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Wei L, Liu C, Wang S, Zhang H, Ruan G, Xie H, Shi H. Sex differences in the obesity paradox of body compositions in non-small cell lung cancer. Nutrition 2025; 132:112690. [PMID: 39938385 DOI: 10.1016/j.nut.2025.112690] [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: 07/20/2024] [Revised: 01/04/2025] [Accepted: 01/12/2025] [Indexed: 02/14/2025]
Abstract
OBJECTIVES This study investigated the correlation between body mass index (BMI), bioelectrical impedance analysis (BIA)-derived specific body compositions, and the obesity paradox, with a focus on sex differences in non-smallcell lung cancer (NSCLC). METHODS This study is a multicenter prospective cohort. Association with survival was determined using Cox proportional hazard regression analysis. The mediating effect of systemic inflammation on the association between body composition and survival rate was determined using mediation analysis. RESULTS Fat mass had a strong positive correlation with BMI, but a weak positive correlation with other BIA-derived body compositions. Obese, overweight, and normal weight patients had significantly longer median survival than patients with BMI <18.5 ([23.2 versus 18.5 versus 17.5 versus 15.8] months, P < 0.001). Increased BMI and BIA-derived body composition indicators were associated with decreased all-cause mortality. Multivariable-adjusted analysis demonstrated that BMI, fat mass (FM), fat-free mass, muscle mass, bone mass, protein mass, total body water, extracellular water, and intracellular water were independent protective factors affecting the prognosis of patients with NSCLC. A difference in body compositions performance in the prognostic assessment of the different sexes was observed. Fat-related body compositions exhibited a significant obesity paradox in females compared to in males. Systemic inflammation played a crucial role in the relationship between body compositions and disease prognosis, with a mediating effect on body fat in males (31%) and females (19.7%). CONCLUSIONS The obesity paradox exists among patients with NSCLC and is not influenced by specific body compositions. In addition, this paradox is notably more common in female patients. TRIAL REGISTRATION Registration number: ChiCTR1800020329.
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Affiliation(s)
- Lishuang Wei
- Department of Geriatric respiratory medicine, the First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
| | - Chongjie Liu
- Department of Gastrointestinal and Gland Surgery, the First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
| | - Shuyao Wang
- Department of Gastrointestinal and Gland Surgery, the First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
| | - Heyang Zhang
- Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Guotian Ruan
- Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Hailun Xie
- Department of Gastrointestinal and Gland Surgery, the First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
| | - Hanping Shi
- Department of Gastrointestinal and Gland Surgery, the First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China.
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2
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Iversen JN, Tai YK, Yap JLY, Abdul Razar RBB, Sukumar VK, Wu KY, Ooi MGM, Kukumberg M, Adam S, Rufaihah AJ, Franco-Obregón A. One Month of Brief Weekly Magnetic Field Therapy Enhances the Anticancer Potential of Female Human Sera: Randomized Double-Blind Pilot Study. Cells 2025; 14:331. [PMID: 40072060 PMCID: PMC11899448 DOI: 10.3390/cells14050331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/16/2025] [Accepted: 02/21/2025] [Indexed: 03/15/2025] Open
Abstract
Preclinical studies have shown that the blood from female mice exposed weekly to magnetic fields inhibited breast cancer growth. This double-blind randomized controlled trial investigated whether analogous magnetic therapy could produce similar anticancer sera from human subjects. Twenty-six healthy adult females (ages 30-45) were assigned to either a magnetic therapy group, receiving twice weekly 1 mT magnetic exposures (10 min/session) for 4 weeks, or a control group, who underwent identical sham exposure. Blood sera were evaluated for their capacity to modulate breast cancer-related cellular responses and epithelial-mesenchymal transition. The sera from the magnetic therapy group subjects exhibited significant anticancer effects that were strongest one month after the last magnetic exposure, whereas the sera from unexposed females or unexposed or exposed males showed no effect. Female sera from the magnetic therapy group (n = 12) reduced breast cancer cell proliferation (16.1%), migration (11.8%) and invasion (28.2%) and reduced the levels of key EMT markers relative to the control sera (n = 14). Magnetic therapy modulated the serum levels of angiogenic and myogenic biomarkers in a manner consistent with improved cancer management. Muscle-targeted magnetic therapy holds the potential to enhance the anticancer properties of human blood via an adaptive process, akin to exercise training.
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Affiliation(s)
- Jan Nikolas Iversen
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (J.N.I.); (J.L.Y.Y.); (R.B.B.A.R.); (V.K.S.); (K.Y.W.); (A.J.R.)
- Institute of Health Technology and Innovation (iHealthtech), National University of Singapore, Singapore 117599, Singapore
- Biolonic Currents Electromagnetic Pulsing Systems Laboratory (BICEPS), National University of Singapore, Singapore 117599, Singapore
| | - Yee Kit Tai
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (J.N.I.); (J.L.Y.Y.); (R.B.B.A.R.); (V.K.S.); (K.Y.W.); (A.J.R.)
- Institute of Health Technology and Innovation (iHealthtech), National University of Singapore, Singapore 117599, Singapore
- Biolonic Currents Electromagnetic Pulsing Systems Laboratory (BICEPS), National University of Singapore, Singapore 117599, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore;
| | - Jasmine Lye Yee Yap
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (J.N.I.); (J.L.Y.Y.); (R.B.B.A.R.); (V.K.S.); (K.Y.W.); (A.J.R.)
- Institute of Health Technology and Innovation (iHealthtech), National University of Singapore, Singapore 117599, Singapore
- Biolonic Currents Electromagnetic Pulsing Systems Laboratory (BICEPS), National University of Singapore, Singapore 117599, Singapore
| | - Rafhanah Banu Binte Abdul Razar
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (J.N.I.); (J.L.Y.Y.); (R.B.B.A.R.); (V.K.S.); (K.Y.W.); (A.J.R.)
- Institute of Health Technology and Innovation (iHealthtech), National University of Singapore, Singapore 117599, Singapore
- Biolonic Currents Electromagnetic Pulsing Systems Laboratory (BICEPS), National University of Singapore, Singapore 117599, Singapore
| | - Viresh Krishnan Sukumar
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (J.N.I.); (J.L.Y.Y.); (R.B.B.A.R.); (V.K.S.); (K.Y.W.); (A.J.R.)
- Institute of Health Technology and Innovation (iHealthtech), National University of Singapore, Singapore 117599, Singapore
- Biolonic Currents Electromagnetic Pulsing Systems Laboratory (BICEPS), National University of Singapore, Singapore 117599, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore;
| | - Kwan Yu Wu
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (J.N.I.); (J.L.Y.Y.); (R.B.B.A.R.); (V.K.S.); (K.Y.W.); (A.J.R.)
- Institute of Health Technology and Innovation (iHealthtech), National University of Singapore, Singapore 117599, Singapore
- Biolonic Currents Electromagnetic Pulsing Systems Laboratory (BICEPS), National University of Singapore, Singapore 117599, Singapore
| | - Melissa Gaik-Ming Ooi
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore;
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
- Department of Haematology-Oncology, National University Cancer Institute, National University Hospital, Singapore 119074, Singapore
| | - Marek Kukumberg
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (M.K.); (S.A.)
| | - Sabrina Adam
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (M.K.); (S.A.)
| | - Abdul Jalil Rufaihah
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (J.N.I.); (J.L.Y.Y.); (R.B.B.A.R.); (V.K.S.); (K.Y.W.); (A.J.R.)
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (M.K.); (S.A.)
- School of Applied Sciences, Temasek Polytechnic, Singapore 529757, Singapore
| | - Alfredo Franco-Obregón
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (J.N.I.); (J.L.Y.Y.); (R.B.B.A.R.); (V.K.S.); (K.Y.W.); (A.J.R.)
- Institute of Health Technology and Innovation (iHealthtech), National University of Singapore, Singapore 117599, Singapore
- Biolonic Currents Electromagnetic Pulsing Systems Laboratory (BICEPS), National University of Singapore, Singapore 117599, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore;
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; (M.K.); (S.A.)
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore
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Solsona-Vilarrasa E, Vousden KH. Obesity, white adipose tissue and cancer. FEBS J 2024. [PMID: 39496581 DOI: 10.1111/febs.17312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 09/27/2024] [Accepted: 10/17/2024] [Indexed: 11/06/2024]
Abstract
White adipose tissue (WAT) is crucial for whole-body energy homeostasis and plays an important role in metabolic and hormonal regulation. While healthy WAT undergoes controlled expansion and contraction to meet the body's requirements, dysfunctional WAT in conditions like obesity is characterized by excessive tissue expansion, alterations in lipid homeostasis, inflammation, hypoxia, and fibrosis. Obesity is strongly associated with an increased risk of numerous cancers, with obesity-induced WAT dysfunction influencing cancer development through various mechanisms involving both systemic and local interactions between adipose tissue and tumors. Unhealthy obese WAT affects circulating levels of free fatty acids and factors like leptin, adiponectin, and insulin, altering systemic lipid metabolism and inducing inflammation that supports tumor growth. Similar mechanisms are observed locally in an adipose-rich tumor microenvironment (TME), where WAT cells can also trigger extracellular matrix remodeling, thereby enhancing the TME's ability to promote tumor growth. Moreover, tumors reciprocally interact with WAT, creating a bidirectional communication that further enhances tumorigenesis. This review focuses on the complex interplay between obesity, WAT dysfunction, and primary tumor growth, highlighting potential targets for therapeutic intervention.
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Gao S, Ding S, Tang Z. A preliminary mechanistic exploration of the effect of leptin on the docetaxel sensitivity of MDA‑MB‑231 triple‑negative breast cancer cells. Mol Clin Oncol 2024; 20:24. [PMID: 38410187 PMCID: PMC10895386 DOI: 10.3892/mco.2024.2722] [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: 10/18/2023] [Accepted: 01/08/2024] [Indexed: 02/28/2024] Open
Abstract
Breast cancer is a common tumor encountered in women, and triple-negative breast cancer (TNBC) has an extremely poor prognosis. The effect of leptin on the docetaxel sensitivity of MDA-MB-231 TNBC cells has not been investigated. The present study aimed to clarify the effect of leptin and M2 tumor-associated macrophages (TAMs) on the chemosensitivity of TNBC cell lines and its possible mechanisms. In the present study, the apoptosis of the MDA-MB-231 cell line was detected at 0, 24, 48 and 72 h using a Cell Counting Kit-8 assay to determine the appropriate concentration of docetaxel as well as the IC50 value. After determining the effect of leptin on TAMs, the conditioned medium with an appropriate concentration of docetaxel was collected to treat the breast cancer cells, and flow cytometry was used to detect the cell cycle distribution and apoptosis in different treatment groups. Interleukin 8 (IL-8) expression was detected using ELISA and western blot assay. The IL-8 antibody was used to neutralize IL-8, and invasion and scratch assays were used to detect changes in invasion and migration of breast cancer cells. Statistical analysis was performed using GraphPad Prism 9.0 and SPSS 22.0. It was revealed that the apoptotic rate of MDA-MB-231 cells in the leptin-treated TAMs group was lower than that in other groups. The expression of IL-8 was notably elevated in the group treated with leptin-activated TAMs compared with that in the other groups. The neutralization of IL-8 resulted in a significant reduction in the invasive migration of MDA-MB-231 cells compared with that in the non-neutralized group.
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Affiliation(s)
- Simeng Gao
- Department of Oncology, The Central Hospital of Yongzhou, Yongzhou, Hunan 425000, P.R. China
| | - Sijuan Ding
- Department of Oncology, The Central Hospital of Yongzhou, Yongzhou, Hunan 425000, P.R. China
| | - Zhaohui Tang
- Department of Oncology, The Central Hospital of Yongzhou, Yongzhou, Hunan 425000, P.R. China
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Bocian-Jastrzębska A, Malczewska-Herman A, Kos-Kudła B. Role of Leptin and Adiponectin in Carcinogenesis. Cancers (Basel) 2023; 15:4250. [PMID: 37686525 PMCID: PMC10486522 DOI: 10.3390/cancers15174250] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/18/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
Hormones produced by adipocytes, leptin and adiponectin, are associated with the process of carcinogenesis. Both of these adipokines have well-proven oncologic potential and can affect many aspects of tumorigenesis, from initiation and primary tumor growth to metastatic progression. Involvement in the formation of cancer includes interactions with the tumor microenvironment and its components, such as tumor-associated macrophages, cancer-associated fibroblasts, extracellular matrix and matrix metalloproteinases. Furthermore, these adipokines participate in the epithelial-mesenchymal transition and connect to angiogenesis, which is critical for cancer invasiveness and cancer cell migration. In addition, an enormous amount of evidence has demonstrated that altered concentrations of these adipocyte-derived hormones and the expression of their receptors in tumors are associated with poor prognosis in various types of cancer. Therefore, leptin and adiponectin dysfunction play a prominent role in cancer and impact tumor invasion and metastasis in different ways. This review clearly and comprehensively summarizes the recent findings and presents the role of leptin and adiponectin in cancer initiation, promotion and progression, focusing on associations with the tumor microenvironment and its components as well as roles in the epithelial-mesenchymal transition and angiogenesis.
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Affiliation(s)
- Agnes Bocian-Jastrzębska
- Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinogy, Medical University of Silesia, 40-514 Katowice, Poland; (A.M.-H.); (B.K.-K.)
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Caruso A, Gelsomino L, Panza S, Accattatis FM, Naimo GD, Barone I, Giordano C, Catalano S, Andò S. Leptin: A Heavyweight Player in Obesity-Related Cancers. Biomolecules 2023; 13:1084. [PMID: 37509120 PMCID: PMC10377641 DOI: 10.3390/biom13071084] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/04/2023] [Accepted: 07/05/2023] [Indexed: 07/30/2023] Open
Abstract
Obesity, defined as the abnormal or excessive expansion of white adipose tissue, has reached pandemic proportions and is recognized as an important health concern since it is a common root for several comorbidities, including malignancies. Indeed, the current knowledge of the white adipose tissue, which shifts its role from an energy storage tissue to an important endocrine and metabolic organ, has opened up new avenues for the discovery of obesity's effects on tumor biology. In this review, we will report the epidemiological studies concerning the strong impact of obesity in several types of cancer and describe the mechanisms underlying the heterotypic signals between cancer cell lines and adipocytes, with particular emphasis on inflammation, the insulin/IGF-1 axis, and adipokines. Among the adipokines, we will further describe the in vitro, in vivo, and clinical data concerning the role of leptin, recognized as one of the most important mediators of obesity-associated cancers. In fact, leptin physiologically regulates energy metabolism, appetite, and reproduction, and several studies have also described the role of leptin in affecting cancer development and progression. Finally, we will summarize the newest pharmacological strategies aimed at mitigating the protumorigenic effects of leptin, underlining their mechanisms of action.
