion of progesterone. APLN-13 (all doses) and APLN-17 (10-8 and 10-9 M) improved the proliferation of granulosa cells. Moreover, preincubation of the cells for an hour by APLN receptor antagonist (ML221, 10 µM) did not significantly affect the proliferation of cells induced by APLN. Neither APLN-13 nor APLN-17 were not cytotoxic for the cells compared to the control treatment. APLN-13 at the doses of 10-6 and 10-8 M substantially up and down-regulated Bax protein expression; however, such effects were not observed when the cells were preincubated with ML221. In addition, APLN-17 did not influence the expression amount of Bax. Furthermore, both APLN-13 and -17 improved the total antioxidant capacity of the ovarian granulosa cells, but such effects were not seen when the cells were preincubated with ML221. According to these results, APLN enhanced the steroidogenesis induced by IGF1 but did not affect the steroidogenesis induced by FSH. APLN also enhanced the cell proliferation and antioxidant capacity of buffalo ovaries follicular granulosa cells; however, its effect on Bax expression was different.
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Affiliation(s)
- Borhan Shokrollahi
- Key Laboratory of Buffalo Genetics, Breeding and Reproduction Technology, Guangxi Buffalo Research Institute, Chinese Academy of Agricultural Sciences, Nanning, 530001, China
- Department of Animal Science, Sanandaj Branch, Islamic Azad University, Sanandaj, Kurdistan, Iran
| | - Hai-Ying Zheng
- Key Laboratory of Buffalo Genetics, Breeding and Reproduction Technology, Guangxi Buffalo Research Institute, Chinese Academy of Agricultural Sciences, Nanning, 530001, China
| | - Xiao-Ya Ma
- Key Laboratory of Buffalo Genetics, Breeding and Reproduction Technology, Guangxi Buffalo Research Institute, Chinese Academy of Agricultural Sciences, Nanning, 530001, China
| | - Jiang-Hua Shang
- Key Laboratory of Buffalo Genetics, Breeding and Reproduction Technology, Guangxi Buffalo Research Institute, Chinese Academy of Agricultural Sciences, Nanning, 530001, China.
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Wang W, Chen H, Yin S, Yang Z, Zhang F. Targeting adipocyte-immune cell crosstalk to control breast cancer progression. J Cancer Res Clin Oncol 2023; 149:7969-7979. [PMID: 36914785 DOI: 10.1007/s00432-023-04685-3] [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: 12/03/2022] [Accepted: 03/05/2023] [Indexed: 03/16/2023]
Abstract
Adipocytes are crucial components of breast cancer and are involved in regulating the progression, therapeutic efficacy, and prognosis of breast cancer patients. Characterized by storing energy and producing a variety of secretory factors, adipocytes are responsible for inducing obesity and regulating the tumor immune activity. Adipocytes communicate with tumor infiltrating immune cells through the secreted adipokines, cytokines, and exosomes in the breast cancer TIME, which shapes the tumor supporting environment to facilitate the immune escape of tumor cells. In-depth studies of the crosstalk between adipocytes and TIME can not only provide a more comprehensive regulatory landscape of TIME, but also be conducive to screening novel targets for future precision targeted therapy. The aim of this review is to discuss recent studies for understanding the role of crosstalk between adipocytes and immune cells in shaping the breast cancer immune microenvironment.
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Affiliation(s)
- Weihua Wang
- Department of Breast and Thyroid Surgery, Chongqing General Hospital, 118 Xingguang Avenue, Chongqing, 401147, People's Republic of China
| | - Hongdan Chen
- Department of Breast and Thyroid Surgery, Chongqing General Hospital, 118 Xingguang Avenue, Chongqing, 401147, People's Republic of China
| | - Supeng Yin
- Department of Breast and Thyroid Surgery, Chongqing General Hospital, 118 Xingguang Avenue, Chongqing, 401147, People's Republic of China
| | - Zeyu Yang
- Department of Breast and Thyroid Surgery, Chongqing General Hospital, 118 Xingguang Avenue, Chongqing, 401147, People's Republic of China.
| | - Fan Zhang
- Department of Breast and Thyroid Surgery, Chongqing General Hospital, 118 Xingguang Avenue, Chongqing, 401147, People's Republic of China.
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8
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Samaddar S, Buckles D, Saha S, Zhang Q, Bansal A. Translating Molecular Biology Discoveries to Develop Targeted Cancer Interception in Barrett's Esophagus. Int J Mol Sci 2023; 24:11318. [PMID: 37511077 PMCID: PMC10379200 DOI: 10.3390/ijms241411318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 07/05/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
Esophageal adenocarcinoma (EAC) is a rapidly increasing lethal tumor. It commonly arises from a metaplastic segment known as Barrett's esophagus (BE), which delineates the at-risk population. Ample research has elucidated the pathogenesis of BE and its progression from metaplasia to invasive carcinoma; and multiple molecular pathways have been implicated in this process, presenting several points of cancer interception. Here, we explore the mechanisms of action of various agents, including proton pump inhibitors, non-steroidal anti-inflammatory drugs, metformin, and statins, and explain their roles in cancer interception. Data from the recent AspECT trial are discussed to determine how viable a multipronged approach to cancer chemoprevention would be. Further, novel concepts, such as the repurposing of chemotherapeutic drugs like dasatinib and the prevention of post-ablation BE recurrence using itraconazole, are discussed.
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Affiliation(s)
- Sohini Samaddar
- Department of Internal Medicine, University of Kansas Health System, Kansas City, KS 66160, USA
| | - Daniel Buckles
- Department of Gastroenterology and Hepatology, University of Kansas Health System, Kansas City, KS 66160, USA
| | - Souvik Saha
- Department of Internal Medicine, University of Kansas Health System, Kansas City, KS 66160, USA
| | - Qiuyang Zhang
- Center for Esophageal Diseases, Department of Medicine, Baylor University Medical Center, Dallas, TX 75246, USA
- Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, TX 75246, USA
| | - Ajay Bansal
- Department of Gastroenterology and Hepatology, University of Kansas Health System, Kansas City, KS 66160, USA
- University of Kansas Cancer Center, Kansas City, KS 66160, USA
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9
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Dana N, Ferns GA, Nedaeinia R, Haghjooy Javanmard S. Leptin signaling in breast cancer and its crosstalk with peroxisome proliferator-activated receptors α and γ. Clin Transl Oncol 2023; 25:601-610. [PMID: 36348225 DOI: 10.1007/s12094-022-02988-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 10/18/2022] [Indexed: 11/09/2022]
Abstract
Obesity may create a mitogenic microenvironment that influences tumor initiation and progression. The obesity-associated adipokine, leptin regulates energy metabolism and has been implicated in cancer development. It has been shown that some cell types other than adipocytes can express leptin and leptin receptors in tumor microenvironments. It has been shown that peroxisome proliferator-activated receptors (PPAR) agonists can affect leptin levels and vice versa leptin can affect PPARs. Activation of PPARs affects the expression of several genes involved in aspects of lipid metabolism. In addition, PPARs regulate cancer cell progression through their action on the tumor cell proliferation, metabolism, and cellular environment. Some studies have shown an association between obesity and several types of cancer, including breast cancer. There is some evidence that suggests that there is crosstalk between PPARs and leptin during the development of breast cancer. Through a systematic review of previous studies, we have reviewed the published relevant articles regarding leptin signaling in breast cancer and its crosstalk with peroxisome proliferator-activated receptors α and γ.
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Affiliation(s)
- Nasim Dana
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton and Sussex Medical School, Falmer, Brighton, BN1 9PH, Sussex, UK
| | - Reza Nedaeinia
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shaghayegh Haghjooy Javanmard
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran.
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Cancer-Associated Adipocytes and Breast Cancer: Intertwining in the Tumor Microenvironment and Challenges for Cancer Therapy. Cancers (Basel) 2023; 15:cancers15030726. [PMID: 36765683 PMCID: PMC9913307 DOI: 10.3390/cancers15030726] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 01/15/2023] [Accepted: 01/16/2023] [Indexed: 01/26/2023] Open
Abstract
Adipocytes are the main components in breast tissue, and cancer-associated adipocytes (CAAs) are one of the most important components in the tumor microenvironment of breast cancer (BC). Bidirectional regulation was found between CAAs and BC cells. BC facilitates the dedifferentiation of adjacent adipocytes to form CAAs with morphological and biological changes. CAAs increase the secretion of multiple cytokines and adipokines to promote the tumorigenesis, progression, and metastasis of BC by remodeling the extracellular matrix, changing aromatase expression, and metabolic reprogramming, and shaping the tumor immune microenvironment. CAAs are also associated with the therapeutic response of BC and provide potential targets in BC therapy. The present review provides a comprehensive description of the crosstalk between CAAs and BC and discusses the potential strategies to target CAAs to overcome BC treatment resistance.
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Zhang J, Hu Z, Horta CA, Yang J. Regulation of epithelial-mesenchymal transition by tumor microenvironmental signals and its implication in cancer therapeutics. Semin Cancer Biol 2023; 88:46-66. [PMID: 36521737 DOI: 10.1016/j.semcancer.2022.12.002] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 12/06/2022] [Accepted: 12/08/2022] [Indexed: 12/15/2022]
Abstract
Epithelial-mesenchymal transition (EMT) has been implicated in various aspects of tumor development, including tumor invasion and metastasis, cancer stemness, and therapy resistance. Diverse stroma cell types along with biochemical and biophysical factors in the tumor microenvironment impinge on the EMT program to impact tumor progression. Here we provide an in-depth review of various tumor microenvironmental signals that regulate EMT in cancer. We discuss the molecular mechanisms underlying the role of EMT in therapy resistance and highlight new therapeutic approaches targeting the tumor microenvironment to impact EMT and tumor progression.