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Affiliation(s)
- Amanda Caruso
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Luca Gelsomino
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
- Centro Sanitario, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Salvatore Panza
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Felice Maria Accattatis
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Giuseppina Daniela Naimo
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Ines Barone
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
- Centro Sanitario, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Cinzia Giordano
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
- Centro Sanitario, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Stefania Catalano
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
- Centro Sanitario, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
- Centro Sanitario, Via P. Bucci, University of Calabria, Arcavacata di Rende (CS), 87036 Cosenza, Italy
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7
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Ayed K, Nabi L, Akrout R, Mrizak H, Gorrab A, Bacha D, Boussen H, Gati A. Obesity and cancer: focus on leptin. Mol Biol Rep 2023:10.1007/s11033-023-08525-y. [PMID: 37227675 DOI: 10.1007/s11033-023-08525-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 05/12/2023] [Indexed: 05/26/2023]
Abstract
Over the past decades, obesity has grown to epidemic proportions worldwide. It has been associated with an increased risk for different types of cancer. In addition, obesity has been associated with a poor prognosis, an increased risk of metastasis and mortality, and resistance to anti-cancer therapies. The pathophysiological mechanisms underlying the obesity-cancer connection have not yet been fully elucidated. However, this connection could result, at least in part, from the action of adipokines, whose levels are increased in obesity. Among these adipokines, evidence suggests leptin's critical role in linking obesity to cancer. In this review, we first summarize the current state of the literature regarding the implication of leptin in tumorigenic processes. Next, we focus on the effects of leptin on the anti-tumor immune response. Then, we discuss the influence of leptin on the efficiency of antineoplastic treatments and the development of tumor resistance. Finally, we highlight the use of leptin as a potential target for the prevention and treatment of cancer.
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Affiliation(s)
- Khouloud Ayed
- Laboratory of Genetics, Immunology, and Human Pathology, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Lamis Nabi
- Laboratory of Genetics, Immunology, and Human Pathology, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Rym Akrout
- Laboratory of Genetics, Immunology, and Human Pathology, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Hela Mrizak
- Laboratory of Genetics, Immunology, and Human Pathology, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Amal Gorrab
- Laboratory of Genetics, Immunology, and Human Pathology, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Dhouha Bacha
- Anatomopathology Department, Mongi Slim Hospital, Tunis, Tunisia
| | - Hamouda Boussen
- Medical Oncology Department, Salah Azaiez Institute, Faculty of Medicine of Tunis, University of Tunis El Manar, Ariana, Tunisia
| | - Asma Gati
- Laboratory of Genetics, Immunology, and Human Pathology, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia.
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8
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Sanhueza S, Simón L, Cifuentes M, Quest AFG. The Adipocyte-Macrophage Relationship in Cancer: A Potential Target for Antioxidant Therapy. Antioxidants (Basel) 2023; 12:126. [PMID: 36670988 PMCID: PMC9855200 DOI: 10.3390/antiox12010126] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/20/2022] [Accepted: 12/22/2022] [Indexed: 01/06/2023] Open
Abstract
Obesity has emerged as a major public health concern with a staggering 39% worldwide prevalence as of 2021. Given the magnitude of the problem and considering its association with chronic low-grade systemic inflammation, it does not come as a surprise that obesity is now considered one of the major risk factors for the development of several chronic diseases, such as diabetes, cardiovascular problems, and cancer. Adipose tissue dysfunction in obesity has taken center stage in understanding how changes in its components, particularly adipocytes and macrophages, participate in such processes. In this review, we will initially focus on how changes in adipose tissue upon excess fat accumulation generate endocrine signals that promote cancer development. Moreover, the tumor microenvironment or stroma, which is also critical in cancer development, contains macrophages and adipocytes, which, in reciprocal paracrine communication with cancer cells, generate relevant signals. We will discuss how paracrine signaling in the tumor microenvironment between cancer cells, macrophages, and adipocytes favors cancer development and progression. Finally, as reactive oxygen species participate in many of these signaling pathways, we will summarize the information available on how antioxidants can limit the effects of endocrine and paracrine signaling due to dysfunctional adipose tissue components in obesity.
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Affiliation(s)
- Sofía Sanhueza
- Cellular Communication Laboratory, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago 8380492, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago 8380492, Chile
- Laboratory of Obesity and Metabolism in Geriatrics and Adults (OMEGA), Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Santiago 7830490, Chile
| | - Layla Simón
- Cellular Communication Laboratory, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago 8380492, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago 8380492, Chile
- Escuela de Nutrición y Dietética, Universidad Finis Terrae, Santiago 7501015, Chile
| | - Mariana Cifuentes
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago 8380492, Chile
- Laboratory of Obesity and Metabolism in Geriatrics and Adults (OMEGA), Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Santiago 7830490, Chile
| | - Andrew F. G. Quest
- Cellular Communication Laboratory, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago 8380492, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago 8380492, Chile
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9
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Hillers-Ziemer LE, Kuziel G, Williams AE, Moore BN, Arendt LM. Breast cancer microenvironment and obesity: challenges for therapy. Cancer Metastasis Rev 2022; 41:627-647. [PMID: 35435599 PMCID: PMC9470689 DOI: 10.1007/s10555-022-10031-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 03/30/2022] [Indexed: 02/07/2023]
Abstract
Women with obesity who develop breast cancer have a worsened prognosis with diminished survival rates and increased rates of metastasis. Obesity is also associated with decreased breast cancer response to endocrine and chemotherapeutic treatments. Studies utilizing multiple in vivo models of obesity as well as human breast tumors have enhanced our understanding of how obesity alters the breast tumor microenvironment. Changes in the complement and function of adipocytes, adipose-derived stromal cells, immune cells, and endothelial cells and remodeling of the extracellular matrix all contribute to the rapid growth of breast tumors in the context of obesity. Interactions of these cells enhance secretion of cytokines and adipokines as well as local levels of estrogen within the breast tumor microenvironment that promote resistance to multiple therapies. In this review, we will discuss our current understanding of the impact of obesity on the breast tumor microenvironment, how obesity-induced changes in cellular interactions promote resistance to breast cancer treatments, and areas for development of treatment interventions for breast cancer patients with obesity.
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Affiliation(s)
- Lauren E Hillers-Ziemer
- Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI, 53706, USA
- Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Genevra Kuziel
- Program in Cancer Biology, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Abbey E Williams
- Comparative Biomedical Sciences Program, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Brittney N Moore
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Lisa M Arendt
- Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI, 53706, USA.
- Program in Cancer Biology, University of Wisconsin-Madison, Madison, WI, 53705, USA.
- Comparative Biomedical Sciences Program, University of Wisconsin-Madison, Madison, WI, 53706, USA.
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, 53706, USA.
- School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Dr. Rm 4354A, Madison, WI, 53706, USA.
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10
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Kratofil RM, Shim HB, Shim R, Lee WY, Labit E, Sinha S, Keenan CM, Surewaard BGJ, Noh JY, Sun Y, Sharkey KA, Mack M, Biernaskie J, Deniset JF, Kubes P. A monocyte-leptin-angiogenesis pathway critical for repair post-infection. Nature 2022; 609:166-173. [PMID: 35948634 DOI: 10.1038/s41586-022-05044-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 06/29/2022] [Indexed: 11/09/2022]
Abstract
During infection, inflammatory monocytes are thought to be key for bacterial eradication, but this is hard to reconcile with the large numbers of neutrophils that are recruited for each monocyte that migrates to the afflicted tissue, and the much more robust microbicidal functions of the neutrophils. However, unlike neutrophils, monocytes have the capacity to convert to situationally specific macrophages that may have critical functions beyond infection control1,2. Here, using a foreign body coated with Staphylococcus aureus and imaging over time from cutaneous infection to wound resolution, we show that monocytes and neutrophils are recruited in similar numbers with low-dose infection but not with high-dose infection, and form a localization pattern in which monocytes surround the infection site, whereas neutrophils infiltrate it. Monocytes did not contribute to bacterial clearance but converted to macrophages that persisted for weeks after infection, regulating hypodermal adipocyte expansion and production of the adipokine hormone leptin. In infected monocyte-deficient mice there was increased persistent hypodermis thickening and an elevated leptin level, which drove overgrowth of dysfunctional blood vasculature and delayed healing, with a thickened scar. Ghrelin, which opposes leptin function3, was produced locally by monocytes, and reduced vascular overgrowth and improved healing post-infection. In sum, we find that monocytes function as a cellular rheostat by regulating leptin levels and revascularization during wound repair.
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Affiliation(s)
- Rachel M Kratofil
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Hanjoo B Shim
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Raymond Shim
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Woo Yong Lee
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Elodie Labit
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.,Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Sarthak Sinha
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.,Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Catherine M Keenan
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Bas G J Surewaard
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Ji Yeon Noh
- Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Yuxiang Sun
- Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Keith A Sharkey
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Matthias Mack
- Department of Internal Medicine II - Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Jeff Biernaskie
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.,Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Justin F Deniset
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. .,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. .,Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. .,Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
| | - Paul Kubes
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. .,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
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11
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Oshi M, Roy AM, Gandhi S, Tokumaru Y, Yan L, Yamada A, Endo I, Takabe K. The clinical relevance of unfolded protein response signaling in breast cancer. Am J Cancer Res 2022; 12:2627-2640. [PMID: 35812054 PMCID: PMC9251678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 05/19/2022] [Indexed: 06/15/2023] Open
Abstract
Protein homeostasis regulated by the Endoplasmic Reticulum (ER) is a recognized process involved in cancer progression. ER stress activates the Unfolded Protein Response (UPR) and has been implicated in a variety of cancers. Given the role of the UPR activation in carcinogenesis, we hypothesized that UPR activation could be associated with pathological progression, higher clinical stage, and worse survival in breast cancer. A total of 4,416 breast cancer patients from multiple independent cohorts were analyzed. We defined the UPR pathway score by the degree of enrichment by Gene Set Variant Analysis and median was used to divide high vs. low score groups in each cohort. High UPR breast cancer significantly enriched not only cell proliferation-related but also other pro-cancerous gene sets consistently in both METABIC and GSE96058 cohort. Majority of UPR pathway score high cells in the bulk tumor were tumor cells compared to other cells, including stromal, T-, B-, and myeloid-cells (P<0.001). UPR score was significantly associated with advanced stage, high grade, and triple negative breast cancer (TNBC) (all P<0.001). High UPR breast cancer was associated with worse patient survival in both cohorts (all P<0.001). Among breast cancer subtype, ER-positive/HER2-negative breast cancer with high UPR was significantly associated with worse survival, but neither HER-positive nor TNBC. High UPR ER-positive/HER2-negative breast cancer was infiltrated with high level of Th1 and Th2 cells, M1 macrophage, and plasma cells. On the other hand, they were significantly infiltrated with high level of several types of stromal cells in tumor microenvironment (all P<0.001). Finally, high UPR metastatic breast cancer was also associated with worse patient survival (P=0.041). UPR signaling is associated with cancer aggressiveness, and worse survival, especially ER-positive/HER2-negative breast cancer subtype.
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Affiliation(s)
- Masanori Oshi
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Arya Mariam Roy
- Department of Medical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Shipra Gandhi
- Department of Medical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Yoshihisa Tokumaru
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Akimitsu Yamada
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Kazuaki Takabe
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, New York 14263, USA
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of MedicineFukushima 960-1295, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
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12
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Li Y, Li C, Wu G, Yang W, Wang X, Duan L, Niu L, Chen J, Zhang Y, Zhou W, Liu J, Hong L, Fan D. The obesity paradox in patients with colorectal cancer: a systematic review and meta-analysis. Nutr Rev 2022; 80:1755-1768. [PMID: 35182150 DOI: 10.1093/nutrit/nuac005] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
CONTEXT Obesity is widely regarded as an established risk factor for colorectal cancer (CRC). However, recent studies have shown that lower mortality and better cancer-specific survival were observed in CRC patients with elevated body mass index (BMI), an example of the obesity paradox, which is the inverse correlation between obesity and mortality in some populations. OBJECTIVE The aim of this systematic review and meta-analysis was to investigate the association between BMI and CRC outcomes. DATA SOURCES PubMed, Web of Science, MEDLINE, the Cochrane Library, and Embase databases were searched for relevant articles published from inception to December 31, 2020. STUDY SELECTION Studies comparing the prognosis of CRC patients with obesity or overweight with that of normal-weight CRC patients were eligible. DATA EXTRACTION Data were extracted by 2 reviewers independently; differences were resolved by a third reviewer. BMI was classified according to WHO categories. DATA ANALYSIS To assess the prognostic effects of different BMI categories in CRC patients, hazard ratios and 95%CIs of overall survival, disease-free survival, and cancer-specific survival were extracted from included articles. RESULTS Sixteen studies (55 391 patients in total) were included. Higher BMI was significantly associated with more favorable CRC outcomes. Compared with normal-weight patients, underweight patients had worse overall survival (HR = 1.26; 95%CI, 1.15-1.37) and disease-free survival (HR = 1.19; 95%CI, 1.11-1.27, while patients with overweight had better overall survival (HR = 0.92; 95%CI, 0.86-0.99), disease-free survival (HR = 0.96; 95%CI, 0.93-1.00), and cancer-specific survival (HR = 0.86; 95%CI, 0.76-0.98). Patients with morbid obesity had worse overall survival (HR = 1.12; 95%CI, 1.02-1.22) and disease-free survival (HR = 1.15; 95%CI, 1.07-1.24) than normal-weight patients. There was no significant difference in cancer-specific survival between patients with obesity (HR = 0.94; 95%CI, 0.76-1.16) and patients with normal weight, nor between patients with underweight and patients with normal weight (HR = 1.14; 95%CI, 0.82-1.58). CONCLUSIONS CRC patients with a higher BMI appear to have reduced mortality compared with normal-weight CRC patients, even though higher BMI/obesity is an established determinant for the development of CRC. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration no. CRD42020202320.
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Affiliation(s)
- Yiding Li
- the State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Chenhan Li
- College of Life Science, Northwest University, Xi'an, Shaanxi Province, China
| | - Guiling Wu
- Key Laboratory of Ministry of Education, School of Aerospace Medicine, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Wanli Yang
- the State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases , Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Xiaoqian Wang
- the State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province , China
| | - Lili Duan
- the State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an , Shaanxi Province, China
| | - Liaoran Niu
- the State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University , Xi'an, Shaanxi Province, China
| | - Junfeng Chen
- the State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Yujie Zhang
- the State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Wei Zhou
- the State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Jinqiang Liu
- the State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Liu Hong
- the State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases , Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Daiming Fan
- the State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province, China
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13
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Zastosowanie leptyny rekombinowanej w leczeniu różnych typów lipodystrofii Treatment options with recombinant leptin in various types of lipodystrophy. POSTEP HIG MED DOSW 2022. [DOI: 10.2478/ahem-2021-0016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstrakt
Lipodystrofie to grupa chorób objawiających się zanikiem i/lub nieprawidłowym rozmieszczeniem tkanki tłuszczowej w organizmie człowieka. W związku z tym, że tkanka tłuszczowa jest narządem hormonalnie czynnym, jej niedobór doprowadza do powstania wielu zaburzeń metabolicznych i hormonalnych, wynikających w dużej mierze ze zmniejszonego wytwarzania leptyny, jednego z ważniejszych hormonów wydzielanych przez tkankę tłuszczową. Leptyna jest cytokiną, która po połączeniu z receptorem leptynowym uczestniczy przede wszystkim w regulacji ośrodka głodu, ale także wywołuje angiogenezę i stymuluje układ odpornościowy, przez stymulację wysp beta trzustki reguluje glikemię, działa protekcyjnie na układ kostny, wpływa na płodność, cykl menstruacyjny i ciążę, hamuje syntezę triglicerydów w wątrobie i tkance tłuszczowej oraz stymuluje lipolizę. W związku z tym uważa się, że to właśnie niedobór leptyny jest odpowiedzialny za zaburzenia metaboliczne powstałe w przebiegu lipodystrofii. Badania kliniczne wskazują na możliwość wykorzystania rekombinowanej leptyny – metreleptyny w celu uzupełnienia niedoboru hormonu. U pacjentów z różnymi typami lipodystrofii po zastosowaniu metreleptyny zaobserwowano normalizację poziomu glukozy, triglicerydów i cholesterolu frakcji HDL. Ponadto pacjenci sygnalizowali zmniejszenie apetytu i spadek BMI przy jednoczesnym braku istotnych działań niepożądanych leku. W związku z tym dopuszczono wykorzystanie metreleptyny w Stanach Zjednoczonych i Europie do leczenia chorych z niektórymi typami lipodystrofii. Natomiast zastosowanie leku w innych schorzeniach objawiających się zaburzeniami metabolicznymi jest w fazie badań klinicznych.
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Roškar L, Roškar I, Rižner TL, Smrkolj Š. Diagnostic and Therapeutic Values of Angiogenic Factors in Endometrial Cancer. Biomolecules 2021; 12:7. [PMID: 35053155 PMCID: PMC8773847 DOI: 10.3390/biom12010007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/16/2021] [Accepted: 12/18/2021] [Indexed: 12/12/2022] Open
Abstract
Endometrial cancer (EC) is the most frequent gynecological malignancy in developed countries and requires a relatively invasive diagnostic evaluation and operative therapy as the primary therapeutic approach. Angiogenesis is one of the main processes needed for cancer growth and spread. The production of angiogenic factors (AFs) appears early in the process of carcinogenesis. The detection of AFs in plasma and tissue and a better understanding of the angiogenic properties of EC may contribute not only to earlier but also more specific diagnosis and consequently tailored and individual therapeutic approaches. AFs and their receptors also have high potential as binding sites for targeted cancer therapy. In this review, we discuss angiogenesis in EC and the characteristics of the AFs that most contribute to angiogenesis in EC. We also highlight therapeutic strategies that target angiogenesis as potential EC therapy.
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Affiliation(s)
- Luka Roškar
- Department of Gynaecology and Obstetrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia;
| | - Irena Roškar
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; (I.R.); (T.L.R.)
| | - Tea Lanišnik Rižner
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; (I.R.); (T.L.R.)
| | - Špela Smrkolj
- Department of Gynaecology and Obstetrics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia;
- Division of Gynaecology and Obstetrics, University Medical Centre, 1000 Ljubljana, Slovenia
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15
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Leptin Protein Expression and Promoter Methylation in Ovarian Cancer: A Strong Prognostic Value with Theranostic Promises. Int J Mol Sci 2021; 22:ijms222312872. [PMID: 34884678 PMCID: PMC8657586 DOI: 10.3390/ijms222312872] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/23/2021] [Accepted: 11/24/2021] [Indexed: 12/13/2022] Open
Abstract
Ovarian cancer (OC) is the deadliest among all gynecological cancers. Epidemiological studies showed that obesity might influence many cancers including OC. One of the key factors that may link obesity and OC is leptin (LEP), known as an adipokine with pleiotropic effects on body homeostasis. This study aims to investigate the expression pattern of LEP, assess the methylation profiles of LEP and their associations with clinicopathological features including survival outcomes of OC patients. The protein expression of LEP was evaluated in 208 samples using both tissue microarray and immunohistochemistry techniques. The methylation profiles of LEP were measured in 63 formalin-fixed, paraffin-embedded tumor tissues by quantitative polymerase chain reaction using a MethyLight assay. Our results showed a significant association of LEP protein overexpression with several clinicopathological variables, mainly tumor subtype, LVI, age of menarche, tumor size and stage (p < 0.04). Kaplan-Meier analysis (using low expression versus high expression as a discriminator) indicated that LEP protein overexpression is a powerful positive prognosticator of both OC recurrence (DFS) and disease-specific survival (DSS) in our OC cohort (log-rank p = 0.01 and p = 0.002, respectively). This implies that patients with high LEP expression profiles live longer with less recurrence rates. Methylation analysis results demonstrated a clear association between no/low LEP protein expression pattern (38%) and LEP promoter CpG island hypermethylation (43%). Results of this study suggest that LEP is a powerful prognosticator of OC recurrence and DSS. LEP expression in OC seems to be regulated by its promoter hypermethylation through gene partial/total silencing. Further multi-institutional studies using larger cohorts are required to demystify the intricate molecular functions of this leptin-driven effects in OC pathophysiology and to accurately assess its theranostic potential and validate its prognostic/predictive power in OC onset, progression towards more effective and personalized management of OC patients.
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16
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Binișor I, Baniță IM, Alexandru D, Mehedinți MC, Jurja S, Andrei AM, Pisoschi CG. Progranulin: A proangiogenic factor in visceral adipose tissue in tumoral and non-tumoral visceral pathology. Exp Ther Med 2021; 22:1337. [PMID: 34630691 PMCID: PMC8495564 DOI: 10.3892/etm.2021.10772] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 08/23/2021] [Indexed: 11/10/2022] Open
Abstract
The connection between central obesity and the development and metastasis of various visceral tumors is largely accepted and one of the main causes seems to be the local synthesis of proangiogenic molecules. Progranulin (PRG), recently identified as an adipokine, is a novel pleiotropic growth factor acting on the proliferation and development of fast-growing epithelial cells, cancer cells, and also a proangiogenic factor whose expression is induced in activated endothelial cells. One of the molecules that seems to trigger the angiogenic activity of PRG is vascular endothelial growth factor (VEGF). Two groups of human subjects were considered and adipose tissue was processed for an immunohistochemical and morphometric study after surgery for abdominal tumoral or non-tumoral pathology. The presence of PRG in adipose pads of the omentum was analyzed and its association with VEGF, CD34 and collagen IV in tumoral and non-tumoral visceral pathology was examined. The results showed that PRG but not VEGF expression was upregulated in adipose tissue in tumoral visceral pathology. In conclusion, the involvement of the proangiogenic activity of PRG and VEGF in adipose tissue under tumor conditions may be dependent on the visceral tumor type.
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Affiliation(s)
- Ioana Binișor
- Department of Histology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Ileana Monica Baniță
- Department of Histology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Dragoș Alexandru
- Department of Medical Informatics and Biostatistics, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | | | - Sanda Jurja
- Department of Ophthalmology, ‘Ovidius’ University of Constanta, 900470 Constanta, Romania
| | - Ana-Marina Andrei
- Department of Biochemistry, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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17
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Cobb LP, Siamakpour-Reihani S, Zhang D, Qin X, Owzar K, Zhou C, Conrads TP, Maxwell GL, Darcy KM, Bateman NW, Litzi T, Bae-Jump V, Secord AA. Obesity and altered angiogenic-related gene expression in endometrial cancer. Gynecol Oncol 2021; 163:320-326. [PMID: 34538531 PMCID: PMC11018267 DOI: 10.1016/j.ygyno.2021.08.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/12/2021] [Accepted: 08/14/2021] [Indexed: 11/22/2022]
Abstract
OBJECTIVES Evaluate association between obesity and angiogenic-related gene expression in endometrial cancer (EC). Evaluate interaction between diet and metformin on angiogenic-related gene expression. METHODS We evaluated the association between 168 human angiogenic-related genes and body mass index (BMI) in the TCGA Uterine Corpus Endometrial Carcinoma cohort (endometrioid endometrial cancer (EEC) cohort n = 290, and copy number high cohort n = 55), an independent validation cohort from Gynecologic Cancer Center of Excellence (GYN-COE) (n = 62) and corresponding 185 homologous mouse genes in an LKB1fl/flp53fl/fl mouse model of EC (n = 20). Mice received 60% of calories from fat in a high-fat diet (HFD), mimicking diet-induced obesity, versus 10% of calories from fat in a low-fat diet (LFD). After tumor growth, HFD (n = 5) and LFD (n = 5) mice were treated with metformin (200 mg/kg/day) or control. Whole transcriptome analysis of mouse tumors was performed using RNA-Seq. RESULTS At a false-discovery rate of 10%, twenty-one angiogenic-related genes were differentially expressed with respect to BMI when adjusting for grade in the TCGA EEC cohort. Evaluation of these genes in the mouse model control group revealed association between increased Edil3 expression in HFD versus LFD mice (2.5-fold change (FC); unadjusted p = 0.03). An interaction was observed for expression of Edil3 between diet and metformin treatment (unadjusted p = 0.009). Association between BMI and increased expression of EDIL3 was validated in one of four EDIL3 probesets in the GYN-COE cohort (p = 0.0011, adjusted p = 0.0342). CONCLUSIONS Obesity may promote tumor progression via differential modulation of angiogenic pathways in EEC. Our exploratory findings demonstrated that EDIL3 may be a candidate gene of interest.
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Affiliation(s)
- Lauren Patterson Cobb
- Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center, Houston, TX, USA; Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
| | - Sharareh Siamakpour-Reihani
- Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University Medical Center, USA
| | - Dadong Zhang
- Bioinformatics Shared Resource, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
| | - Xiaodi Qin
- Bioinformatics Shared Resource, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
| | - Kouros Owzar
- Bioinformatics Shared Resource, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA; Duke Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA
| | - Chunxiao Zhou
- Division of Gynecologic Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Thomas P Conrads
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; Women's Health Integrated Research Center, Women's Service Line, Inova Health System, Falls Church, VA, USA
| | - G Larry Maxwell
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; Women's Health Integrated Research Center, Women's Service Line, Inova Health System, Falls Church, VA, USA; Inova Schar Cancer Institute, Inova Center for Personalized Health, Falls Church, VA, USA
| | - Kathleen M Darcy
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, USA
| | - Nicholas W Bateman
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, USA
| | - Tracy Litzi
- Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, USA
| | - Victoria Bae-Jump
- Division of Gynecologic Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Angeles Alvarez Secord
- Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
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Malhab LJB, Saber-Ayad MM, Al-Hakm R, Nair VA, Paliogiannis P, Pintus G, Abdel-Rahman WM. Chronic Inflammation and Cancer: The Role of Endothelial Dysfunction and Vascular Inflammation. Curr Pharm Des 2021; 27:2156-2169. [PMID: 33655853 DOI: 10.2174/1381612827666210303143442] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 12/17/2020] [Indexed: 01/17/2023]
Abstract
Long-lasting subclinical inflammation is associated with a wide range of human diseases, particularly at a middle and older age. Recent reports showed that there is a direct causal link between inflammation and cancer development, as several cancers were found to be associated with chronic inflammatory conditions. In patients with cancer, healthy endothelial cells regulate vascular homeostasis, and it is believed that they can limit tumor growth, invasiveness, and metastasis. Conversely, dysfunctional endothelial cells that have been exposed to the inflammatory tumor microenvironment can support cancer progression and metastasis. Dysfunctional endothelial cells can exert these effects via diverse mechanisms, including dysregulated adhesion, permeability, and activation of NF-κB and STAT3 signaling. In this review, we highlight the role of vascular inflammation in predisposition to cancer within the context of two common disease risk factors: obesity and smoking. In addition, we discuss the molecular triggers, pathophysiological mechanisms, and the biological consequences of vascular inflammation during cancer development and metastasis. Finally, we summarize the current therapies and pharmacological agents that target vascular inflammation and endothelial dysfunction.
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Affiliation(s)
- Lara J Bou Malhab
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Maha M Saber-Ayad
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Ranyah Al-Hakm
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Vidhya A Nair
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Panagiotis Paliogiannis
- Department of Medical, Surgical, and Experimental Surgery, University of Sassari, Viale San Pietro 43,07100 Sassari, Italy
| | - Gianfranco Pintus
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Wael M Abdel-Rahman
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
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19
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Manjunathan R, Devarajan N, Ragunathan M. Possible Mechanism of Human Recombinant Leptin-Induced VEGF A Synthesis via PI3K/Akt/mTOR/S6 Kinase Signaling Pathway while Inducing Angiogenesis: An Analysis Using Chicken Chorioallantoic Membrane Model. J Vasc Res 2021; 58:343-360. [PMID: 34167108 DOI: 10.1159/000516498] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 04/09/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION The present study aimed to realize human recombinant leptin 's ability to synthesize VEGF A while inducing neovascularization through PI3K/Akt/mTOR/S6 kinase involved signaling pathway. METHODS To examine the PI3K/Akt/mTOR/S6 kinase pathway involvement in leptin-induced VEGF A synthesis, the chick chorioallantoic membrane (CAM) was incubated with human recombinant leptin and specific inhibitors of the proposed signaling molecules (rapamycin and wortmannin). We analyzed the role of specified signaling molecules in human recombinant leptin-induced physiological angiogenesis via VEGF A synthesis in detail with the support of various methodologies. RESULTS Human recombinant leptin's ability to synthesize VEGF A is diminished significantly in the presence of inhibitors. This observation supported the role of PI3K/Akt/mTOR/S6 kinase signaling molecules in human recombinant leptin-mediated VEGF A synthesis while inducing angiogenesis in CAM. CONCLUSION Synthesis of VEGF A, followed by the growth of new blood vessels, by human recombinant leptin via the activation of the PI3K/Akt/mTOR/S6 kinase signaling pathway reflects mechanistic therapeutic application of human recombinant leptin. The data also signify the role of mTOR and S6 kinase molecules in angiogenesis under a physiological environment.