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Affiliation(s)
- Jing Zhang
- Department of Pharmacology, Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Zhimin Hu
- Department of Pharmacology, Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Calista A Horta
- Department of Pharmacology, Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Jing Yang
- Department of Pharmacology, Moores Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
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12
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Hayes AR, Luong TV, Banks J, Shah H, Watkins J, Lim E, Patel A, Grossman AB, Navalkissoor S, Krell D, Caplin ME. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH): Prevalence, clinicopathological characteristics and survival outcome in a cohort of 311 patients with well-differentiated lung neuroendocrine tumours. J Neuroendocrinol 2022; 34:e13184. [PMID: 36121922 DOI: 10.1111/jne.13184] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 05/25/2022] [Accepted: 06/24/2022] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is considered to be a rare condition associated with lung neuroendocrine tumours (NET), and its natural history is poorly described. We aimed to assess the prevalence and clinicopathologic characteristics of DIPNECH in the lung NET population, and to investigate predictors of time-to-progression (TTP) and overall survival (OS). METHODS We retrospectively identified patients diagnosed with DIPNECH between April 2005 and December 2020. Clinical data were collected from medical records. The relationship between baseline characteristics and TTP and OS was analysed using the Kaplan-Meier method. Univariate analysis was performed using the Cox proportional hazards model. RESULTS Of 311 patients with well-differentiated lung NETs, 61 (20%) had DIPNECH and were included in the study. Baseline demographics described 95% female, 59% never smokers and mean body mass index 34.4 kg m-2 ; 77% were typical carcinoids (TC), 13% atypical carcinoids (AC), and 10% both TC and AC (multicentric). At presentation, 54% of patients were asymptomatic. Multicentric NETs were demonstrated in 16 (26%) on histopathology, and a further 32 (52%) had synchronous NETs suggested on imaging (multiple nodules ≥ 5 mm). Seven (11%) patients developed metastases and the median OS from time of first metastasis was 37 months. AC histopathology and NET TNM stage ≥ IIA were associated with poorer TTP and OS. Of the DIPNECH cohort, the 15-year survival rate was 86%. CONCLUSIONS DIPNECH may be more prevalent in the lung NET population than previously appreciated, especially in women. Although our results confirm that DIPNECH is predominantly an indolent disease associated with TC, 23% developed AC and these patients may warrant closer observation.
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Affiliation(s)
- Aimee R Hayes
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
| | - Tu Vinh Luong
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
| | - Jamie Banks
- Medical School, University College of London, London, UK
| | - Heer Shah
- Medical School, University College of London, London, UK
| | - Jennifer Watkins
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
| | - Eric Lim
- Department of Thoracic Surgery, Royal Brompton Hospital, London, UK
| | - Anant Patel
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
| | - Ashley B Grossman
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
| | - Shaunak Navalkissoor
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
| | - Daniel Krell
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
| | - Martyn E Caplin
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
- University College of London, London, UK
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Wu Y, Li X, Li Q, Cheng C, Zheng L. Adipose tissue-to-breast cancer crosstalk: Comprehensive insights. Biochim Biophys Acta Rev Cancer 2022; 1877:188800. [PMID: 36103907 DOI: 10.1016/j.bbcan.2022.188800] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/29/2022] [Accepted: 09/06/2022] [Indexed: 10/14/2022]
Abstract
The review focuses on mechanistic evidence for the link between obesity and breast cancer. According to the IARC study, there is sufficient evidence that obesity is closely related to a variety of cancers. Among them, breast cancer is particularly disturbed by adipose tissue due to the unique histological structure of the breast. The review introduces the relationship between obesity and breast cancer from two aspects, including factors that promote tumorigenesis or metastasis. We summarize alterations in adipokines and metabolic pathways that contribute to breast cancer development. Breast cancer metastasis is closely related to obesity-induced pro-inflammatory microenvironment, adipose stem cells, and miRNAs. Based on the mechanism by which obesity causes breast cancer, we list possible therapeutic directions, including reducing the risk of breast cancer and inhibiting the progression of breast cancer. We also discussed the risk of autologous breast remodeling and fat transplantation. Finally, the causes of the obesity paradox and the function of enhancing immunity are discussed. Evaluating the balance between obesity-induced inflammation and enhanced immunity warrants further study.
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Affiliation(s)
- Yuan Wu
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Xu Li
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, PR China
| | - Qiong Li
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Chienshan Cheng
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Lan Zheng
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China.
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Jin TY, Saindane M, Park KS, Kim S, Nam S, Yoo Y, Yang JH, Yun I. LEP as a potential biomarker in prognosis of breast cancer: Systemic review and meta analyses (PRISMA). Medicine (Baltimore) 2021; 100:e26896. [PMID: 34414945 PMCID: PMC8376305 DOI: 10.1097/md.0000000000026896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 05/16/2021] [Accepted: 07/17/2021] [Indexed: 01/04/2023] Open
Abstract
PURPOSE Obesity strongly affects the prognosis of various malignancies, including breast cancer. Leptin (LEP) may be associated with obesity and breast cancer prognosis. The purpose of our study was to determine the prognostic value of LEP in breast cancer. METHOD We conducted a multi-omic analysis to determine the prognostic role of LEP. Different public bioinformatics platforms (Oncomine, Gene Expression Profiling Interactive Analysis, University of California Santa Cruz Xena, bc-GenExMiner, PrognoScan database, R2-Kaplan-Meier Scanner, UALCAN, Search Tool for the Retrieval of Interacting Genes/Proteins database , and The Database for Annotation, Visualization and Integrated Discovery) were used to evaluate the roles of LEP. Clinicopathological variables were evaluated. RESULTS LEP was downregulated in breast cancer tissues compared to levels in normal tissues. By co-expressed gene analysis, a positive correlation between LEP and SLC19A3 was observed. Based on the clinicopathological analysis, low LEP expression was associated with older age, higher stage, lymph node status, human epidermal growth factor receptor 2 (HER2) status, estrogen receptor (ER+) positivity, and progesterone receptor (PR+) positivity. Kaplan-Meier survival analysis showed that low LEP expression indicated a poorer prognosis. LEP is hypermethylated in breast cancer tissues in PrognoScan and R2-Kaplan Meier Scanner, and low LEP expression was correlated with poor prognosis. LEP protein-protein interactions were analyzed using Search Tool for the Retrieval of Interacting Genes/Proteins database. Gene ontology analysis results showed that cellular component is mainly associated with the endosome lumen, cytosol, and secretory granules and is upregulated. For the biological process energy reserve, metabolic processes exhibited the greatest regulation compared to the others. In molecular function, it was mainly enriched in a variety of combinations, but hormone activity showed the highest regulation. CONCLUSION Our study provides evidence for the prognostic role of LEP in breast cancer and as a novel potential therapeutic target in such malignancies. Nevertheless, further validation is required.
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Affiliation(s)
- Tong Yi Jin
- Department of Surgery, Konkuk University School of Medicine, Seoul, South Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, South Korea
| | - Madhuri Saindane
- Department of Surgery, Konkuk University School of Medicine, Seoul, South Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, South Korea
| | - Kyoung Sik Park
- Department of Surgery, Konkuk University School of Medicine, Seoul, South Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, South Korea
- Department of Surgery, Konkuk University Medical Center, Seoul, South Korea
| | - SeongHoon Kim
- Department of Surgery, Konkuk University Medical Center, Seoul, South Korea
| | - SangEun Nam
- Department of Surgery, Konkuk University School of Medicine, Seoul, South Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, South Korea
- Department of Surgery, Konkuk University Medical Center, Seoul, South Korea
| | - YoungBum Yoo
- Department of Surgery, Konkuk University School of Medicine, Seoul, South Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, South Korea
- Department of Surgery, Konkuk University Medical Center, Seoul, South Korea
| | - Jung-Hyun Yang
- Department of Surgery, Konkuk University School of Medicine, Seoul, South Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, South Korea
- Department of Surgery, Konkuk University Medical Center, Seoul, South Korea
| | - IkJin Yun
- Department of Surgery, Konkuk University School of Medicine, Seoul, South Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, South Korea
- Department of Surgery, Konkuk University Medical Center, Seoul, South Korea
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Gameiro A, Urbano AC, Ferreira F. Emerging Biomarkers and Targeted Therapies in Feline Mammary Carcinoma. Vet Sci 2021; 8:164. [PMID: 34437486 PMCID: PMC8402877 DOI: 10.3390/vetsci8080164] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/09/2021] [Accepted: 08/09/2021] [Indexed: 12/19/2022] Open
Abstract
Feline mammary carcinoma (FMC) is a common aggressive malignancy with a low survival rate that lacks viable therapeutic options beyond mastectomy. Recently, increasing efforts have been made to understand the molecular mechanisms underlying FMC development, using the knowledge gained from studies on human breast cancer to discover new diagnostic and prognostic biomarkers, thus reinforcing the utility of the cat as a cancer model. In this article, we review the current knowledge on FMC pathogenesis, biomarkers, and prognosis factors and offer new insights into novel therapeutic options for HER2-positive and triple-negative FMC subtypes.
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Affiliation(s)
| | | | - Fernando Ferreira
- CIISA—Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, Avenida da Universidade Técnica, 1300-477 Lisboa, Portugal; (A.G.); (A.C.U.)
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16
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Leptin-Activity Modulators and Their Potential Pharmaceutical Applications. Biomolecules 2021; 11:biom11071045. [PMID: 34356668 PMCID: PMC8301849 DOI: 10.3390/biom11071045] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/08/2021] [Accepted: 07/13/2021] [Indexed: 12/12/2022] Open
Abstract
Leptin, a multifunctional hormone primarily, but not exclusively, secreted in adipose tissue, is implicated in a wide range of biological functions that control different processes, such as the regulation of body weight and energy expenditure, reproductive function, immune response, and bone metabolism. In addition, leptin can exert angiogenic and mitogenic actions in peripheral organs. Leptin biological activities are greatly related to its interaction with the leptin receptor. Both leptin excess and leptin deficiency, as well as leptin resistance, are correlated with different human pathologies, such as autoimmune diseases and cancers, making leptin and leptin receptor important drug targets. The development of leptin signaling modulators represents a promising strategy for the treatment of cancers and other leptin-related diseases. In the present manuscript, we provide an update review about leptin-activity modulators, comprising leptin mutants, peptide-based leptin modulators, as well as leptin and leptin receptor specific monoclonal antibodies and nanobodies.
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17
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Binienda A, Ziolkowska S, Pluciennik E. The Anticancer Properties of Silibinin: Its Molecular Mechanism and Therapeutic Effect in Breast Cancer. Anticancer Agents Med Chem 2021; 20:1787-1796. [PMID: 31858905 DOI: 10.2174/1871520620666191220142741] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 10/29/2019] [Accepted: 11/12/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Silibinin (SB), the main component of Silymarin (SM), is a natural substance obtained from the seeds of the milk thistle. SM contains up to 70% of SB as two isoforms: A and B. It has an antioxidant and anti-inflammatory effect on hepatocytes and is known to inhibit cell proliferation, induce apoptosis, and curb angiogenesis. SB has demonstrated activity against many cancers, such as skin, liver, lung, bladder, and breast carcinomas. METHODS This review presents current knowledge of the use of SM in breast cancer, this being one of the most common types of cancer in women. It describes selected molecular mechanisms of the action of SM; for example, although SB influences both Estrogen Receptors (ER), α and β, it has opposite effects on the two. Its action on ERα influences the PI3K/AKT/mTOR and RAS/ERK signaling pathways, while by up-regulating ERβ, it increases the numbers of apoptotic cells. In addition, ERα is involved in SB-induced autophagy, while ERβ is not. Interestingly, SB also inhibits metastasis by suppressing TGF-β2 expression, thus suppressing Epithelial to Mesenchymal Transition (EMT). It also influences migration and invasive potential via the Jak2/STAT3 pathway. RESULTS SB may be a promising enhancement of BC treatment: when combined with chemotherapeutic drugs such as carboplatin, cisplatin, and doxorubicin, the combination exerts a synergistic effect against cancer cells. This may be of value when treating aggressive types of mammary carcinoma. CONCLUSION Summarizing, SB inhibits proliferation, induces apoptosis, and restrains metastasis via several mechanisms. It is possible to combine SB with different anticancer drugs, an approach that represents a promising therapeutic strategy for patients suffering from BC.
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Affiliation(s)
- Agata Binienda
- Faculty of Biomedical Sciences and Postgraduate Education, Medical University of Lodz, Lodz, Poland
| | - Sylwia Ziolkowska
- Faculty of Biomedical Sciences and Postgraduate Education, Medical University of Lodz, Lodz, Poland
| | - Elzbieta Pluciennik
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
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18
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Erkasap N, Ozyurt R, Ozkurt M, Erkasap S, Yasar F, Ihtiyar E, Ciftci E, Canaz F, Colak E. Role of Notch, IL-1 and leptin expression in colorectal cancer. Exp Ther Med 2021; 21:600. [PMID: 33884038 PMCID: PMC8056113 DOI: 10.3892/etm.2021.10032] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 03/11/2021] [Indexed: 11/10/2022] Open
Abstract
An increasing number of studies have shown that angiogenesis has an important role in the progression of cancer. The growth of a new network of blood vessels is crucial for tumor growth and metastasis, which is promoted by several proangiogenic factors. Leptin, an essential adipokine that is secreted from fat tissue, is one of these pro-angiogenic factors. It has been shown that the inhibition of leptin-induced angiogenesis resulted in decreased levels of vascular endothelial growth factor (VEGF)/VEGFR2, hypoxia inducible factor (HIF) 1α, NF-κB, IL-1 and Notch and reduced the tumor growth in breast cancer. Leptin induces angiogenesis in breast cancer either by upregulating VEGFR2 in endothelial cells or by increasing VEGF/VEGFR2 expression through the Notch, IL-1 and leptin crosstalk outcome (NILCO) pathway. NILCO is a novel mechanism that interacts with proinflammatory and proangiogenic signals, which are critical for cell proliferation and angiogenesis in cancer. Several studies have shown that components of NILCO may affect human cancer incidence and progression. However, to the best of our knowledge, the interactions between Notch, IL-1 and leptin in human colorectal cancer have not been yet studied at the molecular level. The aim of the present study was to investigate the expression levels of genes related to the NILCO pathway in human colorectal cancer specimens. The current results demonstrated that leptin, leptin receptor (ObR) b, Notch-1, Notch-4, IL-1α, IL-1β, IL-1R, IL-6, JAK-2, STAT-1, STAT-3, VEGFA, VEGFR1, VEGFR2, TNF-α and NF-κB mRNA expression levels in the cancer tissue were increased compared with the normal tissue. No significant changes in the mRNA expression levels of Jagged-1, HIF-1α and TNF receptor 1 were observed. Western blotting revealed that the protein expression levels of IκB were increased in the cancer tissue compared with normal tissue, whereas HIF-1α and phosphorylated STAT-1 levels were decreased. IL-6 and VEGFA plasma concentrations were statistically raised and the leptin plasma concentration was also raised, although significantly, patients with cancer compared with control individuals. Together, the present findings indicated that Notch, IL-1 and leptin may serve a crucial role in the development of colorectal cancer.
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Affiliation(s)
- Nilufer Erkasap
- Department of Physiology, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
| | - Rumeysa Ozyurt
- Department of Physiology, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
| | - Mete Ozkurt
- Department of Physiology, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
| | - Serdar Erkasap
- Department of General Surgery, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
| | - Fatih Yasar
- Department of General Surgery, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
| | - Enver Ihtiyar
- Department of General Surgery, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
| | - Evrim Ciftci
- Department of Pathology, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
| | - Funda Canaz
- Department of Pathology, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
| | - Ertugrul Colak
- Department of Biostatistics, Eskisehir Osmangazi University Medical Faculty, Odunpazari, Eskisehir 26040, Turkey
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Dong S, Wang Z, Shen K, Chen X. Metabolic Syndrome and Breast Cancer: Prevalence, Treatment Response, and Prognosis. Front Oncol 2021; 11:629666. [PMID: 33842335 PMCID: PMC8027241 DOI: 10.3389/fonc.2021.629666] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 03/11/2021] [Indexed: 12/13/2022] Open
Abstract
Metabolic syndrome is a type of multifactorial metabolic disease with the presence of at least three factors: obesity, diabetes mellitus, low high-density lipoprotein, hypertriglyceridemia, and hypertension. Recent studies have shown that metabolic syndrome and its related components exert a significant impact on the initiation, progression, treatment response, and prognosis of breast cancer. Metabolic abnormalities not only increase the disease risk and aggravate tumor progression but also lead to unfavorable treatment responses and more treatment side effects. Moreover, biochemical reactions caused by the imbalance of these metabolic components affect both the host general state and organ-specific tumor microenvironment, resulting in increased rates of recurrence and mortality. Therefore, this review discusses the recent advances in the association of metabolic syndrome and breast cancer, providing potential novel therapeutic targets and intervention strategies to improve breast cancer outcome.
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Affiliation(s)
| | | | - Kunwei Shen
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaosong Chen
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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20
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Rajesh Y, Sarkar D. Association of Adipose Tissue and Adipokines with Development of Obesity-Induced Liver Cancer. Int J Mol Sci 2021; 22:ijms22042163. [PMID: 33671547 PMCID: PMC7926723 DOI: 10.3390/ijms22042163] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/20/2022] Open
Abstract
Obesity is rapidly dispersing all around the world and is closely associated with a high risk of metabolic diseases such as insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD), leading to carcinogenesis, especially hepatocellular carcinoma (HCC). It results from an imbalance between food intake and energy expenditure, leading to an excessive accumulation of adipose tissue (AT). Adipocytes play a substantial role in the tumor microenvironment through the secretion of several adipokines, affecting cancer progression, metastasis, and chemoresistance via diverse signaling pathways. AT is considered an endocrine organ owing to its ability to secrete adipokines, such as leptin, adiponectin, resistin, and a plethora of inflammatory cytokines, which modulate insulin sensitivity and trigger chronic low-grade inflammation in different organs. Even though the precise mechanisms are still unfolding, it is now established that the dysregulated secretion of adipokines by AT contributes to the development of obesity-related metabolic disorders. This review focuses on several obesity-associated adipokines and their impact on obesity-related metabolic diseases, subsequent metabolic complications, and progression to HCC, as well as their role as potential therapeutic targets. The field is rapidly developing, and further research is still required to fully understand the underlying mechanisms for the metabolic actions of adipokines and their role in obesity-associated HCC.
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Affiliation(s)
- Yetirajam Rajesh
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Devanand Sarkar
- Massey Cancer Center, Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA
- Correspondence: ; Tel.: +1-804-827-2339
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21
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Dragano NRV, Fernø J, Diéguez C, López M, Milbank E. Reprint of: Recent Updates on Obesity Treatments: Available Drugs and Future Directions. Neuroscience 2020; 447:191-215. [PMID: 33046217 DOI: 10.1016/j.neuroscience.2020.08.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In the last thirty years, obesity has reached epidemic proportions and is now regarded as a major health issue in contemporary society trending to serious economic and social burdens. The latest projections of the World Health Organization are alarming. By 2030, nearly 60% of the worldwide population could be either obese or overweight, highlighting the needs to find innovative treatments. Currently, bariatric surgery is the most effective way to efficiently lower body mass. Although great improvements in terms of recovery and patient care were made in these surgical procedures, bariatric surgery remains an option for extreme forms of obesity and seems unable to tackle obesity pandemic expansion. Throughout the last century, numerous pharmacological strategies targeting either peripheral or central components of the energy balance regulatory system were designed to reduce body mass, some of them reaching sufficient levels of efficiency and safety. Nevertheless, obesity drug therapy remains quite limited on its effectiveness to actually overcome the obesogenic environment. Thus, innovative unimolecular polypharmacology strategies, able to simultaneously target multiple actors involved in the obesity initiation and expansion, were developed during the last ten years opening a new promising avenue in the pharmacological management of obesity. In this review, we first describe the clinical features of obesity-associated conditions and then focus on the outcomes of currently approved drug therapies for obesity as well as new ones expecting to reach the clinic in the near future.
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Affiliation(s)
- Nathalia R V Dragano
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain.
| | - Johan Fernø
- Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen, Norway
| | - Carlos Diéguez
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
| | - Miguel López
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
| | - Edward Milbank
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain.
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22
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Kothari C, Diorio C, Durocher F. The Importance of Breast Adipose Tissue in Breast Cancer. Int J Mol Sci 2020; 21:ijms21165760. [PMID: 32796696 PMCID: PMC7460846 DOI: 10.3390/ijms21165760] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 07/31/2020] [Accepted: 08/06/2020] [Indexed: 02/07/2023] Open
Abstract
Adipose tissue is a complex endocrine organ, with a role in obesity and cancer. Adipose tissue is generally linked to excessive body fat, and it is well known that the female breast is rich in adipose tissue. Hence, one can wonder: what is the role of adipose tissue in the breast and why is it required? Adipose tissue as an organ consists of adipocytes, an extracellular matrix (ECM) and immune cells, with a significant role in the dynamics of breast changes throughout the life span of a female breast from puberty, pregnancy, lactation and involution. In this review, we will discuss the importance of breast adipose tissue in breast development and its involvement in breast changes happening during pregnancy, lactation and involution. We will focus on understanding the biology of breast adipose tissue, with an overview on its involvement in the various steps of breast cancer development and progression. The interaction between the breast adipose tissue surrounding cancer cells and vice-versa modifies the tumor microenvironment in favor of cancer. Understanding this mutual interaction and the role of breast adipose tissue in the tumor microenvironment could potentially raise the possibility of overcoming breast adipose tissue mediated resistance to therapies and finding novel candidates to target breast cancer.