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Affiliation(s)
- Reji Manjunathan
- Department of Genetics, Dr. ALM PG IBMS, Taramani Campus, University of Madras, Chennai, India
| | - Nalini Devarajan
- Central Research Laboratory, Meenakshi Ammal Dental College, Chennai, India
| | - Malathi Ragunathan
- Department of Genetics, Dr. ALM PG IBMS, Taramani Campus, University of Madras, Chennai, India
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20
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Gandhi S, Oshi M, Murthy V, Repasky EA, Takabe K. Enhanced Thermogenesis in Triple-Negative Breast Cancer Is Associated with Pro-Tumor Immune Microenvironment. Cancers (Basel) 2021; 13:2559. [PMID: 34071012 PMCID: PMC8197168 DOI: 10.3390/cancers13112559] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/07/2021] [Accepted: 05/19/2021] [Indexed: 12/11/2022] Open
Abstract
Mild cold stress induced by housing mice with a 4T1 triple-negative breast cancer (TNBC) cell implantation model at 22 °C increases tumor growth rate with a pro-tumorigenic immune microenvironment (lower CD8 +T cells, higher myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs)). Since cold stress also activates thermogenesis, we hypothesized that enhanced thermogenesis is associated with more aggressive cancer biology and unfavorable tumor microenvironment (TME) in TNBC patients. A total of 6479 breast cancer patients from METABRIC, TCGA, GSE96058, GSE20194, and GSE25066 cohorts were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) thermogenesis score. High-thermogenesis TNBC was associated with a trend towards worse survival and with angiogenesis, adipogenesis, and fatty acid metabolism pathways. On the other hand, low-thermogenesis TNBC enriched most of the hallmark cell-proliferation-related gene sets (i.e., mitotic spindle, E2F targets, G2M checkpoint, MYC targets), as well as immune-related gene sets (i.e., IFN-α and IFN-γ response). Favorable cytotoxic T-cell-attracting chemokines CCL5, CXCL9, CXCL10, and CXCL11 were lower; while the MDSC- and Treg-attracting chemokine CXCL12 was higher. There were higher M2 but lower M1 macrophages and Tregs. In conclusion, high-thermogenesis TNBC is associated with pro-tumor immune microenvironment and may serve as biomarker for testing strategies to overcome this immunosuppression.
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Affiliation(s)
- Shipra Gandhi
- Department of Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (V.M.); (K.T.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Vijayashree Murthy
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (V.M.); (K.T.)
| | - Elizabeth A. Repasky
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (V.M.); (K.T.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
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21
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LEP (-2548G>A LEP) and LEPR (223Gln>Arg, 109Lys>Arg) polymorphisms as breast cancer risk factors in the Polish female population. Mol Biol Rep 2021; 48:3237-3244. [PMID: 33864589 PMCID: PMC8172510 DOI: 10.1007/s11033-021-06328-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 03/31/2021] [Indexed: 12/02/2022]
Abstract
On a global scale, breast cancer is the most common type of cancer in women, and it is still a growing problem. Therefore, new prognostic or diagnostic markers are required that would facilitate the assessment of patients or provide more efficient therapy, respectively. In these studies, we analyzed the contribution of LEP (2548G>A) and LEPR (109 Lys>Arg and 223Gln>Arg) genes polymorphisms to the risk of breast cancer development. The study involved 209 women aged 59.6 ± 11 years diagnosed with breast cancer and 202 healthy women aged 57.8 ± 8.2 years, who were blood donors. Polymorphism were evaluated by PCR–RFLP reaction followed by the verification of part of the samples by sequencing. The results of the study confirmed obesity as a significant breast cancer development risk factor in Polish women. However, no significant association between the studied polymorphisms and breast cancer risk or severity of the neoplastic disease was found. Interestingly, it was shown that wild type 223Gln>Gln leptin receptor (LEPR) was statistically more common in women with human epidermal growth factor receptor 2 negative (HER2−) than human epidermal groth factor receptor 2 positive (HER2+) breast cancer and wild type form of 2548G>A LEP was more common in women with progesterone receptor positive (PR+) than progesterone receptor negative (PR−) breast cancer. Studied polymorphisms of the LEP and LEPR genes do not increase breast cancer risk in the population of Polish women. However, they can affect PR an HER receptors expression and thus the severity of the disease. Noteworthy, this interesting correlation is being reported for the first time and might constitute an essential contribution to the identification of molecular mechanisms of carcinogenesis.
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22
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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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23
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Liu C, Zhao Q, Yu X. Bone Marrow Adipocytes, Adipocytokines, and Breast Cancer Cells: Novel Implications in Bone Metastasis of Breast Cancer. Front Oncol 2020; 10:561595. [PMID: 33123472 PMCID: PMC7566900 DOI: 10.3389/fonc.2020.561595] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 08/27/2020] [Indexed: 02/05/2023] Open
Abstract
Accumulating discoveries highlight the importance of interaction between marrow stromal cells and cancer cells for bone metastasis. Bone is the most common metastatic site of breast cancer and bone marrow adipocytes (BMAs) are the most abundant component of the bone marrow microenvironment. BMAs are unique in their origin and location, and recently they are found to serve as an endocrine organ that secretes adipokines, cytokines, chemokines, and growth factors. It is reasonable to speculate that BMAs contribute to the modification of bone metastatic microenvironment and affecting metastatic breast cancer cells in the bone marrow. Indeed, BMAs may participate in bone metastasis of breast cancer through regulation of recruitment, invasion, survival, colonization, proliferation, angiogenesis, and immune modulation by their production of various adipocytokines. In this review, we provide an overview of research progress, focusing on adipocytokines secreted by BMAs and their potential roles for bone metastasis of breast cancer, and investigating the mechanisms mediating the interaction between BMAs and metastatic breast cancer cells. Based on current findings, BMAs may function as a pivotal modulator of bone metastasis of breast cancer, therefore targeting BMAs combined with conventional treatment programs might present a promising therapeutic option.
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Affiliation(s)
- Chang Liu
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Qian Zhao
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Department of General Practice, West China Hospital, Sichuan University, Chengdu, China
| | - Xijie Yu
- Department of Endocrinology and Metabolism, Laboratory of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
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24
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Tokumaru Y, Oshi M, Katsuta E, Yan L, Huang JL, Nagahashi M, Matsuhashi N, Futamura M, Yoshida K, Takabe K. Intratumoral Adipocyte-High Breast Cancer Enrich for Metastatic and Inflammation-Related Pathways but Associated with Less Cancer Cell Proliferation. Int J Mol Sci 2020; 21:E5744. [PMID: 32796516 PMCID: PMC7461211 DOI: 10.3390/ijms21165744] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/08/2020] [Accepted: 08/10/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer-associated adipocytes are known to cause inflammation, leading to cancer progression and metastasis. The clinicopathological and transcriptomic data from 2256 patients with breast cancer were obtained based on three cohorts: The Cancer Genome Atlas (TCGA), GSE25066, and a study by Yau et al. For the current study, we defined the adipocyte, which is calculated by utilizing a computational algorithm, xCell, as "intratumoral adipocyte". These intratumoral adipocytes appropriately reflected mature adipocytes in a bulk tumor. The amount of intratumoral adipocytes demonstrated no relationship with survival. Intratumoral adipocyte-high tumors significantly enriched for metastasis and inflammation-related gene sets and are associated with a favorable tumor immune microenvironment, especially in the ER+/HER2- subtype. On the other hand, intratumoral adipocyte-low tumors significantly enriched for cell cycle and cell proliferation-related gene sets. Correspondingly, intratumoral adipocyte-low tumors are associated with advanced pathological grades and inversely correlated with MKI67 expression. In conclusion, a high amount of intratumoral adipocytes in breast cancer was associated with inflammation, metastatic pathways, cancer stemness, and favorable tumor immune microenvironment. However, a low amount of adipocytes was associated with a highly proliferative tumor in ER-positive breast cancer. This cancer biology may explain the reason why patient survival did not differ by the amount of adipocytes.
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Affiliation(s)
- Yoshihisa Tokumaru
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (Y.T.); (M.O.); (E.K.); (J.L.H.)
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (N.M.); (M.F.); (K.Y.)
| | - Masanori Oshi
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (Y.T.); (M.O.); (E.K.); (J.L.H.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Eriko Katsuta
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (Y.T.); (M.O.); (E.K.); (J.L.H.)
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Jing Li Huang
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (Y.T.); (M.O.); (E.K.); (J.L.H.)
| | - Masayuki Nagahashi
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan;
| | - Nobuhisa Matsuhashi
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (N.M.); (M.F.); (K.Y.)
| | - Manabu Futamura
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (N.M.); (M.F.); (K.Y.)
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (N.M.); (M.F.); (K.Y.)
| | - Kazuaki Takabe
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (Y.T.); (M.O.); (E.K.); (J.L.H.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan;
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY 14263, USA
- Department of Breast Oncology and Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku, Tokyo 160-8402, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
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25
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Greco F, Quarta LG, Grasso RF, Beomonte Zobel B, Mallio CA. Increased visceral adipose tissue in clear cell renal cell carcinoma with and without peritumoral collateral vessels. Br J Radiol 2020; 93:20200334. [PMID: 32516557 DOI: 10.1259/bjr.20200334] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
OBJECTIVE The excessive amount of adipose tissue, mainly visceral, determines adiposopathy. With respect to oncogenesis, visceral adipose tissue (VAT) releases secretes adipokines, proinflammatory citokines and growth factors, considered mediating molecules in the development of obesity-related tumors. In this study, we quantify VAT in male patients with clear cell renal cell carcinoma (ccRCC) subgrouped according to the presence or absence of peritumoral collateral vessels. METHODS in this retrospective study, we enrolled 141 male caucasian patients divided into 2 groups: the ccRCC group (n = 106) composed of patients with ccRCC and control group (n = 35). The ccRCC group was further divided into two subgroups: the ccRCCa subgroup which showed absence of collateral vessels (n = 48) and ccRCCp subgroup with collateral vessels (n = 58).Total adipose tissue (TAT) area, VAT area and subcutaneous adipose tissue (SAT) area were measured in the groups and subgroups. VAT/SAT ratio was calculated for each subject. RESULTS Statistically significant differences were obtained between ccRCC group and control group for TAT area (p < 0.005), VAT area (p < 0.005) and SAT area (p = 0.01). Between ccRCCa subgroup and control group for TAT area (p < 0.001), VAT area (p = 0.005) and SAT area (p = 0.001). Between ccRCCp subgroup and control group for TAT area (p = 0.01) and VAT area (p = 0.01). CONCLUSION This study confirms the increase of abdominal, especially visceral, adipose tissue in ccRCC patients and demonstrates a significant VAT accumulation in both categories of patients with and without peritumoral collateral vessels. ADVANCES IN KNOWLEDGE Visceral adiposity is present in patients with ccRCC regardless the presence of peritumoral collateral vessels, with surprisingly stronger results in the ccRCCa subgroup.
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Affiliation(s)
- Federico Greco
- Diagnostica per Immagini Territoriale Aziendale, Cittadella della Salute Azienda Sanitaria Locale di Lecce, Piazza Filippo Bottazzi, 73100, Lecce, Italy
| | - Luigi Giuseppe Quarta
- Diagnostica per Immagini Territoriale Aziendale, Cittadella della Salute Azienda Sanitaria Locale di Lecce, Piazza Filippo Bottazzi, 73100, Lecce, Italy
| | - Rosario Francesco Grasso
- Unit of Diagnostic Imaging, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128, Rome, Italy
| | - Bruno Beomonte Zobel
- Unit of Diagnostic Imaging, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128, Rome, Italy
| | - Carlo Augusto Mallio
- Unit of Diagnostic Imaging, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21, 00128, Rome, Italy
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26
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Obesity Promotes Cooperation of Cancer Stem-Like Cells and Macrophages to Enhance Mammary Tumor Angiogenesis. Cancers (Basel) 2020; 12:cancers12020502. [PMID: 32098183 PMCID: PMC7072330 DOI: 10.3390/cancers12020502] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 02/13/2020] [Accepted: 02/19/2020] [Indexed: 02/06/2023] Open
Abstract
Obesity is correlated with worsened prognosis and treatment resistance in breast cancer. Macrophage-targeted therapies are currently in clinical trials, however, little is known about how obesity may impact treatment efficacy. Within breast adipose tissue, obesity leads to chronic, macrophage-driven inflammation, suggesting that obese breast cancer patients may benefit from these therapies. Using a high fat diet model of obesity, we orthotopically transplanted cancer cell lines into the mammary glands of obese and lean mice. We quantified changes in tumor invasiveness, angiogenesis and metastasis, and examined the efficacy of macrophage depletion to diminish tumor progression in obese and lean mice. Mammary tumors from obese mice grew significantly faster, were enriched for cancer stem-like cells (CSCs) and were more locally invasive and metastatic. Tumor cells isolated from obese mice demonstrated enhanced expression of stem cell-related pathways including Sox2 and Notch2. Despite more rapid growth, mammary tumors from obese mice had reduced necrosis, higher blood vessel density, and greater macrophage recruitment. Depletion of macrophages in obese tumor-bearing mice resulted in increased tumor necrosis, reduced endothelial cells, and enhanced recruitment of CD8+ T cells compared to IgG-treated controls. Macrophages may be an important clinical target to improve treatment options for obese breast cancer patients.