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Affiliation(s)
- Charu Kothari
- Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec, QC G1T 1C2, Canada;
- Cancer Research Centre, CHU de Quebec Research Centre, Quebec, QC G1V 4G2, Canada;
| | - Caroline Diorio
- Cancer Research Centre, CHU de Quebec Research Centre, Quebec, QC G1V 4G2, Canada;
- Department of Preventive and Social Medicine, Faculty of Medicine, Laval University, Quebec, QC G1T 1C2, Canada
| | - Francine Durocher
- Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec, QC G1T 1C2, Canada;
- Cancer Research Centre, CHU de Quebec Research Centre, Quebec, QC G1V 4G2, Canada;
- Correspondence: ; Tel.: +1-(418)-525-4444 (ext. 48508)
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Lipsey CC, Harbuzariu A, Robey RW, Huff LM, Gottesman MM, Gonzalez-Perez RR. Leptin Signaling Affects Survival and Chemoresistance of Estrogen Receptor Negative Breast Cancer. Int J Mol Sci 2020; 21:E3794. [PMID: 32471192 PMCID: PMC7311967 DOI: 10.3390/ijms21113794] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/15/2020] [Accepted: 05/21/2020] [Indexed: 12/18/2022] Open
Abstract
Estrogen-receptor-negative breast cancer (BCER-) is mainly treated with chemotherapeutics. Leptin signaling can influence BCER- progression, but its effects on patient survival and chemoresistance are not well understood. We hypothesize that leptin signaling decreases the survival of BCER- patients by, in part, inducing the expression of chemoresistance-related genes. The correlation of expression of leptin receptor (OBR), leptin-targeted genes (CDK8, NANOG, and RBP-Jk), and breast cancer (BC) patient survival was determined from The Cancer Genome Atlas (TCGA) mRNA data. Leptin-induced expression of proliferation and chemoresistance-related molecules was investigated in triple-negative BC (TNBC) cells that respond differently to chemotherapeutics. Leptin-induced gene expression in TNBC was analyzed by RNA-Seq. The specificity of leptin effects was assessed using OBR inhibitors (shRNA and peptides). The results show that OBR and leptin-targeted gene expression are associated with lower survival of BCER- patients. Importantly, the co-expression of these genes was also associated with chemotherapy failure. Leptin signaling increased the expression of tumorigenesis and chemoresistance-related genes (ABCB1, WNT4, ADHFE1, TBC1D3, LL22NC03, RDH5, and ITGB3) and impaired chemotherapeutic effects in TNBC cells. OBR inhibition re-sensitized TNBC to chemotherapeutics. In conclusion, the co-expression of OBR and leptin-targeted genes may be used as a predictor of survival and drug resistance of BCER- patients. Targeting OBR signaling could improve chemotherapeutic efficacy.
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Affiliation(s)
- Crystal C. Lipsey
- Microbiology, Biochemistry, and Immunology, GEBS, Morehouse School of Medicine, Atlanta, GA 30310, USA; (C.C.L.); (A.H.)
- Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA; (R.W.R.); (L.M.H.); (M.M.G.)
| | - Adriana Harbuzariu
- Microbiology, Biochemistry, and Immunology, GEBS, Morehouse School of Medicine, Atlanta, GA 30310, USA; (C.C.L.); (A.H.)
| | - Robert W. Robey
- Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA; (R.W.R.); (L.M.H.); (M.M.G.)
| | - Lyn M. Huff
- Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA; (R.W.R.); (L.M.H.); (M.M.G.)
| | - Michael M. Gottesman
- Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA; (R.W.R.); (L.M.H.); (M.M.G.)
| | - Ruben R. Gonzalez-Perez
- Microbiology, Biochemistry, and Immunology, GEBS, Morehouse School of Medicine, Atlanta, GA 30310, USA; (C.C.L.); (A.H.)
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24
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Dragano NRV, Fernø J, Diéguez C, López M, Milbank E. Recent Updates on Obesity Treatments: Available Drugs and Future Directions. Neuroscience 2020; 437:215-239. [PMID: 32360593 DOI: 10.1016/j.neuroscience.2020.04.034] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 04/17/2020] [Accepted: 04/20/2020] [Indexed: 12/12/2022]
Abstract
In the last thirty years, obesity has reached epidemic proportions and is now regarded as a major health issue in contemporary society trending to serious economic and social burdens. The latest projections of the World Health Organization are alarming. By 2030, nearly 60% of the worldwide population could be either obese or overweight, highlighting the needs to find innovative treatments. Currently, bariatric surgery is the most effective way to efficiently lower body mass. Although great improvements in terms of recovery and patient care were made in these surgical procedures, bariatric surgery remains an option for extreme forms of obesity and seems unable to tackle obesity pandemic expansion. Throughout the last century, numerous pharmacological strategies targeting either peripheral or central components of the energy balance regulatory system were designed to reduce body mass, some of them reaching sufficient levels of efficiency and safety. Nevertheless, obesity drug therapy remains quite limited on its effectiveness to actually overcome the obesogenic environment. Thus, innovative unimolecular polypharmacology strategies, able to simultaneously target multiple actors involved in the obesity initiation and expansion, were developed during the last ten years opening a new promising avenue in the pharmacological management of obesity. In this review, we first describe the clinical features of obesity-associated conditions and then focus on the outcomes of currently approved drug therapies for obesity as well as new ones expecting to reach the clinic in the near future.
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Affiliation(s)
- Nathalia R V Dragano
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain.
| | - Johan Fernø
- Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen, Norway
| | - Carlos Diéguez
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
| | - Miguel López
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
| | - Edward Milbank
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain.
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25
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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.
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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.
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26
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Abstract
Drug targets for the treatment of obesity and comorbidities represent an ever-renewable source of research opportunities worldwide. One of the earliest is the leptin–leptin receptor system that was discovered in the mid-1990s. Leptin, a satiety hormone, is overproduced in overweight patients but the protein is unable to cross the blood–brain barrier and remains inactive. Circulating high levels of leptin induces a series of conditions that would not be manifested without leptin overproduction, including various forms of cancer and inflammatory and cardiovascular diseases. Current pharmaceutical research focuses on improving the blood–brain barrier penetration of leptin receptor agonists and the development of monofunctional antagonists with broad spectrum therapeutic efficacies but without unwanted side effects. Designer peptides with their expanded chemical space as well as well controllable receptor binding and elimination properties slowly replace full-sized leptin products in the drug development pipeline.
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27
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Abstract
Accumulating evidence highlights the importance of interactions between tumour cells and stromal cells for tumour initiation, progression, and metastasis. In tumours that contain adipocyte in their stroma, adipocytes contribute to modification of tumour microenvironment and affect metabolism of tumour and tumour progression by production of cytokines and adipokines from the lipids. The omentum and bone marrow (BM) are highly adipocyte-rich and are also common metastatic and primary tumour developmental sites. Omental adipocytes exhibit metabolic cross-talk, immune modulation, and angiogenesis. BM adipocytes secrete adipokines, and participate in solid tumour metastasis through regulation of the CCL2/CCR2 axis and metabolic interactions. BM adipocytes also contribute to the progression of hematopoietic neoplasms. Here, we here provide an overview of research progress on the cross-talks between omental/BM adipocytes and tumour cells, which may be pivotal modulators of tumour biology, thus highlighting novel therapeutic targets. Abbreviations: MCP-1, monocyte chemoattractant protein 1IL, interleukinSTAT3, signal transducer and activator of transcription 3FABP4, fatty acid binding protein 4PI3K/AKT, phosphoinositide 3-kinase/protein kinase BPPAR, peroxisome proliferator-activated receptorPUFA, polyunsaturated fatty acidTAM, tumour-associated macrophagesVEGF, vascular endothelial growth factorVEGFR, vascular endothelial growth factor receptorBM, bone marrowBMA, bone marrow adipocytesrBMA, regulated BMAcBMA, constitutive BMAUCP-1, uncoupling protein-1TNF-α, tumour necrosis factor-alphaRANKL, receptor activator of nuclear factor kappa-Β ligandVCAM-1, vascular cell adhesion molecule 1JAK2, Janus kinase 2CXCL (C–X–C motif) ligandPGE2, prostaglandin E2COX-2, cyclooxygenase-2CCL2, C-C motif chemokine ligand 2NF-κB, nuclear factor-kappa BMM, multiple myelomaALL, acute lymphoblastic leukemiaAML, acute myeloid leukemiaGDF15, growth differentiation factor 15AMPK, AMP-activated protein kinaseMAPK, mitogen-activated protein kinaseAPL, acute promyelocytic leukemiaCCR2, C-C motif chemokine receptor 2SDF-1α, stromal cell-derived factor-1 alphaFFA, free fatty acidsLPrA, leptin peptide receptor antagonistMCD, malonyl-CoA decarboxylase.
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Affiliation(s)
- Yoon Jin Cha
- Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
| | - Ja Seung Koo
- Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
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28
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Christodoulatos GS, Spyrou N, Kadillari J, Psallida S, Dalamaga M. The Role of Adipokines in Breast Cancer: Current Evidence and Perspectives. Curr Obes Rep 2019; 8:413-433. [PMID: 31637624 DOI: 10.1007/s13679-019-00364-y] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE The current review shows evidence for the role of adipokines in breast cancer (BC) pathogenesis summarizing the mechanisms underlying the association between adipokines and breast malignancy. Special emphasis is given also on intriguing insights into the relationship between obesity and BC as well as on the role of novel adipokines in BC development. RECENT FINDINGS Recent evidence has underscored the role of the triad of obesity, insulin resistance, and adipokines in postmenopausal BC. Adipokines exert independent and joint effects on activation of major intracellular signal networks implicated in BC cell proliferation, growth, survival, invasion, and metastasis, particularly in the context of obesity, considered a systemic endocrine dysfunction characterized by chronic inflammation. To date, more than 10 adipokines have been linked to BC, and this catalog is continuously increasing. The majority of circulating adipokines, such as leptin, resistin, visfatin, apelin, lipocalin 2, osteopontin, and oncostatin M, is elevated in BC, while some adipokines such as adiponectin and irisin (adipo-myokine) are generally decreased in BC and considered protective against breast carcinogenesis. Further evidence from basic and translational research is necessary to delineate the ontological role of adipokines and their interplay in BC pathogenesis. More large-scale clinical and longitudinal studies are awaited to assess their clinical utility in BC prognosis and follow-up. Finally, novel more effective and safer adipokine-centered therapeutic strategies could pave the way for targeted oncotherapy.