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27
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Sanchez A, Furberg H, Kuo F, Vuong L, Ged Y, Patil S, Ostrovnaya I, Petruzella S, Reising A, Patel P, Mano R, Coleman J, Russo P, Liu CH, Dannenberg AJ, Chan TA, Motzer R, Voss MH, Hakimi AA. Transcriptomic signatures related to the obesity paradox in patients with clear cell renal cell carcinoma: a cohort study. Lancet Oncol 2019; 21:283-293. [PMID: 31870811 DOI: 10.1016/s1470-2045(19)30797-1] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 11/02/2019] [Accepted: 11/05/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Obesity is associated with an increased risk of developing clear cell renal cell carcinoma (RCC) but, paradoxically, obesity is also associated with improved oncological outcomes in this cancer. Because the biological mechanisms underlying this paradoxical association are poorly understood, we aimed to identify transcriptomic differences in primary tumour and peritumoral adipose tissue between obese patients and those at a normal weight. METHODS In this cohort study, we assessed data from five independent clinical cohorts of patients with clear cell RCC aged 18 years and older. Overweight patients were excluded from each cohort for our analysis. We assessed patients from the COMPARZ phase 3 clinical trial, a cohort from the Cancer Genome Atlas (TCGA), and a Memorial Sloan Kettering (MSK) observational immunotherapy cohort for their inclusion into our study. We assessed overall survival in obese patients (those with a body-mass index [BMI] ≥30 kg/m2) and in patients with a normal weight (BMI 18·5-24·9 kg/m2, as per WHO's BMI categories), defined as the time from treatment initiation (in the COMPARZ and MSK immunotherapy cohorts) or surgery (in the TCGA cohort) to the date of any-cause death or of censoring on the day of the last follow-up. We also evaluated and validated transcriptomic differences in the primary tumours of obese patients compared with those of a normal weight. We compared gene-expression differences in peritumoral adipose tissue and tumour tissue in an additional, prospectively collected cohort of patients with non-metastatic clear cell RCC (the MSK peritumoral adipose tissue cohort). We analysed differences in gene expression between obese patients and those at a normal weight in the COMPARZ, TCGA, and peritumoral adipose tissue cohorts. We also assessed the tumour immune microenvironment in a prospective cohort of patients who had nephrectomy for localised RCC at MSK. FINDINGS Of the 453 patients in the COMPARZ trial, 375 (83%) patients had available microarray data, pretreatment BMI measurements, and overall survival data for analyses, and we excluded 119 (26%) overweight patients, leaving a final cohort of 256 (68%) patients from this study for our analyses. From 332 patients in the TCGA cohort, we evaluated clinical and demographic data from 152 (46%) patients with advanced (ie, stages III and IV) clear cell RCC treated by nephrectomy; after exclusion of 59 (39%) overweight patients, our final cohort consisted of 93 (61%) patients. After exclusion of 74 (36%) overweight patients from the initial MSK immunotherapy study population of 203 participants, our final cohort for overall survival analysis comprised 129 (64%) participants. We found that overall survival was longer in obese patients than in those with normal weight in the TCGA cohort, after adjustment for stage or grade (adjusted HR 0·41, 95% CI 0·22-0·75), and in the COMPARZ clinical trial after adjustment for International Metastatic RCC Database (IMDC) risk score (0·68, 0·48-0·96). In the MSK immunotherapy cohort, the inverse association of BMI with mortality (HR 0·54, 95% CI 0·31-0·95) was not significant after adjustment for IMDC risk score (adjusted HR 0·72, 95% CI 0·40-1·30). Tumours of obese patients showed higher angiogenic scores on gene-set enrichment analysis-derived hallmark gene set angiogenesis signatures than did those of patients at a normal weight, but the degree of immune cell infiltration did not differ by BMI. We found increased peritumoral adipose tissue inflammation in obese patients relative to those at a normal weight, especially in peritumoral fat near the tumour. INTERPRETATION We found aspects of the tumour microenvironment that vary by BMI in the tumour and peritumoral adipose tissue, which might contribute to the apparent survival advantage in obese patients with clear cell RCC compared with patients at a normal weight. The complex interplay between the clear cell RCC tumour and peritumoral adipose tissue microenvironment might have clinical relevance and warrants further investigation. FUNDING Ruth L Kirschstein Research Service Award, American Society of Clinical Oncology Young Investigator Award, MSK's Ludwig Center, Weiss Family Kidney Research Fund, Novartis, The Sidney Kimmel Center for Prostate and Urologic Cancers, and the National Institutes of Health (National Cancer Institute) Cancer Center Support Grant.
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Affiliation(s)
- Alejandro Sanchez
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Department of Surgery, Division of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Helena Furberg
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Fengshen Kuo
- Immunogenomics & Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Lynda Vuong
- Immunogenomics & Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yasser Ged
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sujata Patil
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Irina Ostrovnaya
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Stacey Petruzella
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | | | - Roy Mano
- Department of Surgery, Division of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jonathan Coleman
- Department of Surgery, Division of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Paul Russo
- Department of Surgery, Division of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Catherine H Liu
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | | | - Timothy A Chan
- Immunogenomics & Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Robert Motzer
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Martin H Voss
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - A Ari Hakimi
- Department of Surgery, Division of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Transcription Factor Prospero Homeobox 1 (PROX1) as a Potential Angiogenic Regulator of Follicular Thyroid Cancer Dissemination. Int J Mol Sci 2019; 20:ijms20225619. [PMID: 31717665 PMCID: PMC6888435 DOI: 10.3390/ijms20225619] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 11/06/2019] [Accepted: 11/07/2019] [Indexed: 01/25/2023] Open
Abstract
It is well known that Prospero homeobox 1 (PROX1) is a crucial regulator of lymphangiogenesis, that reprograms blood endothelial cells to lymphatic phenotype. However, the role of PROX1 in tumor progression, especially in angiogenesis remains controversial. Herein, we studied the role of PROX1 in angiogenesis in cell lines derived from follicular thyroid cancer (FTC: FTC-133) and squamous cell carcinoma of the thyroid gland (SCT: CGTH-W-1) upon PROX1 knockdown. The genes involved in angiogenesis were selected by RNA-seq, and the impact of PROX1 on vascularization potential was investigated using human umbilical vein endothelial cells (HUVECs) cultured in conditioned medium collected from FTC- or SCT-derived cancer cell lines after PROX1 silencing. The angiogenic phenotype was examined in connection with the analysis of focal adhesion and correlated with fibroblast growth factor 2 (FGF2) levels. Additionally, the expression of selected genes involved in angiogenesis was detected in human FTC tissues. As a result, we demonstrated that PROX1 knockdown resulted in upregulation of factors associated with vascularization, such as metalloproteinases (MMP1 and 3), FGF2, vascular endothelial growth factors C (VEGFC), BAI1 associated protein 2 (BAIAP2), nudix hydrolase 6 (NUDT6), angiopoietin 1 (ANGPT1), and vascular endothelial growth factor receptor 2 (KDR). The observed molecular changes resulted in the enhanced formation of capillary-like structures by HUVECs and upregulated focal adhesion in FTC-133 and CGTH-W-1 cells. The signature of selected angiogenic genes' expression in a series of FTC specimens varied depending on the case. Interestingly, PROX1 and FGF2 showed opposing expression levels in FTC tissues and seven thyroid tumor-derived cell lines. In summary, our data revealed that PROX1 is involved in the spreading of thyroid cancer cells by regulation of angiogenesis.
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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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Bruna FA, Romeo LR, Campo-Verde-Arbocco F, Contador D, Gómez S, Santiano F, Sasso CV, Zyla L, López-Fontana C, Calvo JC, Carón RW, Pistone-Creydt V. Human renal adipose tissue from normal and tumor kidney: its influence on renal cell carcinoma. Oncotarget 2019; 10:5454-5467. [PMID: 31534630 PMCID: PMC6739217 DOI: 10.18632/oncotarget.27157] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 07/29/2019] [Indexed: 12/24/2022] Open
Abstract
Tumor cells can interact with neighboring adipose tissue. We evaluated components present in human adipose explants from normal (hRAN) and kidney cancer (hRAT) tissue, and we evaluated the effects of conditioned media (CMs) from hRAN and hRAT on proliferation, adhesion and migration of tumor and non-tumor human renal epithelial cell lines. In addition, we evaluated the expression of AdipoR1, ObR, CD44, vimentin, pERK and pPI3K on cell lines incubated with CMs. hRAN were obtained from healthy operated donors, and hRAT from patients who underwent a nephrectomy. hRAT showed increased levels of versican, leptin and ObR; and decreased levels of perilipin, adiponectin and AdipoR1, compared to hRAN. Cell lines showed a significant decrease in cell adhesion and increase in cell migration after incubation with hRAT-CMs vs. hRAN- or control-CMs. Surprisingly, HK-2, 786-O and ACHN cells showed a significant decrease in cell migration after incubation with hRAN-CMs vs. control-CMs. No difference in proliferation of cell lines was found after 24 or 48 h of treatment with CMs. AdipoR1 in ACHN and Caki-1 cells decreased significantly after incubation with hRAT-CMs vs. hRAN-CMs and control-CMs. ObR and CD44 increased in tumor line cells, and vimentin increased in non-tumor cells, after incubation with hRAT-CMs vs. hRAN-CMs and control-CMs. We observed an increase in the expression of pERK and pPI3K in HK-2, 786-O and ACHN, incubated with hRAT-CMs. In conclusion, results showed that adipose microenvironment can regulate the behavior of tumor and non tumor human renal epithelial cells.
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Affiliation(s)
- Flavia Alejandra Bruna
- Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Centro Científico y Tecnológico Mendoza, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mendoza, Argentina.,Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana, Universidad del Desarrollo, Santiago, Chile.,Universidad Nacional de Cuyo, Facultad de Odontología, Mendoza, Argentina
| | - Leonardo Rafael Romeo
- Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Centro Científico y Tecnológico Mendoza, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mendoza, Argentina.,Departamento de Urología y Transplante Renal, Hospital Español de Mendoza, Mendoza, Argentina
| | - Fiorella Campo-Verde-Arbocco
- Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Centro Científico y Tecnológico Mendoza, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mendoza, Argentina
| | - David Contador
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana, Universidad del Desarrollo, Santiago, Chile
| | - Silvina Gómez
- Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Centro Científico y Tecnológico Mendoza, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mendoza, Argentina
| | - Flavia Santiano
- Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Centro Científico y Tecnológico Mendoza, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mendoza, Argentina
| | - Corina Verónica Sasso
- Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Centro Científico y Tecnológico Mendoza, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mendoza, Argentina
| | - Leila Zyla
- Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Centro Científico y Tecnológico Mendoza, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mendoza, Argentina
| | - Constanza López-Fontana
- Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Centro Científico y Tecnológico Mendoza, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mendoza, Argentina
| | - Juan Carlos Calvo
- Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.,Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Rubén Walter Carón
- Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Centro Científico y Tecnológico Mendoza, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mendoza, Argentina
| | - Virginia Pistone-Creydt
- Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Centro Científico y Tecnológico Mendoza, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mendoza, Argentina.,Universidad Nacional de Cuyo, Facultad de Ciencias Médicas, Departamento de Fisiología, Mendoza, Argentina
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Barone I, Giordano C, Bonofiglio D, Andò S, Catalano S. The weight of obesity in breast cancer progression and metastasis: Clinical and molecular perspectives. Semin Cancer Biol 2019; 60:274-284. [PMID: 31491560 DOI: 10.1016/j.semcancer.2019.09.001] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 09/01/2019] [Indexed: 02/06/2023]
Abstract
The escalating epidemic of overweight and obesity is currently recognized as one of the most significant health and economic concern worldwide. At the present time, over 1.9 billion adults and more than 600 million people can be, respectively, classified as overweight or obese, and numbers will continue to increase in the coming decades. This alarming scenario implies important clinical implications since excessive adiposity can progressively cause and/or exacerbate a wide spectrum of co-morbidities, including type 2 diabetes mellitus, hypertension, cardiovascular disease, and even certain types of cancer, including breast cancer. Indeed, pathological remodelling of white adipose tissue and increased levels of fat-specific cytokines (mainly leptin), as a consequence of the obesity condition, have been associated with several hallmarks of breast cancer, such as sustained proliferative signaling, cellular energetics, inflammation, angiogenesis, activating invasion and metastasis. Different preclinical and clinical data have provided evidence indicating that obesity may worsen the incidence, the severity, and the mortality of breast cancer. In the present review, we will discuss the epidemiological connection between obesity and breast cancer progression and metastasis and we will highlight the candidate players involved in this dangerous relationship. Since the major cause of death from cancer is due to widespread metastases, understanding these complex mechanisms will provide insights for establishing new therapeutic interventions to prevent/blunt the effects of obesity and thwart breast tumor progression and metastatic growth.
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Affiliation(s)
- Ines Barone
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, 87036, Rende, CS, Italy.
| | - Cinzia Giordano
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, 87036, Rende, CS, Italy; Centro Sanitario, University of Calabria, Via P Bucci, 87036, Rende, CS, Italy
| | - Daniela Bonofiglio
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, 87036, Rende, CS, Italy
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, 87036, Rende, CS, Italy; Centro Sanitario, University of Calabria, Via P Bucci, 87036, Rende, CS, Italy
| | - Stefania Catalano
- Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, 87036, Rende, CS, Italy.
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Kong Y, Dong Q, Ji H, Sang M, Ding Y, Zhao M, Yang H, Geng C. The Effect of the Leptin and Leptin Receptor Expression on the Efficacy of Neoadjuvant Chemotherapy in Breast Cancer. Med Sci Monit 2019; 25:3005-3013. [PMID: 31015393 PMCID: PMC6496971 DOI: 10.12659/msm.915368] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background The purpose of the present study was to evaluate the effect of leptin and leptin receptor (LEPR) expression on the efficacy of neoadjuvant chemotherapy in breast cancer. Material/Methods There were 325 breast cancer patients with complete data enrolled in this study. Patients were categorized into 3 groups: pathological complete response group, non-pathological complete response group, and progressive disease group. Immunohistochemistry was performed to determine leptin and its receptor LEPR expression levels that were compared among the 3 groups. Results Compared with the non-pathological complete response group, patients in the pathological complete response group had increased leptin and LEPR expression, although the difference was not statistically significant (P=0.194, P=0.110). In addition, the expression of leptin and LEPR in the pathological complete response group was also higher than that in the progressive disease group, and the difference of LEPR expression was statistically significant (P=0.008) while the leptin expression was not (P=0.065). There were more HER2+ breast cancer patients in the pathological complete response group categorized into strong positive, and positive expression of leptin and LEPR compared with the progressive disease group (P<0.05). There were significant differences of leptin and LEPR expression among breast cancer patients under different molecular subtypes HER2+, HR+, and triple negative, in which the triple negative patients had the highest expression of leptin and LEPR. In addition, patients in the progressive disease group had high and low expression of leptin and LEPR: 13.25% versus 11.32% and 13.1% versus 10.42% respectively. Conclusions Overexpression of leptin and LEPR improved the therapeutic efficacy of neoadjuvant chemotherapy for patients with breast cancer, especially for those with HER2+ subtype. Overexpression of leptin and LEPR was distinct among the different molecular subtypes of breast cancer, suggesting a certain predictive value for breast cancer prognosis.
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Affiliation(s)
- Yan Kong
- Department of Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China (mainland)
| | - Qian Dong
- Department of Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China (mainland)
| | - Hong Ji
- Department of Gland Surgery, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China (mainland)
| | - Meixiang Sang
- Research Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China (mainland)
| | - Yan Ding
- Department of Pathology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China (mainland)
| | - Meng Zhao
- Department of Pathology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China (mainland)
| | - Huichai Yang
- Department of Pathology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China (mainland)
| | - Cuizhi Geng
- Breast Medical Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China (mainland)
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Crean-Tate KK, Reizes O. Leptin Regulation of Cancer Stem Cells in Breast and Gynecologic Cancer. Endocrinology 2018; 159:3069-3080. [PMID: 29955847 PMCID: PMC6669812 DOI: 10.1210/en.2018-00379] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Accepted: 06/19/2018] [Indexed: 12/18/2022]
Abstract
It is well established that obesity increases the incidence and worsens the prognosis of women's cancer. For breast cancer, women with obesity exhibit more than a twofold increase in the odds of being diagnosed with cancer, with a greater risk of advanced stage at diagnosis, and ≤40% greater risk of recurrence and death than their normal-weight counterparts. These findings are similar in gynecologic cancers, where women who are obese with a body mass index (BMI) >40 kg/m2 have up to six times greater risk of developing endometrial cancer and a 9.2% increase in mortality with every 10% increase in BMI. Likewise, patients with obesity exhibit a twofold higher risk of premenopausal ovarian cancer, and patients who are obese with advanced stage ovarian cancer have shown a shorter time to recurrence and poorer overall survival. Obesity is accompanied by changes in expression of adipose factors that act on local tissues and systemically. Once obesity was recognized as a factor in cancer incidence and progression, the adipose cytokine (adipokine) leptin became the focus of intense investigation as a putative link, with nearly 3000 publications on the topic. Leptin has been shown to increase cell proliferation, inhibit apoptosis, promote angiogenesis, and increase therapeutic resistance. These characteristics are associated with a subset of cells in both liquid and solid tumors known as cancer stem cells (CSCs), or tumor initiating cells. We will review the literature discussing leptin's role in breast and gynecologic cancer, focusing on its role in CSCs, and consider goals for targeting future therapy in this arena to disrupt tumor initiation and progression in women's cancer.
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Affiliation(s)
- Katie K Crean-Tate
- Department of Obstetrics and Gynecology, Women’s Health Institute, Cleveland Clinic, Cleveland, Ohio
| | - Ofer Reizes
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio
- Case Comprehensive Cancer Center, Cleveland, Ohio
- Correspondence: Ofer Reizes, PhD, Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NC10, Cleveland, Ohio 44195. E-mail:
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Lopes-Coelho F, Gouveia-Fernandes S, Serpa J. Metabolic cooperation between cancer and non-cancerous stromal cells is pivotal in cancer progression. Tumour Biol 2018; 40:1010428318756203. [DOI: 10.1177/1010428318756203] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The way cancer cells adapt to microenvironment is crucial for the success of carcinogenesis, and metabolic fitness is essential for a cancer cell to survive and proliferate in a certain organ/tissue. The metabolic remodeling in a tumor niche is endured not only by cancer cells but also by non-cancerous cells that share the same microenvironment. For this reason, tumor cells and stromal cells constitute a complex network of signal and organic compound transfer that supports cellular viability and proliferation. The intensive dual-address cooperation of all components of a tumor sustains disease progression and metastasis. Herein, we will detail the role of cancer-associated fibroblasts, cancer-associated adipocytes, and inflammatory cells, mainly monocytes/macrophages (tumor-associated macrophages), in the remodeling and metabolic adaptation of tumors.
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Affiliation(s)
- Filipa Lopes-Coelho
- Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
- Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisbon, Portugal
| | - Sofia Gouveia-Fernandes
- Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
- Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisbon, Portugal
| | - Jacinta Serpa
- Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
- Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisbon, Portugal
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Huang Y, Jin Q, Su M, Ji F, Wang N, Zhong C, Jiang Y, Liu Y, Zhang Z, Yang J, Wei L, Chen T, Li B. Leptin promotes the migration and invasion of breast cancer cells by upregulating ACAT2. Cell Oncol (Dordr) 2017; 40:537-547. [PMID: 28770546 DOI: 10.1007/s13402-017-0342-8] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/13/2017] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Previously, it has been shown that obesity may be considered as a risk factor for breast cancer in postmenopausal women. Leptin, a hormone whose level is elevated in obesity, has been suggested to be involved in the development of breast cancer, and univariate survival analyses have shown that over-expression of ACAT2, an enzyme that is involved in the production of cholesteryl esters, may be associated with a poor prognosis. Here, we aimed to investigate the effect of leptin on the proliferation, migration and invasion of breast cancer cells, as well as to elucidate its underlying mode of action. METHODS Gene expression changes in leptin treated breast cancer-derived MCF-7, T47D and BT474 cells were assessed using PCR array, qRT-PCR and Western blot analyses. The expression patterns of Ob-R (leptin receptor) and ACAT2 in breast cancer cells and primary breast cancer tissue samples were analyzed using immunofluorescence and immunohistochemistry, respectively. Leptin-induced proliferation of breast cancer cells was assessed using a CCK8 assay, and scratch wound and Transwell assays were used to assess breast cancer cell invasion and migration. RESULTS We found that, among the genes tested, ACAT2 expression exhibited the most significant changes in the leptin treated cells. In addition, we found that inhibition of ACAT2 expression using pyripyropene A (PPPA) or siRNA-mediated gene silencing significantly decreased leptin-induced proliferation, migration and invasion of MCF-7 and T47D cells. Subsequent Western blot analyses strongly indicated that the PI3K/AKT/SREBP2 signaling pathway was involved in leptin-induced ACAT2 upregulation in both MCF-7 and T47D cells. Finally, through the analysis of primary breast cancer tissue samples we found that ACAT2 may affect cancer progression through activation of the Ob-R. CONCLUSIONS Our data indicate that leptin may enhance the proliferation, migration and invasion of breast cancer cells via ACAT2 up-regulation through the PI3K/AKT/SREBP2 signaling pathway. Therefore, the leptin/ACAT2 axis may represent an attractive therapeutic target for breast cancer, particularly in postmenopausal and/or obese women.
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Affiliation(s)
- Yunxiu Huang
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Qianni Jin
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Min Su
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Feihu Ji
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Nian Wang
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Changli Zhong
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Yulin Jiang
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Yifeng Liu
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Zhiqian Zhang
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Junhong Yang
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Lan Wei
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Tingmei Chen
- Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Bing Li
- Department of Otolarynology, Chongqing Medical University, Chongqing, 400016, China.
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Ray A, Cleary MP. The potential role of leptin in tumor invasion and metastasis. Cytokine Growth Factor Rev 2017; 38:80-97. [PMID: 29158066 DOI: 10.1016/j.cytogfr.2017.11.002] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 11/07/2017] [Indexed: 02/07/2023]
Abstract
The adipocyte-released hormone-like cytokine/adipokine leptin behaves differently in obesity compared to its functions in the normal healthy state. In obese individuals, elevated leptin levels act as a pro-inflammatory adipokine and are associated with certain types of cancers. Further, a growing body of evidence suggests that higher circulating leptin concentrations and/or elevated expression of leptin receptors (Ob-R) in tumors may be poor prognostic factors. Although the underlying pathological mechanisms of leptin's association with poor prognosis are not clear, leptin can impact the tumor microenvironment in several ways. For example, leptin is associated with a number of biological components that could lead to tumor cell invasion and distant metastasis. This includes interactions with carcinoma-associated fibroblasts, tumor promoting effects of infiltrating macrophages, activation of matrix metalloproteinases, transforming growth factor-β signaling, etc. Recent studies also have shown that leptin plays a role in the epithelial-mesenchymal transition, an important phenomenon for cancer cell migration and/or metastasis. Furthermore, leptin's potentiating effects on insulin-like growth factor-I, epidermal growth factor receptor and HER2/neu have been reported. Regarding unfavorable prognosis, leptin has been shown to influence both adenocarcinomas and squamous cell carcinomas. Features of poor prognosis such as tumor invasion, lymph node involvement and distant metastasis have been recorded in several cancer types with higher levels of leptin and/or Ob-R. This review will describe the current scenario in a precise manner. In general, obesity indicates poor prognosis in cancer patients.
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Affiliation(s)
- Amitabha Ray
- Lake Erie College of Osteopathic Medicine, Seton Hill University, Greensburg, PA 15601, United States
| | - Margot P Cleary
- The Hormel Institute, University of Minnesota, Austin, MN 55912, United States.
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Picon‐Ruiz M, Morata‐Tarifa C, Valle‐Goffin JJ, Friedman ER, Slingerland JM. Obesity and adverse breast cancer risk and outcome: Mechanistic insights and strategies for intervention. CA Cancer J Clin 2017; 67:378-397. [PMID: 28763097 PMCID: PMC5591063 DOI: 10.3322/caac.21405] [Citation(s) in RCA: 557] [Impact Index Per Article: 69.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 06/07/2017] [Accepted: 06/07/2017] [Indexed: 02/06/2023] Open
Abstract
Answer questions and earn CME/CNE Recent decades have seen an unprecedented rise in obesity, and the health impact thereof is increasingly evident. In 2014, worldwide, more than 1.9 billion adults were overweight (body mass index [BMI], 25-29.9 kg/m2 ), and of these, over 600 million were obese (BMI ≥30 kg/m2 ). Although the association between obesity and the risk of diabetes and coronary artery disease is widely known, the impact of obesity on cancer incidence, morbidity, and mortality is not fully appreciated. Obesity is associated both with a higher risk of developing breast cancer, particularly in postmenopausal women, and with worse disease outcome for women of all ages. The first part of this review summarizes the relationships between obesity and breast cancer development and outcomes in premenopausal and postmenopausal women and in those with hormone receptor-positive and -negative disease. The second part of this review addresses hypothesized molecular mechanistic insights that may underlie the effects of obesity to increase local and circulating proinflammatory cytokines, promote tumor angiogenesis and stimulate the most malignant cancer stem cell population to drive cancer growth, invasion, and metastasis. Finally, a review of observational studies demonstrates that increased physical activity is associated with lower breast cancer risk and better outcomes. The effects of recent lifestyle interventions to decrease sex steroids, insulin/insulin-like growth factor-1 pathway activation, and inflammatory biomarkers associated with worse breast cancer outcomes in obesity also are discussed. Although many observational studies indicate that exercise with weight loss is associated with improved breast cancer outcome, further prospective studies are needed to determine whether weight reduction will lead to improved patient outcomes. It is hoped that several ongoing lifestyle intervention trials, which are reviewed herein, will support the systematic incorporation of weight loss intervention strategies into care for patients with breast cancer. CA Cancer J Clin 2017;67:378-397. © 2017 American Cancer Society.
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Affiliation(s)
- Manuel Picon‐Ruiz
- Postdoctoral Associate, Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer CenterUniversity of MiamiMiamiFL
| | - Cynthia Morata‐Tarifa
- Postdoctoral Associate, Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer CenterUniversity of MiamiMiamiFL
| | | | - Eitan R. Friedman
- Resident in Internal Medicine, Department of MedicineUniversity of MiamiMiamiFL
| | - Joyce M. Slingerland
- Director, Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer CenterUniversity of MiamiMiamiFL
- Professor, Division of Medical Oncology, Department of MedicineDivision of Hematology Oncology, University of MiamiMiamiFL
- Professor, Department of Biochemistry and Molecular BiologyUniversity of Miami Miller School of MedicineMiamiFL.
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Thiagarajan PS, Zheng Q, Bhagrath M, Mulkearns-Hubert EE, Myers MG, Lathia JD, Reizes O. STAT3 activation by leptin receptor is essential for TNBC stem cell maintenance. Endocr Relat Cancer 2017; 24:415-426. [PMID: 28729467 PMCID: PMC5551450 DOI: 10.1530/erc-16-0349] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 06/09/2017] [Indexed: 12/31/2022]
Abstract
Leptin (LEP) binds to the long form of the leptin receptor (LEPRb), leading to the activation of multiple signaling pathways that are potential targets for disrupting the obesity-breast cancer link. In triple-negative breast cancer (TNBC), LEP is hypothesized to predominantly mediate its tumorigenic effects via a subpopulation of LEPRb-positive tumor cells termed cancer stem cells (CSCs) that can initiate tumors and induce tumor progression. Previously, we showed that LEP promotes CSC survival in vivo Moreover, silencing LEPRb in TNBC cells compromised the CSC state. The mechanisms by which LEPRb regulates TNBC CSC intracellular signaling are not clear. We hypothesized that activation of LEPRb signaling is sufficient to drive CSC maintenance in TNBC. Here, we show that activation of LEPRb in non-CSCs isolated using our CSC reporter system resulted in a transition to the stem cell state. In CSCs, LEP induced STAT3 phosphorylation, whereas LEP did not induce STAT3 phosphorylation in non-CSCs. Introduction of constitutively active STAT3 into LEPRb-transfected non-CSCs significantly induced NANOG, SOX2 and OCT4 expression compared with control non-CSCs. To determine the intracellular phospho-tyrosine residue of LEPRb that is necessary for the induction of the stem cell state in non-CSCs, we transfected the tyrosine residue point mutants L985, F1077 and S1138 into non-CSCs. Non-CSCs transfected with the L985 mutant exhibited increased STAT3 phosphorylation, increased SOCS3 expression and an induction of GFP expression compared with non-CSCs expressing the F1077 and S1138 mutants. Our data demonstrate that LEPRb-induced STAT3 activation is essential for the induction and maintenance of TNBC CSCs.