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Affiliation(s)
- Gerasimos Socrates Christodoulatos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias, Goudi, 11527, Athens, Greece
- Laboratory of Microbiology, KAT Hospital, 2 Nikis, Kifisia, 14561, Athens, Greece
| | - Nikolaos Spyrou
- 251 Airforce General Hospital, 3 Kanellopoulou, 11525, Athens, Greece
| | - Jona Kadillari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias, Goudi, 11527, Athens, Greece
| | - Sotiria Psallida
- Laboratory of Microbiology, KAT Hospital, 2 Nikis, Kifisia, 14561, Athens, Greece
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias, Goudi, 11527, Athens, Greece.
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29
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Zimta AA, Tigu AB, Muntean M, Cenariu D, Slaby O, Berindan-Neagoe I. Molecular Links between Central Obesity and Breast Cancer. Int J Mol Sci 2019; 20:ijms20215364. [PMID: 31661891 PMCID: PMC6862548 DOI: 10.3390/ijms20215364] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 10/21/2019] [Accepted: 10/25/2019] [Indexed: 02/07/2023] Open
Abstract
Worldwide, breast cancer (BC) is the most common malignancy in women, in regard to incidence and mortality. In recent years, the negative role of obesity during BC development and progression has been made abundantly clear in several studies. However, the distribution of body fat may be more important to analyze than the overall body weight. In our review of literature, we reported some key findings regarding the role of obesity in BC development, but focused more on central adiposity. Firstly, the adipose microenvironment in obese people bears many similarities with the tumor microenvironment, in respect to associated cellular composition, chronic low-grade inflammation, and high ratio of reactive oxygen species to antioxidants. Secondly, the adipose tissue functions as an endocrine organ, which in obese people produces a high level of tumor-promoting hormones, such as leptin and estrogen, and a low level of the tumor suppressor hormone, adiponectin. As follows, in BC this leads to the activation of oncogenic signaling pathways: NFκB, JAK, STAT3, AKT. Moreover, overall obesity, but especially central obesity, promotes a systemic and local low grade chronic inflammation that further stimulates the increase of tumor-promoting oxidative stress. Lastly, there is a constant exchange of information between BC cells and adipocytes, mediated especially by extracellular vesicles, and which changes the transcription profile of both cell types to an oncogenic one with the help of regulatory non-coding RNAs.
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Affiliation(s)
- Alina-Andreea Zimta
- MEDFUTURE-Research Center for Advanced Medicine, University of Medicine, and Pharmacy Iuliu-Hatieganu, 23 Marinescu Street, 400337 Cluj-Napoca, Romania.
| | - Adrian Bogdan Tigu
- MEDFUTURE-Research Center for Advanced Medicine, University of Medicine, and Pharmacy Iuliu-Hatieganu, 23 Marinescu Street, 400337 Cluj-Napoca, Romania.
- Babeș-Bolyai University, Faculty of Biology, and Geology, 42 Republicii Street, 400015 Cluj-Napoca, Romania.
| | - Maximilian Muntean
- Department of Plastic Surgery, University of Medicine and Pharmacy "Iuliu Hatieganu", 400337 Cluj-Napoca, Romania.
| | - Diana Cenariu
- MEDFUTURE-Research Center for Advanced Medicine, University of Medicine, and Pharmacy Iuliu-Hatieganu, 23 Marinescu Street, 400337 Cluj-Napoca, Romania.
| | - Ondrej Slaby
- Central European Institute of Technology, Masaryk University, 62100 Brno, Czech Republic.
- Masaryk Memorial Cancer Institute, Department of Comprehensive Cancer Care, 60200 Brno, Czech Republic.
| | - Ioana Berindan-Neagoe
- MEDFUTURE-Research Center for Advanced Medicine, University of Medicine, and Pharmacy Iuliu-Hatieganu, 23 Marinescu Street, 400337 Cluj-Napoca, Romania.
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu" University of Medicine, and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania.
- Department of Functional Genomics, and Experimental Pathology, The Oncology Institute "Prof. Dr. Ion Chiricuta", Republicii 34th street, 400015 Cluj-Napoca, Romania.
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30
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Apelin abrogates the stimulatory effects of 17β-estradiol and insulin-like growth factor-1 on proliferation of epithelial and granulosa ovarian cancer cell lines via crosstalk between APLNR and ERα/IGF1R. Mol Biol Rep 2019; 46:6325-6338. [DOI: 10.1007/s11033-019-05073-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 09/10/2019] [Indexed: 12/18/2022]
Abstract
Abstract
Apelin and chemerin are adipocytokines that play important roles in many physiological and pathological processes throughout the body. Our previous study demonstrated that these two adipokines are expressed and secreted by epithelial and granulosa cancer cell lines. 17β-estradiol (E2) and insulin-like growth factor-1 (IGF-1) are important regulators of ovarian functions, and their roles are well known. This study investigated whether apelin and chemerin regulate proliferation and apoptosis of epithelial (OVCAR-3) and granulosa (COV434) ovarian cancer cell lines by interacting with E2 and IGF-1. Apelin and chemerin did not affect caspase-3 activation in either cell line. However, apelin abrogated the stimulatory effects of E2 on proliferation of OVCAR-3 cells and of IGF-1 on proliferation of COV434 cells independently of ERK1/2 and PI3K via crosstalk of apelin receptor with estrogen receptor alpha and IGF-1 receptor, respectively.
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31
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Sabol RA, Giacomelli P, Beighley A, Bunnell BA. Adipose Stem Cells and Cancer: Concise Review. Stem Cells 2019; 37:1261-1266. [DOI: 10.1002/stem.3050] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 05/11/2019] [Accepted: 06/04/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Rachel A. Sabol
- Center for Stem Cell Research; Tulane University School of Medicine; New Orleans Louisiana USA
| | - Paulina Giacomelli
- Center for Stem Cell Research; Tulane University School of Medicine; New Orleans Louisiana USA
| | - Adam Beighley
- Center for Stem Cell Research; Tulane University School of Medicine; New Orleans Louisiana USA
| | - Bruce A. Bunnell
- Center for Stem Cell Research; Tulane University School of Medicine; New Orleans Louisiana USA
- Department of Pharmacology; Tulane University; New Orleans Louisiana USA
- Division of Regenerative Medicine; Tulane National Primate Research Center; Covington Louisiana USA
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32
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Foglesong GD, Queen NJ, Huang W, Widstrom KJ, Cao L. Enriched environment inhibits breast cancer progression in obese models with intact leptin signaling. Endocr Relat Cancer 2019; 26:483-495. [PMID: 30856610 PMCID: PMC6717689 DOI: 10.1530/erc-19-0075] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 03/11/2019] [Indexed: 12/11/2022]
Abstract
Obesity is becoming a global epidemic and is a risk factor for breast cancer. Environmental enrichment (EE), a model recapitulating an active lifestyle, leads to leanness, resistance to diet-induced obesity (DIO) and cancer. One mechanism is the activation of the hypothalamic-sympathoneural-adipocyte (HSA) axis. This results in the release of norepinephrine onto adipose tissue inducing a drop of leptin. This study aimed to test the effects of EE on breast cancer onset and progression while considering the effect of leptin by utilizing the transgenic MMTV-PyMT model as well as several models of varied leptin signaling. EE was highly effective at reducing weight gain, regardless of the presence of leptin. However, the effects of EE on tumor progression were dependent on leptin signaling. EE decreased leptin and reduced mammary tumor growth rate in MMTV-PyMT spontaneous and DIO transplantation models; in contrast, the absence of leptin in ob/ob mice resulted in increased tumor growth likely due to elevated norepinephrine levels. Our results suggest that the microenvironment is critical in breast tumorigenesis and that the drop in leptin is an important peripheral mediator of the EE anti-breast cancer effects, offsetting the potential pro-tumorigenic effects of norepinephrine responding to a complex environment.
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Affiliation(s)
- Grant D Foglesong
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Nicholas J Queen
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Wei Huang
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Kyle J Widstrom
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Lei Cao
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
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Avgerinos KI, Spyrou N, Mantzoros CS, Dalamaga M. Obesity and cancer risk: Emerging biological mechanisms and perspectives. Metabolism 2019; 92:121-135. [PMID: 30445141 DOI: 10.1016/j.metabol.2018.11.001] [Citation(s) in RCA: 900] [Impact Index Per Article: 150.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 11/02/2018] [Accepted: 11/03/2018] [Indexed: 02/07/2023]
Abstract
Continuously rising trends in obesity-related malignancies render this disease spectrum a public health priority. Worldwide, the burden of cancer attributable to obesity, expressed as population attributable fraction, is 11.9% in men and 13.1% in women. There is convincing evidence that excess body weight is associated with an increased risk for cancer of at least 13 anatomic sites, including endometrial, esophageal, renal and pancreatic adenocarcinomas; hepatocellular carcinoma; gastric cardia cancer; meningioma; multiple myeloma; colorectal, postmenopausal breast, ovarian, gallbladder and thyroid cancers. We first synopsize current epidemiologic evidence; the obesity paradox in cancer risk and mortality; the role of weight gain and weight loss in the modulation of cancer risk; reliable somatometric indicators for obesity and cancer research; and gender differences in obesity related cancers. We critically summarize emerging biological mechanisms linking obesity to cancer encompassing insulin resistance and abnormalities of the IGF-I system and signaling; sex hormones biosynthesis and pathway; subclinical chronic low-grade inflammation and oxidative stress; alterations in adipokine pathophysiology; factors deriving from ectopic fat deposition; microenvironment and cellular perturbations including vascular perturbations, epithelial-mesenchymal transition, endoplasmic reticulum stress and migrating adipose progenitor cells; disruption of circadian rhythms; dietary nutrients; factors with potential significance such as the altered intestinal microbiome; and mechanic factors in obesity and cancer. Future perspectives regarding prevention, diagnosis and therapeutics are discussed. The aim of this review is to investigate how the interplay of these main potential mechanisms and risk factors, exerts their effects on target tissues provoking them to acquire a cancerous phenotype.
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Affiliation(s)
| | - Nikolaos Spyrou
- 251 Airforce General Hospital, Kanellopoulou 3, 11525, Athens, Greece
| | - Christos S Mantzoros
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, 11527 Athens, Greece.
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34
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Vokuda RS, B H S, Madhugiri VS, Velusamy SK, Verma SK. The Expression of Leptin and Its Receptor During Tumorigenesis of Diffuse Gliomas such as Astrocytoma and Oligodendroglioma- Grade II, III and IV (NOS). Asian Pac J Cancer Prev 2019; 20:479-485. [PMID: 30803210 PMCID: PMC6897042 DOI: 10.31557/apjcp.2019.20.2.479] [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] [Indexed: 11/25/2022] Open
Abstract
Background: Leptin, an adipocytokine functions via the leptin receptor, OB-Rb that contains an intact intracellular
domain and activates the JAK/STAT signalling cascade. It stimulates growth, migration and invasion of cancer cells in
vitro potentiating angiogenesis. Recently, the involvement of leptin in tumor progression is being explored. Gliomas
exhibit poor prognosis, low survival rates demanding for novel therapeutic regimens resulting in discovery of many
potential biomarkers and pharmaceutical targets. We analysed the potential role of leptin and OB-Rb in carcinogenesis
of malignant gliomas. Methods: Sixty fresh tissue samples of diffuse gliomas were collected after tumor excision. Real
time PCR, immunohistochemical (IHC) analysis and western blot analysis were carried out to assess the expression of
leptin and its receptor. Results: The present study demonstrates the expression of leptin and LepR and their involvement
in tumor progression. Of the 60 cases, 57 cases (95%) and 53 cases (88.3%) showed amplification for leptin and
OB-Rb respectively. The expression of these proteins were measured semi-quantitatively and correlated with degree of
malignancy (p<0.05). The bands were visualised on western blot. Conclusion: Leptin may be valued as a pharmaceutical
target and anti-leptin compounds could be developed as drugs in mono- or combined therapies for these tumors.
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Affiliation(s)
- Ramya S Vokuda
- Department of Pathology, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Puducherry, India.
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35
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Nyasani E, Munir I, Perez M, Payne K, Khan S. Linking obesity-induced leptin-signaling pathways to common endocrine-related cancers in women. Endocrine 2019; 63:3-17. [PMID: 30218381 DOI: 10.1007/s12020-018-1748-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 09/04/2018] [Indexed: 12/13/2022]
Abstract
Obesity is related to many major diseases and cancers. Women have higher rates of obesity and obesity is linked to commonly occurring cancers in women. However, there is a lack of knowledge of the unique mechanism(s) involved in each type of cancer. The objective of this review is to highlight the need for novel experimental approaches and a better understanding of the common and unique pathways to resolve controversies regarding the role of obesity in cancer. In women, there is a link between hormones and obesity-associated genes in cancer development. Leptin is an obesity-associated gene that has been studied extensively in cancers; however, whether the defect is in the leptin gene or in its signaling pathways remains unclear. Both leptin and its receptor have been positively correlated with cancer progression in some endocrine-related cancers in women. This review offers an up-to-date and cohesive review of both upstream and downstream pathways of leptin signaling in cancer and a comprehensive picture of cancer pathogenesis in light of current evidence of leptin effects in several major types of cancer. This work is intended to aid in the design of better therapeutic strategies for obese/overweight women with cancer.
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Affiliation(s)
- Eunice Nyasani
- Center for Health Disparities & Molecular Medicine, Loma Linda, CA, USA
| | - Iqbal Munir
- Riverside University Health System, Moreno Valley, CA, USA
| | - Mia Perez
- Department of Pathology & Human Anatomy, Loma Linda, USA
| | - Kimberly Payne
- Department of Pathology & Human Anatomy, Loma Linda, USA
| | - Salma Khan
- Center for Health Disparities & Molecular Medicine, Loma Linda, CA, USA.
- Division of Biochemistry, Loma Linda University, Loma Linda, CA, USA.
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Butti R, Gunasekaran VP, Kumar TVS, Banerjee P, Kundu GC. Breast cancer stem cells: Biology and therapeutic implications. Int J Biochem Cell Biol 2018; 107:38-52. [PMID: 30529656 DOI: 10.1016/j.biocel.2018.12.001] [Citation(s) in RCA: 128] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 12/03/2018] [Accepted: 12/03/2018] [Indexed: 12/12/2022]
Abstract
Breast cancer remains to be a dreadful disease even with several advancements in radiation and chemotherapies, owing to the drug resistance and tumor relapse caused by breast cancer stem cells. Cancer stem cells are a minute population of cells of solid tumors which show self-renewal and differentiation properties as well as tumorigenic potential. Several signaling pathways including Notch, Hippo, Wnt and Hedgehog and tumor-stroma exchanges play a critical role in the self-renewal and differentiation of cancer stem cells in breast cancer. Cancer stem cells can grow anchorage-independent manner so they disseminate to different parts of the body to form secondary tumors. Cancer stem cells promote angiogenesis by dedifferentiating to endothelial cells as well as secreting proangiogenic and angiogenic factors. Moreover, multidrug resistance genes and drug efflux transporters expressed in breast cancer stem cells confer resistance to various conventional chemotherapeutic drugs. Indeed, these therapies are recognised to enhance the percent of cancer stem cell population in tumors leading to cancer relapse with increased aggressiveness. Hence, devising the therapeutic interventions to target cancer stem cells would be useful in increasing patients' survival rates. In addition, targeting the self-renewal pathways and tumor-stromal cross-talk helps in eradicating this population. Reversal of the cancer stem cell-mediated drug resistance would increase the sensitivity to various conventional drugs for the effective management of breast cancer. In this review, we have discussed the cancer stem cell origin and their involvement in angiogenesis, metastasis and therapy-resistance. We have also summarized different therapeutic approaches to eradicate the same for the successful treatment of breast cancer.
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Affiliation(s)
- Ramesh Butti
- National Centre for Cell Science, SP Pune University Campus, Pune 411007, India.
| | | | - Totakura V S Kumar
- National Centre for Cell Science, SP Pune University Campus, Pune 411007, India.
| | - Pinaki Banerjee
- National Centre for Cell Science, SP Pune University Campus, Pune 411007, India.
| | - Gopal C Kundu
- National Centre for Cell Science, SP Pune University Campus, Pune 411007, India.
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Spyrou N, Avgerinos KI, Mantzoros CS, Dalamaga M. Classic and Novel Adipocytokines at the Intersection of Obesity and Cancer: Diagnostic and Therapeutic Strategies. Curr Obes Rep 2018; 7:260-275. [PMID: 30145771 DOI: 10.1007/s13679-018-0318-7] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW In this review, we investigate the role of classic and novel adipocytokines in cancer pathogenesis synopsizing the mechanisms underlying the association between adipocytokines and malignancy. Special emphasis is given on novel adipocytokines as new evidence is emerging regarding their entanglement in neoplastic development. RECENT FINDINGS Recent data have emphasized the role of the triad of overweight/obesity, insulin resistance and adipocytokines in cancer. In the setting of obesity, classic and novel adipocytokines present independent and joint effects on activation of major intracellular signaling pathways implicated in cell proliferation, expansion, survival, adhesion, invasion, and metastasis. Until now, more than 15 adipocytokines have been associated with cancer, and this list continues to expand. While the plethora of circulating pro-inflammatory adipocytokines, such as leptin, resistin, extracellular nicotinamide phosphoribosyl transferase, and chemerin are elevated in malignancies, some adipocytokines such as adiponectin and omentin-1 are generally decreased in cancers and are considered protective against carcinogenesis. Elucidating the intertwining of inflammation, cellular bioenergetics, and adiposopathy is significant for the development of preventive, diagnostic, and therapeutic strategies against cancer. Novel more effective and safe adipocytokine-centered therapeutic interventions may pave the way for targeted oncotherapy.
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Affiliation(s)
- Nikolaos Spyrou
- 251 Airforce General Hospital, Kanellopoulou 3, 11525, Athens, Greece
| | | | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
- Section of Endocrinology, VA Boston Healthcare System, Boston, MA, USA
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, 11527, Athens, Greece.
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Abstract
INTRODUCTION Adipocytes, which represent a substantial part of the tumor microenvironment in breast cancer, secrete several adipokines that affect tumorigenesis, cancer progression, metastasis, and treatment resistance via multiple signaling pathways. Areas covered: In this review, we focus on the role of leptin, adiponectin, autotaxin, and interleukin-6 in breast cancer initiation, progression, metastasis, and drug response. Furthermore, we investigated adipokines as potential targets of breast cancer-specific drugs. Expert opinion: Adipokines and adipokine receptors are deregulated in breast cancer. Adipokines play various roles in breast cancer initiation, progression, metastasis, and drug response, hence, adipokine signaling could be an effective drug target. Several clinical trials are in progress to test the efficacy of adipokine targeting agents. However, adipokines also affect metabolic homeostasis; hence, the adverse effects of the targeted drug should be investigated and addressed.
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Affiliation(s)
- Yoon Jin Cha
- a Department of Pathology , Yonsei University College of Medicine, Severance Hospital , Seoul , South Korea
| | - Ja Seung Koo
- a Department of Pathology , Yonsei University College of Medicine, Severance Hospital , Seoul , South Korea
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Yan L, Sundaram S. A high-sucrose diet does not enhance spontaneous metastasis of Lewis lung carcinoma in mice. Nutr Res 2018; 58:55-61. [PMID: 30340815 DOI: 10.1016/j.nutres.2018.07.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 07/02/2018] [Accepted: 07/03/2018] [Indexed: 11/29/2022]
Abstract
A high energy intake contributes to obesity, a risk factor for cancer. We previously reported that an excessive intake of dietary fat enhances malignant spread in mice. This study tested the hypothesis that consumption of a diet with an excessive amount of sucrose enhances metastasis. In a spontaneous metastasis model of Lewis lung carcinoma (LLC), male C57BL/6 mice were maintained on an AIN93G, a high-fat, or a high-sucrose diet for the duration of the study. Pulmonary metastases from a primary tumor, established by a subcutaneous injection of LLC cells, were quantified. There were no differences in energy intake among the 3 groups. The percent body fat mass of the high-sucrose group, while higher than that of the AIN93G group, was lower than that of the high-fat group. The number and size of lung metastases were significantly higher in the high-fat group than in the AIN93G group; these measurements in the high-sucrose group remained similar to those in the AIN93G group. Hepatic concentrations of triacylglycerols and plasma concentrations of insulin, proinflammatory cytokines (leptin, plasminogen activator inhibitor-1, and monocyte chemotactic protein-1) and angiogenic factors (vascular endothelial growth factor and tissue inhibitor of metalloproteinase-1) in the high-sucrose group were significantly lower than those in the high-fat group. In conclusion, the high-sucrose diet does not enhance spontaneous metastasis of LLC. This null effect may be due to the inadequate production of tumorigenic proinflammatory cytokines and angiogenic factors by the high-sucrose diet compared to the high-fat diet.
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Affiliation(s)
- Lin Yan
- U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202.
| | - Sneha Sundaram
- U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202.