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Affiliation(s)
- Praveena S Thiagarajan
- Department of Cellular and Molecular MedicineLerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular MedicineCleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - Qiao Zheng
- Department of Cellular and Molecular MedicineLerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Manvir Bhagrath
- Department of Cellular and Molecular MedicineLerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Erin E Mulkearns-Hubert
- Department of Cellular and Molecular MedicineLerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Martin G Myers
- Departments of Internal Medicine and Molecular and Integrative PhysiologyUniversity of Michigan, Ann Arbor, Michigan, USA
| | - Justin D Lathia
- Department of Cellular and Molecular MedicineLerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular MedicineCleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
- Case Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio, USA
| | - Ofer Reizes
- Department of Cellular and Molecular MedicineLerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular MedicineCleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
- Case Comprehensive Cancer CenterCase Western Reserve University, Cleveland, Ohio, USA
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Alfer J, Happel L, Dittrich R, Beckmann MW, Hartmann A, Gaumann A, Buck VU, Classen-Linke I. Insufficient Angiogenesis: Cause of Abnormally Thin Endometrium in Subfertile Patients? Geburtshilfe Frauenheilkd 2017; 77:756-764. [PMID: 28729745 DOI: 10.1055/s-0043-111899] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 05/21/2017] [Accepted: 05/22/2017] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION This study investigated subfertile patients with abnormally thin endometrium after infertility treatment. As they had adequate serum concentrations of hormones, an endometrial factor for subfertility was suspected. METHODS To elucidate the cause of subfertility, endometrial biopsies were taken in each patient in the late proliferative and mid-secretory phases of one menstrual cycle. Endometrial biopsies from women with normal menstrual cycles and confirmed fertility who were undergoing hysterectomy for benign uterine disease were used as positive controls. The tissue samples were investigated for steroid hormone receptor expression and for the proliferation marker Ki-67. Immunohistochemistry was performed with antibodies against the marker molecules for endometrial receptivity - β 3 integrin, VEGF, LIF, and CD56 (large granular lymphocytes, LGLs). RESULTS The steroid hormone receptors for estrogen (E2) and progesterone (P) were expressed normally (at the first biopsy) and were down-regulated (at the second biopsy) within the cycle. Strikingly, all of the marker molecules investigated showed negative or weak and inadequate expression in the mid-secretory phase. Numbers of LGLs remained as low as in the proliferative phase. In contrast, fertile patients were found to express these marker molecules distinctly in the mid-secretory phase. CONCLUSIONS It may be hypothesized that a severe deficiency of these angiogenesis-related marker molecules leads to defective development of the endometrium, which remains thin. Deficient angiogenetic development may thus provide an explanation for the endometrial factor that causes infertility. Further investigations will need to focus on identifying the regulating factors that act between steroid receptor activation and the expression of these marker molecules.
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Affiliation(s)
- Joachim Alfer
- Institute of Pathology, Kaufbeuren-Ravensburg, Ravensburg, Germany
| | - Lars Happel
- Institute of Reproductive Medicine, IVF-Saar, Saarbrücken, Germany
| | - Ralf Dittrich
- Department of Obstetrics and Gynecology, Erlangen University Hospital Friedrich-Alexander Universität, Erlangen-Nürnberg, Germany
| | - Matthias W Beckmann
- Department of Obstetrics and Gynecology, Erlangen University Hospital Friedrich-Alexander Universität, Erlangen-Nürnberg, Germany
| | - Arndt Hartmann
- Department of Pathology, Erlangen University Hospital Friedrich-Alexander Universität, Erlangen-Nürnberg, Germany
| | - Andreas Gaumann
- Institute of Pathology, Kaufbeuren-Ravensburg, Ravensburg, Germany
| | - Volker U Buck
- Institute of Molecular and Cellular Anatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Irmgard Classen-Linke
- Institute of Molecular and Cellular Anatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany
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Patras L, Sylvester B, Luput L, Sesarman A, Licarete E, Porfire A, Muntean D, Drotar DM, Rusu AD, Nagy AL, Catoi C, Tomuta I, Vlase L, Banciu M, Achim M. Liposomal prednisolone phosphate potentiates the antitumor activity of liposomal 5-fluorouracil in C26 murine colon carcinoma in vivo. Cancer Biol Ther 2017; 18:616-626. [PMID: 28696813 DOI: 10.1080/15384047.2017.1345392] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The antitumor efficacy of 5-fluorouracil (5-FU) in advanced colorectal cancer (CRC) is hindered not only by the low therapeutic index, but also by tumor cell resistance to this cytotoxic drug. Therefore, to enhance the 5-FU antitumor activity, the present research used a novel tumor-targeted therapy based on the co-administration of 5-FU encapsulated in long-circulating liposomes (LCL-5-FU) together with liposomal prednisolone phosphate (LCL-PLP), a formulation with known anti-angiogenic actions on C26 murine colon carcinoma cells. Thus, we assessed the in vivo effects of the combined liposomal drug therapy on C26 carcinoma growth as well as on the production of molecular markers with key roles in tumor development such as angiogenic, inflammatory, and oxidative stress molecules. To get further insight into the polarization state of tumor microenvironment after the treatment, we determined the IL-10/IL-12p70 ratio in tumors. Our results showed that combined liposomal drug therapy inhibited almost totally tumor growth and was superior as antitumor activity to both single liposomal drug therapies tested. The antitumor efficacy of the combined therapy was mainly related to the anti-angiogenic and anti-inflammatory actions on C26 carcinoma milieu, being favored by its controlling effect on intratumor oxidative stress and the skewing of polarization of tumor microenvironmental cells toward their antineoplastic phenotypes. Thus, our study unveils a promising treatment strategy for CRC that should be furthermore considered.
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Affiliation(s)
- Laura Patras
- a Department of Molecular Biology and Biotechnology , Faculty of Biology and Geology, Babes-Bolyai University , Cluj-Napoca , Romania.,b Molecular Biology Centre , Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University , Cluj-Napoca , Romania
| | - Bianca Sylvester
- c Department of Pharmaceutical Technology and Biopharmaceutics , Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Lavinia Luput
- a Department of Molecular Biology and Biotechnology , Faculty of Biology and Geology, Babes-Bolyai University , Cluj-Napoca , Romania.,b Molecular Biology Centre , Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University , Cluj-Napoca , Romania
| | - Alina Sesarman
- a Department of Molecular Biology and Biotechnology , Faculty of Biology and Geology, Babes-Bolyai University , Cluj-Napoca , Romania.,b Molecular Biology Centre , Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University , Cluj-Napoca , Romania
| | - Emilia Licarete
- a Department of Molecular Biology and Biotechnology , Faculty of Biology and Geology, Babes-Bolyai University , Cluj-Napoca , Romania.,b Molecular Biology Centre , Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University , Cluj-Napoca , Romania
| | - Alina Porfire
- c Department of Pharmaceutical Technology and Biopharmaceutics , Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Dana Muntean
- c Department of Pharmaceutical Technology and Biopharmaceutics , Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Denise Minerva Drotar
- a Department of Molecular Biology and Biotechnology , Faculty of Biology and Geology, Babes-Bolyai University , Cluj-Napoca , Romania.,b Molecular Biology Centre , Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University , Cluj-Napoca , Romania
| | - Alexandra Doina Rusu
- a Department of Molecular Biology and Biotechnology , Faculty of Biology and Geology, Babes-Bolyai University , Cluj-Napoca , Romania.,b Molecular Biology Centre , Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University , Cluj-Napoca , Romania
| | - Andras-Laszlo Nagy
- d Department of Veterinary Toxicology , University of Agricultural Sciences and Veterinary Medicine , Cluj-Napoca , Romania
| | - Cornel Catoi
- d Department of Veterinary Toxicology , University of Agricultural Sciences and Veterinary Medicine , Cluj-Napoca , Romania
| | - Ioan Tomuta
- c Department of Pharmaceutical Technology and Biopharmaceutics , Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Laurian Vlase
- c Department of Pharmaceutical Technology and Biopharmaceutics , Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
| | - Manuela Banciu
- a Department of Molecular Biology and Biotechnology , Faculty of Biology and Geology, Babes-Bolyai University , Cluj-Napoca , Romania.,b Molecular Biology Centre , Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University , Cluj-Napoca , Romania
| | - Marcela Achim
- c Department of Pharmaceutical Technology and Biopharmaceutics , Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania
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Duong MN, Geneste A, Fallone F, Li X, Dumontet C, Muller C. The fat and the bad: Mature adipocytes, key actors in tumor progression and resistance. Oncotarget 2017; 8:57622-57641. [PMID: 28915700 PMCID: PMC5593672 DOI: 10.18632/oncotarget.18038] [Citation(s) in RCA: 134] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 05/08/2017] [Indexed: 02/07/2023] Open
Abstract
Growing evidence has raised the important roles of adipocytes as an active player in the tumor microenvironment. In many tumors adipocytes are in close contact with cancer cells. They secrete various factors that can mediate local and systemic effects. The adipocyte-cancer cell crosstalk leads to phenotypical and functional changes of both cell types, which can further enhance tumor progression. Moreover, obesity, which is associated with an increase in adipose mass and an alteration of adipose tissue, has been established as a risk factor for cancer incidence and cancer-related mortality. In this review, we summarize the mechanisms of the adipocyte-cancer cell crosstalk in both obese and lean conditions as well as its impact on cancer cell growth, local invasion, metastatic spread and resistance to treatments. Better characterization of cancer-associated adipocytes and the key molecular events in the adipocyte-cancer cell crosstalk will provide insights into tumor biology and suggest efficient therapeutic opportunities.
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Affiliation(s)
- Minh Ngoc Duong
- Department of Oncology/CHUV-UNIL, Biopole 3, Epalinges, Switzerland
| | - Aline Geneste
- Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052/CNRS 5286, Lyon, France
| | - Frederique Fallone
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Xia Li
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Charles Dumontet
- Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM UMR 1052/CNRS 5286, Lyon, France.,Hospices Civils de Lyon, Lyon, France
| | - Catherine Muller
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France
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Leptin receptor Q223R polymorphism in Egyptian female patients with breast cancer. Contemp Oncol (Pozn) 2017; 21:42-47. [PMID: 28435397 PMCID: PMC5385477 DOI: 10.5114/wo.2017.66655] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 01/29/2017] [Indexed: 01/04/2023] Open
Abstract
Aim of the study Breast cancer is the most common cause of death in women. Obesity has been associated with increased risk of breast cancer in post-menopausal women. It induces chronic inflammation, which increases local and systemic levels of cytokines and adipokines such as leptin. Leptin (LEP) and leptin receptor (LEPR) genes have several polymorphisms in humans. This study aims to assess the association between blood levels of leptin and LEPR Q223R gene polymorphism in patients of cancer breast. Material and methods The current study was carried on 48 female breast cancer patients and 48 heathy female subjects. Carcinoembryonic antigen (CEA), cancer antibody CA15-3, and leptin hormone were determined. Single nucleotide polymorphism of LEPR Q223R was assessed by PCR/RFLP. Statistical analysis used: The statistical analysis of data was done by using SPSS version 20. Results There were significant increases in the concentrations of CEA (p = 0.004), CA15-3 (p < 0.001), and leptin hormone (p < 0.001) in BC patients in relation to the respective concentrations in control subjects. CEA and CA 15-3 showed significant differences between various BC stages. As regard to LEPR Q223R gene polymorphism, AA genotype showed significantly higher frequency in BC patients when compared to their respective controls, with higher risk to develop BC. Conclusions Leptin hormone shows significantly higher concentrations in BC patients. As regard to LEPR Q223R gene polymorphism, AA genotype showed significantly higher frequency in BC patients.
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Human breast adipose tissue: characterization of factors that change during tumor progression in human breast cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:26. [PMID: 28173833 PMCID: PMC5297209 DOI: 10.1186/s13046-017-0494-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 01/27/2017] [Indexed: 01/08/2023]
Abstract
BACKGROUND Adipose microenvironment is involved in signaling pathways that influence breast cancer. We aim to characterize factors that are modified: 1) in tumor and non tumor human breast epithelial cell lines when incubated with conditioned media (CMs) from human breast cancer adipose tissue explants (hATT) or normal breast adipose tissue explants (hATN); 2) in hATN-CMs vs hATT-CMs; 3) in the tumor associated adipocytes vs. non tumor associated adipocytes. METHODS We used hATN or hATT- CMs on tumor and non-tumor breast cancer cell lines. We evaluated changes in versican, CD44, ADAMTS1 and Adipo R1 expression on cell lines or in the different CMs. In addition we evaluated changes in the morphology and expression of these factors in slices of the different adipose tissues. The statistical significance between different experimental conditions was evaluated by one-way ANOVA. Tukey's post-hoc tests were performed within each individual treatment. RESULTS hATT-CMs increase versican, CD44, ADAMTS1 and Adipo R1 expression in breast cancer epithelial cells. Furthermore, hATT-CMs present higher levels of versican expression compared to hATN-CMs. In addition, we observed a loss of effect in cellular migration when we pre-incubated hATT-CMs with chondroitinase ABC, which cleaves GAGs chains bound to the versican core protein, thus losing the ability to bind to CD44. Adipocytes associated with the invasive front are reduced in size compared to adipocytes that are farther away. Also, hATT adipocytes express significantly higher amounts of versican, CD44 and Adipo R1, and significantly lower amounts of adiponectin and perilipin, unlike hATN adipocytes. CONCLUSIONS We conclude that hATT secrete a different set of proteins compared to hATN. Furthermore, versican, a proteoglycan that is overexpressed in hATT-CMs compared to hATN-CMs, might be involved in the tumorogenic behavior observed in both cell lines employed. In addition, we may conclude that adipocytes from the tumor microenvironment show a less differentiated state than adipocytes from normal microenvironment. This would indicate a loss of normal functions in mature adipocytes (such as energy storage), in support of others that might favor tumor growth.