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Stone TW, McPherson M, Gail Darlington L. Obesity and Cancer: Existing and New Hypotheses for a Causal Connection. EBioMedicine 2018; 30:14-28. [PMID: 29526577 PMCID: PMC5952217 DOI: 10.1016/j.ebiom.2018.02.022] [Citation(s) in RCA: 162] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 02/12/2018] [Accepted: 02/23/2018] [Indexed: 02/07/2023] Open
Abstract
Existing explanations of obesity-associated cancer emphasise direct mutagenic effects of dietary components or hormonal imbalance. Some of these hypotheses are reviewed briefly, but recent evidence suggests a major role for chronic inflammation in cancer risk, possibly involving dietary content. These ideas include the inflammation-induced activation of the kynurenine pathway and its role in feeding and metabolism by activation of the aryl hydrocarbon receptor (AHR) and by modulating synaptic transmission in the brain. Evidence for a role of the kynurenine pathway in carcinogenesis then provides a potentially major link between obesity and cancer. A second new hypothesis is based on evidence that serine proteases can deplete cells of the tumour suppressors Deleted in Colorectal Cancer (DCC) and neogenin. These enzymes include mammalian chymotryptic proteases released by pro-inflammatory neutrophils and macrophages. Blood levels of chymotrypsin itself increase in parallel with food intake. The mechanistically similar bacterial enzyme subtilisin is widespread in the environment, animal probiotics, meat processing and cleaning products. Simple public health schemes in these areas, with selective serine protease inhibitors and AHR antagonists and could prevent a range of intestinal and other cancers.
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Affiliation(s)
- Trevor W Stone
- The Kennedy Institute, University of Oxford, Oxford OX3 7FY, UK; Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
| | - Megan McPherson
- School of Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
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Sundaram S, Yan L. Dietary energy restriction reduces high-fat diet-enhanced metastasis of Lewis lung carcinoma in mice. Oncotarget 2018; 7:65669-65675. [PMID: 27582541 PMCID: PMC5323183 DOI: 10.18632/oncotarget.11598] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 08/11/2016] [Indexed: 01/29/2023] Open
Abstract
The objective of this study was to determine whether a reduction in energy intake ameliorated the high-fat diet-enhanced spontaneous metastasis of Lewis lung carcinoma in mice. Male C57BL/6 mice were fed the AIN93G diet, a high-fat diet or a high-fat diet with a 5% restriction of the intake. Energy restriction reduced body adiposity and body weight, but maintained growth similar to mice fed the AIN93G diet. The high-fat diet significantly increased the number and size (cross-sectional area and volume) of metastases formed in lungs. Restricted feeding reduced the number of metastases by 23%, metastatic cross-sectional area by 32% and volume by 45% compared to the high-fat diet. The high-fat diet elevated plasma concentrations of proinflammatory cytokines (monocyte chemotactic protein-1, plasminogen activator inhibitor-1, leptin), angiogenic factors (vascular endothelial growth factor, tissue inhibitor of metalloproteinase-1) and insulin. Restricted feeding significantly reduced the high-fat diet-induced elevations in plasma concentrations of proinflammatory cytokines, angiogenic factors and insulin. These results demonstrated that a reduction in diet intake by 5% reduced high-fat diet-enhanced metastasis, which may be associated with the mitigation of adiposity and down-regulation of cancer-promoting proinflammatory cytokines and angiogenic factors.
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Affiliation(s)
- Sneha Sundaram
- U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202, USA
| | - Lin Yan
- U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202, USA
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Harbuzariu A, Rampoldi A, Daley-Brown DS, Candelaria P, Harmon TL, Lipsey CC, Beech DJ, Quarshie A, Ilies GO, Gonzalez-Perez RR. Leptin-Notch signaling axis is involved in pancreatic cancer progression. Oncotarget 2018; 8:7740-7752. [PMID: 27999190 PMCID: PMC5352357 DOI: 10.18632/oncotarget.13946] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 12/07/2016] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer (PC) shows a high death rate. PC incidence and prognosis are affected by obesity, a pandemic characterized by high levels of leptin. Notch is upregulated by leptin in breast cancer. Thus, leptin and Notch crosstalk could influence PC progression. Here we investigated in PC cell lines (BxPC-3, MiaPaCa-2, Panc-1, AsPC-1), derived tumorspheres and xenografts whether a functional leptin-Notch axis affects PC progression and expansion of pancreatic cancer stem cells (PCSC). PC cells and tumorspheres were treated with leptin and inhibitors of Notch (gamma-secretase inhibitor, DAPT) and leptin (iron oxide nanoparticle-leptin peptide receptor antagonist 2, IONP-LPrA2). Leptin treatment increased cell cycle progression and proliferation, and the expression of Notch receptors, ligands and targeted molecules (Notch1-4, DLL4, JAG1, Survivin and Hey2), PCSC markers (CD24/CD44/ESA, ALDH, CD133, Oct-4), ABCB1 protein, as well as tumorsphere formation. Leptin-induced effects on PC and tumorspheres were decreased by IONP-LPrA2 and DAPT. PC cells secreted leptin and expressed the leptin receptor, OB-R, which indicates a leptin autocrine/paracrine signaling loop could also affect tumor progression. IONP-LPrA2 treatment delayed the onset of MiaPaCa-2 xenografts, and decreased tumor growth and the expression of proliferation and PCSC markers. Present data suggest that leptin-Notch axis is involved in PC. PC has no targeted therapy and is mainly treated with chemotherapy, whose efficiency could be decreased by leptin and Notch activities. Thus, the leptin-Notch axis could be a novel therapeutic target, particularly for obese PC patients.
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Affiliation(s)
- Adriana Harbuzariu
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA
| | - Antonio Rampoldi
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA
| | - Danielle S Daley-Brown
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA
| | - Pierre Candelaria
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA
| | - Tia L Harmon
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA
| | - Crystal C Lipsey
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA
| | - Derrick J Beech
- Department of Surgery, Morehouse School of Medicine, Atlanta, GA, 30310 USA
| | - Alexander Quarshie
- Biomedical Informatics Program and Master of Science in Clinical Research Program, Clinical Research Center, Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - Gabriela Oprea Ilies
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Grady Memorial Hospital, Atlanta, GA, 30303 USA
| | - Ruben R Gonzalez-Perez
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA
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Choi J, Cha YJ, Koo JS. Adipocyte biology in breast cancer: From silent bystander to active facilitator. Prog Lipid Res 2018; 69:11-20. [DOI: 10.1016/j.plipres.2017.11.002] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 11/20/2017] [Accepted: 11/20/2017] [Indexed: 12/12/2022]
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Yan L, Sundaram S. Monocyte chemotactic protein-1 deficiency reduces spontaneous metastasis of Lewis lung carcinoma in mice fed a high-fat diet. Oncotarget 2017; 7:24792-9. [PMID: 27028862 PMCID: PMC5029742 DOI: 10.18632/oncotarget.8364] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 02/28/2016] [Indexed: 01/28/2023] Open
Abstract
Adipose-produced pro-inflammatory cytokines contribute to obesity and cancer. This 2×2 experiment was designed to investigate effects of monocyte chemotactic protein-1 (MCP-1) deficiency on pulmonary metastasis of Lewis lung carcinoma (LLC) in MCP-1 deficient and wild-type mice fed a modified AIN93G diet containing 16% and 45% of energy from corn oil, respectively. The high-fat diet significantly increased the number and size (cross-sectional area and volume) of lung metastases compared to the AIN93G control diet. Deficiency in MCP-1 reduced lung metastases by 37% in high-fat diet-fed mice; it reduced metastatic cross-sectional area by 46% and volume by 69% compared to wild-type mice. Adipose and plasma concentrations of MCP-1 were significantly higher in high-fat diet-fed wild-type mice than in their AIN93G-fed counterparts; they were not detectable in MCP-1 deficient mice regardless of diet. Plasma concentrations of plasminogen activator inhibitor-1, tumor necrosis factor-α, vascular endothelial growth factor and tissue inhibitor of metalloproteinase-1 were significantly higher in MCP-1 deficient mice compared to wild-type mice. We conclude that adipose-produced MCP-1 contributes to high-fat diet-enhanced metastasis. While MCP-1 deficiency reduces metastasis, the elevation of pro-inflammatory cytokines and angiogenic factors in the absence of MCP-1 may support the metastatic development and growth of LLC in MCP-1 deficient mice.
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Affiliation(s)
- Lin Yan
- U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202, U.S.A
| | - Sneha Sundaram
- U.S. Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202, U.S.A
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Liu Y, Choi DS, Sheng J, Ensor JE, Liang DH, Rodriguez-Aguayo C, Polley A, Benz S, Elemento O, Verma A, Cong Y, Wong H, Qian W, Li Z, Granados-Principal S, Lopez-Berestein G, Landis MD, Rosato RR, Dave B, Wong S, Marchetti D, Sood AK, Chang JC. HN1L Promotes Triple-Negative Breast Cancer Stem Cells through LEPR-STAT3 Pathway. Stem Cell Reports 2017; 10:212-227. [PMID: 29249663 PMCID: PMC5768915 DOI: 10.1016/j.stemcr.2017.11.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 11/13/2017] [Accepted: 11/14/2017] [Indexed: 02/08/2023] Open
Abstract
Here, we show that HEMATOLOGICAL AND NEUROLOGICAL EXPRESSED 1-LIKE (HN1L) is a targetable breast cancer stem cell (BCSC) gene that is altered in 25% of whole breast cancer and significantly correlated with shorter overall or relapse-free survival in triple-negative breast cancer (TNBC) patients. HN1L silencing reduced the population of BCSCs, inhibited tumor initiation, resensitized chemoresistant tumors to docetaxel, and hindered cancer progression in multiple TNBC cell line-derived xenografts. Additionally, gene signatures associated with HN1L correlated with shorter disease-free survival of TNBC patients. We defined HN1L as a BCSC transcription regulator for genes involved in the LEPR-STAT3 signaling axis as HN1L binds to a putative consensus upstream sequence of STAT3, LEPTIN RECEPTOR, and MIR-150. Our data reveal that BCSCs in TNBC depend on the transcription regulator HN1L for the sustained activation of the LEPR-STAT3 pathway, which makes it a potentially important target for both prognosis and BCSC therapy.
HN1L expression is correlated with shorter survival of TNBC patients HN1L regulates BCSCs by promoting the STAT3 signaling pathway HN1L: novel transcription regulator of LEPR and miR-150, upstream regulators of STAT3 HN1L-regulated gene signatures can predict clinical outcomes in TNBC patients
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Affiliation(s)
- Yi Liu
- Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main Street, Floor 24, Houston, TX 77030, USA
| | - Dong Soon Choi
- Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main Street, Floor 24, Houston, TX 77030, USA
| | - Jianting Sheng
- Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Joe E Ensor
- Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main Street, Floor 24, Houston, TX 77030, USA
| | - Diana Hwang Liang
- Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Cristian Rodriguez-Aguayo
- Center for RNA Interference and Non-Coding RNA, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | | | - Steve Benz
- NantOmics, LLC, Santa Cruz, CA 95060, USA
| | - Olivier Elemento
- Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USA
| | - Akanksha Verma
- Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USA
| | - Yang Cong
- Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Helen Wong
- Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main Street, Floor 24, Houston, TX 77030, USA
| | - Wei Qian
- Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main Street, Floor 24, Houston, TX 77030, USA
| | - Zheng Li
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Sergio Granados-Principal
- Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main Street, Floor 24, Houston, TX 77030, USA
| | - Gabriel Lopez-Berestein
- Center for RNA Interference and Non-Coding RNA, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA; Department of Experimental Therapeutics, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Melissa D Landis
- Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main Street, Floor 24, Houston, TX 77030, USA
| | - Roberto R Rosato
- Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main Street, Floor 24, Houston, TX 77030, USA
| | - Bhuvanesh Dave
- Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main Street, Floor 24, Houston, TX 77030, USA
| | - Stephen Wong
- Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Dario Marchetti
- Biomarker Research Program, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Anil K Sood
- Center for RNA Interference and Non-Coding RNA, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA; Department of Experimental Therapeutics, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA; Department of Gynecologic Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Jenny C Chang
- Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main Street, Floor 24, Houston, TX 77030, USA.
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Maryam R, Faegheh S, Majid AS, Kazem NK. Effect of quercetin on secretion and gene expression of leptin in breast cancer. J TRADIT CHIN MED 2017. [DOI: 10.1016/s0254-6272(17)30067-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Mishra AK, Parish CR, Wong ML, Licinio J, Blackburn AC. Leptin signals via TGFB1 to promote metastatic potential and stemness in breast cancer. PLoS One 2017; 12:e0178454. [PMID: 28542577 PMCID: PMC5444832 DOI: 10.1371/journal.pone.0178454] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 05/12/2017] [Indexed: 01/05/2023] Open
Abstract
Epidemiological studies have shown obesity to be linked with poorer outcomes in breast cancer patients. The molecular mechanisms responsible for the increased risk of invasive/metastatic disease with obesity are complex, but may include elevated levels of adipokines such as leptin. Using physiological levels of leptin found in obesity in a novel chronic in vitro treatment model (≤200 ng/ml for 14 days), we confirmed the occurrence of leptin-mediated changes in growth, apoptosis and metastatic behavior, and gene expression changes representing epithelial-to-mesenchymal transition (EMT) and a cancer stem cell (CSC) like phenotype in breast epithelial and cancer cell lines (MCF10A, MCF10AT1, MCF7 and MDA-MB-231). Further, we have discovered that these effects were accompanied by increased expression of TGFB1, and could be significantly reduced by co-treatment with neutralizing antibody against TGFB1, indicating that the induction of these characteristics was mediated via TGFB1. Occurring in both MCF7 and MCF10AT1 cells, it suggests these actions of leptin to be independent of estrogen receptor status. By linking leptin signalling to the established TGFB1 pathway of metastasis / EMT, this study gives a direct mechanism by which leptin can contribute to the poorer outcomes of obese cancer patients. Inhibitors of TGFB1 are in currently in phase III clinical trials in other malignancies, thus identifying the connection between leptin and TGFB1 will open new therapeutic opportunities for improving outcomes for obese breast cancer patients.
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Affiliation(s)
- Ameet K. Mishra
- ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT Australia
| | - Christopher R. Parish
- ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT Australia
| | - Ma-Li Wong
- Mind and Brain Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
- School of Medicine, Flinders University, Bedford Park, Adelaide, SA, Australia
| | - Julio Licinio
- Mind and Brain Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
- School of Medicine, Flinders University, Bedford Park, Adelaide, SA, Australia
| | - Anneke C. Blackburn
- ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT Australia
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Candelaria PV, Rampoldi A, Harbuzariu A, Gonzalez-Perez RR. Leptin signaling and cancer chemoresistance: Perspectives. World J Clin Oncol 2017; 8:106-119. [PMID: 28439492 PMCID: PMC5385432 DOI: 10.5306/wjco.v8.i2.106] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 12/20/2016] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
Obesity is a major health problem and currently is endemic around the world. Obesity is a risk factor for several different types of cancer, significantly promoting cancer incidence, progression, poor prognosis and resistance to anti-cancer therapies. The study of this resistance is critical as development of chemoresistance is a serious drawback for the successful and effective drug-based treatments of cancer. There is increasing evidence that augmented adiposity can impact on chemotherapeutic treatment of cancer and the development of resistance to these treatments, particularly through one of its signature mediators, the adipokine leptin. Leptin is a pro-inflammatory, pro-angiogenic and pro-tumorigenic adipokine that has been implicated in many cancers promoting processes such as angiogenesis, metastasis, tumorigenesis and survival/resistance to apoptosis. Several possible mechanisms that could potentially be developed by cancer cells to elicit drug resistance have been suggested in the literature. Here, we summarize and discuss the current state of the literature on the role of obesity and leptin on chemoresistance, particularly as it relates to breast and pancreatic cancers. We focus on the role of leptin and its significance in possibly driving these proposed chemoresistance mechanisms, and examine its effects on cancer cell survival signals and expansion of the cancer stem cell sub-populations.
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Hosney M, Sabet S, El-Shinawi M, Gaafar KM, Mohamed MM. Leptin is overexpressed in the tumor microenvironment of obese patients with estrogen receptor positive breast cancer. Exp Ther Med 2017; 13:2235-2246. [PMID: 28565832 PMCID: PMC5443182 DOI: 10.3892/etm.2017.4291] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 01/26/2017] [Indexed: 12/11/2022] Open
Abstract
The present study aimed to investigate the potential role of leptin in the progression of breast cancer and the associated cell proliferation signalling pathway(s). A total of 44 female patients diagnosed with breast cancer and 24 healthy donors from Ain Shams University Hospitals (Cairo, Egypt) were enrolled in the present study. The present study assessed leptin expression in breast cancer tissues at the gene and protein level using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry. The results demonstrate that the expression of leptin was significantly higher in tissue of breast cancer samples from obese patients than overweight and control samples (P<0.001). ELISA results indicated a significant increase (P<0.001) of leptin expression in obese patients. To investigate whether there is any difference in leptin expression between the peripheral and tumor microenvironment blood of patients with breast cancer, the concentration of leptin was assessed in plasma from both using ELISA assays. The results demonstrated a statistically significant increase in the level of leptin in plasma samples from the tumor microenvironment of obese patients with estrogen receptor positive (ER+) breast cancer, compared with peripheral plasma samples. Furthermore, the leptin gene was overexpressed in obese ER+ breast cancer tissue. RT-qPCR was also performed to assess the expression of genes involved in proliferation pathways including leptin receptor (LEPR), aromatase, mitogen activated protein kinase (MAPK) and signal transducer and activator of transcription-3 (STAT3). A positive association between leptin expression, LEPR, aromatase, MAPK and STAT3 was detected in tissue samples of patients with breast cancer. The current study concluded that leptin may enhance breast cancer progression by inducing the expression of JAK/STAT3, ERK1/2 and estrogen pathways in obese patients breast cancer.
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Affiliation(s)
- Mohamed Hosney
- Department of Zoology, Cancer Biology Research Laboratory (CBRL), Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Salwa Sabet
- Department of Zoology, Cancer Biology Research Laboratory (CBRL), Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Mohamed El-Shinawi
- Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Khadiga M Gaafar
- Department of Zoology, Cancer Biology Research Laboratory (CBRL), Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Mona M Mohamed
- Department of Zoology, Cancer Biology Research Laboratory (CBRL), Faculty of Science, Cairo University, Giza 12613, Egypt
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Harmon T, Harbuzariu A, Lanier V, Lipsey CC, Kirlin W, Yang L, Gonzalez-Perez RR. Nanoparticle-linked antagonist for leptin signaling inhibition in breast cancer. World J Clin Oncol 2017; 8:54-66. [PMID: 28246585 PMCID: PMC5309714 DOI: 10.5306/wjco.v8.i1.54] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 12/06/2016] [Accepted: 12/27/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To develop a leptin peptide receptor antagonist linked to nanoparticles and determine its effect on viability of breast cancer cells. METHODS The leptin antagonist, LPrA2, was coupled via EDAC [1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide] to iron oxide nanoparticles (IONP-LPrA2) to increase its efficacy. IONP-LPrA2 conjugation was confirmed by Western blot and nanoparticle tracking analysis. Human triple negative breast cancer (TNBC) MDA-MB-231, HCC1806 and estrogen receptor positive (ER+) MCF-7 cells were analyzed for the expression of the leptin receptor, Ob-R. The effects of leptin and antagonist on levels of leptin-induced STAT3 phosphorylation and cyclin D1, cell cycle progression, cell proliferation, and tumorsphere formation in breast cancer cells were determined. Doses of the chemotherapeutics [cisplatin (Cis), cyclophosphamide (CTX), doxorubicin (Dox) and paclitaxel (PTX)] to effectively reduce cell viability were calculated. The effects of combination treatments of IONP-LPrA2 and chemotherapeutics on cell viability were determined. RESULTS Western blot analysis of coupling reaction products identified IONP-LPrA2 at approximately 100 kD. IONP-LPrA2 significantly decreased leptin-induced pSTAT3 levels in HCC1806 cells and drastically decreased cyclin D1 levels in all cell lines. IONP-LPrA2 significantly reduced leptin-induced S phase progression and cell proliferation in all breast cancer cell lines and the formation of tumorspheres in MDA-MB-231 cells. Also, IONP-LPrA2 showed an additive effect on the reduction of breast cancer cell survival with chemotherapeutics. Cis plus IONP-LPrA2 produced a significant reduction in the survival of MDA-MB-231 and HCC1806 cells. CTX plus IONP-LPrA2 caused a significant decrease in the survival of MDA-MB-231 cells. Dox plus IONP-LPrA2 caused a marked reduction in the survival of HCC1806 cells. Although, PTX plus IONP-LPrA2 did not have a major effect on the viability of the breast cancer cells when compared to PTX alone. CONCLUSION Present data indicate that IONP-LPrA2 may be a useful adjuvant for chemotherapeutic treatment of breast cancer, particularly for TNBC which lacks targeted therapeutic options.
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