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Bougaret L, Delort L, Billard H, Lequeux C, Goncalves-Mendes N, Mojallal A, Damour O, Vasson MP, Caldefie-Chezet F. Supernatants of Adipocytes From Obese Versus Normal Weight Women and Breast Cancer Cells: In Vitro Impact on Angiogenesis. J Cell Physiol 2016; 232:1808-1816. [PMID: 27886379 DOI: 10.1002/jcp.25701] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 11/21/2016] [Indexed: 01/08/2023]
Abstract
Breast cancer is correlated with a higher risk of metastasis in obese postmenopausal women. Adipokines, whose plasma concentrations are modulated in obese subjects and adipocytes surround mammary cells, suggesting that adipocyte secretome affect mammary tumorogenesis. We hypothesize that mature adipocyte secretions from obese women conditioned or not by breast neoplasic cells, increase changes on the angiogenesis stages. Supernatants of human mature adipocytes, differentiated from stem cells of either adipose tissue of normal weight (MA20) or obese (MA30) women or obtained from co-cultures between MA20 and MA30 and breast cancer cell line MCF-7, were collected. The impact of these supernatants was investigated on proliferation, migration, and tube formation by endothelial cells (HUVEC). MA20 and MA30 showed a preservation of their "metabolic memory" (increase of Leptin, ObR, VEGF, CYP19A1, and a decrease of Adiponectin expression in MA30 compared to MA20). Supernatants from obese-adipocytes increased HUVEC proliferation, migration, and sprouting like with supernatants obtained from co-cultures of MA/MCF-7 regardless the women's BMI. Additional analyses such as the use of neutralizing antibodies, analysis of supernatants (Milliplex®) and variations in gene expression (qRT-PCR), strongly suggest an implication of IL-6, or a synergistic action among adipokines, probably associated with that of VEGF or IL-6. As a conclusion, supernatants from co-cultures of MA30 and MCF-7 cells increase proliferation, migration, and sprouting of HUVEC cells. These results provide insights into the interaction between adipocytes and epithelial cancer cells, particularly in case of obesity. The identification of synergistic action of adipokines would therefore be a great interest in developing preventive strategies. J. Cell. Physiol. 232: 1808-1816, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Lauriane Bougaret
- UMR1019-INRA-UdA, Unité de Nutrition Humaine, Equipe ECREIN, UFR Pharmacie, Université d'Auvergne, Clermont-Ferrand, France
| | - Laetitia Delort
- UMR1019-INRA-UdA, Unité de Nutrition Humaine, Equipe ECREIN, UFR Pharmacie, Université d'Auvergne, Clermont-Ferrand, France
| | - Hermine Billard
- UMR1019-INRA-UdA, Unité de Nutrition Humaine, Equipe ECREIN, UFR Pharmacie, Université d'Auvergne, Clermont-Ferrand, France
| | | | - Nicolas Goncalves-Mendes
- UMR1019-INRA-UdA, Unité de Nutrition Humaine, Equipe ECREIN, UFR Pharmacie, Université d'Auvergne, Clermont-Ferrand, France
| | - Ali Mojallal
- Service de Chirurgie Plastique, Reconstructrice et Esthétique, Hôpital Edouard-Herriot, Lyon, France
| | | | - Marie-Paule Vasson
- UMR1019-INRA-UdA, Unité de Nutrition Humaine, Equipe ECREIN, UFR Pharmacie, Université d'Auvergne, Clermont-Ferrand, France.,Centre Anti-Cancéreux Jean-Perrin, Clermont-Ferrand, France.,Cancéropôle Lyon Auvergne Rhône-Alpes (CLARA), Lyon, France
| | - Florence Caldefie-Chezet
- UMR1019-INRA-UdA, Unité de Nutrition Humaine, Equipe ECREIN, UFR Pharmacie, Université d'Auvergne, Clermont-Ferrand, France.,Cancéropôle Lyon Auvergne Rhône-Alpes (CLARA), Lyon, France
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45
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Fukumura D, Incio J, Shankaraiah RC, Jain RK. Obesity and Cancer: An Angiogenic and Inflammatory Link. Microcirculation 2016; 23:191-206. [PMID: 26808917 DOI: 10.1111/micc.12270] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Accepted: 01/20/2016] [Indexed: 12/15/2022]
Abstract
With the current epidemic of obesity, a large number of patients diagnosed with cancer are overweight or obese. Importantly, this excess body weight is associated with tumor progression and poor prognosis. The mechanisms for this worse outcome, however, remain poorly understood. We review here the epidemiological evidence for the association between obesity and cancer, and discuss potential mechanisms focusing on angiogenesis and inflammation. In particular, we will discuss how the dysfunctional angiogenesis and inflammation occurring in adipose tissue in obesity may promote tumor progression, resistance to chemotherapy, and targeted therapies such as anti-angiogenic and immune therapies. Better understanding of how obesity fuels tumor progression and therapy resistance is essential to improve the current standard of care and the clinical outcome of cancer patients. To this end, we will discuss how an anti-diabetic drug such as metformin can overcome these adverse effects of obesity on the progression and treatment resistance of tumors.
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Affiliation(s)
- Dai Fukumura
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Joao Incio
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.,I3S, Institute for Innovation and Research in Heath, Metabolism, Nutrition and Endocrinology Group, Biochemistry Department, Faculty of Medicine, Porto University, Porto, Portugal.,Department of Internal Medicine, Hospital S. João, Porto, Portugal
| | - Ram C Shankaraiah
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Morphology, Surgery and Experimental Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Rakesh K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Lanier V, Gillespie C, Leffers M, Daley-Brown D, Milner J, Lipsey C, Webb N, Anderson LM, Newman G, Waltenberger J, Gonzalez-Perez RR. Leptin-induced transphosphorylation of vascular endothelial growth factor receptor increases Notch and stimulates endothelial cell angiogenic transformation. Int J Biochem Cell Biol 2016; 79:139-150. [PMID: 27590851 DOI: 10.1016/j.biocel.2016.08.023] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 08/13/2016] [Accepted: 08/29/2016] [Indexed: 02/08/2023]
Abstract
Leptin increases vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), and Notch expression in cancer cells, and transphosphorylates VEGFR-2 in endothelial cells. However, the mechanisms involved in leptin's actions in endothelial cells are not completely known. Here we investigated whether a leptin-VEGFR-Notch axis is involved in these leptin's actions. To this end, human umbilical vein and porcine aortic endothelial cells (wild type and genetically modified to overexpress VEGFR-1 or -2) were cultured in the absence of VEGF and treated with leptin and inhibitors of Notch (gamma-secretase inhibitors: DAPT and S2188, and silencing RNA), VEGFR (kinase inhibitor: SU5416, and silencing RNA) and leptin receptor, OB-R (pegylated leptin peptide receptor antagonist 2: PEG-LPrA2). Interestingly, in the absence of VEGF, leptin induced the expression of several components of Notch signaling pathway in endothelial cells. Inhibition of VEGFR and Notch signaling significantly decreased leptin-induced S-phase progression, proliferation, and tube formation in endothelial cells. Moreover, leptin/OB-R induced transphosphorylation of VEGFR-1 and VEGFR-2 was essential for leptin's effects. These results unveil for the first time a novel mechanism by which leptin could induce angiogenic features via upregulation/trans-activation of VEGFR and downstream expression/activation of Notch in endothelial cells. Thus, high levels of leptin found in overweight and obese patients might lead to increased angiogenesis by activating VEGFR-Notch signaling crosstalk in endothelial cells. These observations might be highly relevant for obese patients with cancer, where leptin/VEGFR/Notch crosstalk could play an important role in cancer growth, and could be a new target for the control of tumor angiogenesis.
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Affiliation(s)
- Viola Lanier
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, United States
| | - Corey Gillespie
- Atlanta Technical College, Bioscience Technology Program, Atlanta, GA 30310, United States
| | | | - Danielle Daley-Brown
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, United States
| | - Joy Milner
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, United States
| | - Crystal Lipsey
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, United States
| | - Nia Webb
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, United States
| | - Leonard M Anderson
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, United States; Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, GA 30310, United States
| | - Gale Newman
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, United States
| | | | - Ruben Rene Gonzalez-Perez
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, United States.
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Delle Monache S, Calgani A, Sanità P, Zazzeroni F, Gentile Warschauer E, Giuliani A, Amicucci G, Angelucci A. Adipose-derived stem cells sustain prolonged angiogenesis through leptin secretion. Growth Factors 2016; 34:87-96. [PMID: 27362575 DOI: 10.1080/08977194.2016.1191481] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Recent studies suggest that adipose-derived stem cells (ASCs) play a role in tissue remodeling through the release of cytokines and growth factors. We compared the secreted cytokine profile of hypoxia-conditioned ASCs (hASCs) with normoxic ASCs (nASCs) and we analyzed the effect of ASCs conditioned medium (CM) on endothelial cells. We found that hypoxia induced a transient upregulation of VEGF in ASCs and a notable and enduring upregulation of leptin mRNA expression 30-fold greater than control after 24 h and up to 60-fold greater than control at day 7. CM from hASC stimulated EC tube formation to a significantly greater extent than CM from nASC. This might be due to leptin-secreted factor. Indeed, exogenous leptin stimulated the expression of HIF2-α, but not HIF1-α, and upregulated the expression of Flt-1 and Tie-1 proangiogenic receptors. In conclusion, hASCs may be particularly efficient in sustaining angiogenesis through the release of leptin.
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Affiliation(s)
| | - Alessia Calgani
- a Department of Biotechnological and Applied Clinical Sciences and
| | - Patrizia Sanità
- a Department of Biotechnological and Applied Clinical Sciences and
| | | | - Emilio Gentile Warschauer
- a Department of Biotechnological and Applied Clinical Sciences and
- b Division of Surgery , University of L'Aquila , L'Aquila , Italy
| | - Antonio Giuliani
- a Department of Biotechnological and Applied Clinical Sciences and
- b Division of Surgery , University of L'Aquila , L'Aquila , Italy
| | - Gianfranco Amicucci
- a Department of Biotechnological and Applied Clinical Sciences and
- b Division of Surgery , University of L'Aquila , L'Aquila , Italy
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48
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Yang WH, Chang AC, Wang SW, Wang SJ, Chang YS, Chang TM, Hsu SK, Fong YC, Tang CH. Leptin promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-27b in human chondrosarcoma cells. Sci Rep 2016; 6:28647. [PMID: 27345723 PMCID: PMC4921910 DOI: 10.1038/srep28647] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 06/06/2016] [Indexed: 12/24/2022] Open
Abstract
Chondrosarcoma is the second most frequently occurring type of bone malignancy that is characterized by the distant metastasis propensity. Vascular endothelial growth factor-C (VEGF-C) is the chief lymphangiogenic mediator, and makes crucial contributions to tumor lymphangiogenesis. Leptin is an adipocytokine and has been indicated to facilitate tumorigenesis, angiogenesis and metastasis. However, the effect of leptin on VEGF-C regulation and lymphangiogenesis in human chondrosarcoma has hugely remained a mystery. Our results showed a clinical correlation between leptin and VEGF-C as well as tumor stage in human chondrosarcoma tissues. We further demonstrated that leptin promoted VEGF-C production and secretion in human chondrosarcoma cells. The conditioned medium from leptin-treated chondrosarcoma cells induced lymphangiogenesis of human lymphatic endothelial cells. We also found that leptin-induced VEGF-C is mediated by the FAK, PI3K and Akt signaling pathway. Furthermore, the expression of microRNA-27b was negatively regulated by leptin via the FAK, PI3K and Akt cascade. Our study is the first to describe the mechanism of leptin-promoted lymphangiogenesis by upregulating VEGF-C expression in chondrosarcomas. Thus, leptin could serve as a therapeutic target in chondrosarcoma metastasis and lymphangiogenesis.
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Affiliation(s)
- Wei-Hung Yang
- Department of Orthopedic Surgery, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan.,School of Chinese Medicine, China Medical University, Taichung, Taiwan.,Department of Nursing, National Taichung University of Science and Technology, Taichung, Taiwan.,Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan
| | - An-Chen Chang
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Shih-Wei Wang
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
| | - Shoou-Jyi Wang
- Department of Orthopedic Surgery, Chang-Hua Hospital, Ministry of Health and Welfare, Puhsin Township, Changhua County, Taiwan
| | - Yung-Sen Chang
- Department of Orthopedic Surgery, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan
| | - Tzu-Ming Chang
- Department of Orthopedic Surgery, Tungs' Taichung Metroharbor Hospital, Taichung, Taiwan
| | - Shao-Keh Hsu
- Department of Orthopedic Surgery, Tungs' Taichung Metroharbor Hospital, Taichung, Taiwan
| | - Yi-Chin Fong
- Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan.,Department of Orthopedic Surgery, China Medical University Beigang Hospital, Yunlin County, Taiwan
| | - Chih-Hsin Tang
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.,Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.,Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
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49
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Lipsey CC, Harbuzariu A, Daley-Brown D, Gonzalez-Perez RR. Oncogenic role of leptin and Notch interleukin-1 leptin crosstalk outcome in cancer. World J Methodol 2016; 6:43-55. [PMID: 27019796 PMCID: PMC4804251 DOI: 10.5662/wjm.v6.i1.43] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 11/11/2015] [Accepted: 03/09/2016] [Indexed: 02/06/2023] Open
Abstract
Obesity is a global pandemic characterized by high levels of body fat (adiposity) and derived-cytokines (i.e., leptin). Research shows that adiposity and leptin provide insight on the link between obesity and cancer progression. Leptin’s main function is to regulate energy balance. However, obese individuals routinely develop leptin resistance, which is the consequence of the breakdown in the signaling mechanism controlling satiety resulting in the accumulation of leptin. Therefore, leptin levels are often chronically elevated in human obesity. Elevated leptin levels are related to higher incidence, increased progression and poor prognosis of several human cancers. In addition to adipose tissue, cancer cells can also secrete leptin and overexpress leptin receptors. Leptin is known to act as a mitogen, inflammatory and pro-angiogenic factor that induces cancer cell proliferation and tumor angiogenesis. Moreover, leptin signaling induces cancer stem cells, which are involved in cancer recurrence and drug resistance. A novel and complex signaling crosstalk between leptin, Notch and interleukin-1 (IL-1) [Notch, IL-1 and leptin crosstalk outcome (NILCO)] seems to be an important driver of leptin-induced oncogenic actions. Leptin and NILCO signaling mediate the activation of cancer stem cells that can affect drug resistance. Thus, leptin and NILCO signaling are key links between obesity and cancer progression. This review presents updated data suggesting that adiposity affects cancer incidence, progression, and response to treatment. Here we show data supporting the oncogenic role of leptin in breast, endometrial, and pancreatic cancers.
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50
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Nepal S, Kim MJ, Hong JT, Kim SH, Sohn DH, Lee SH, Song K, Choi DY, Lee ES, Park PH. Autophagy induction by leptin contributes to suppression of apoptosis in cancer cells and xenograft model: involvement of p53/FoxO3A axis. Oncotarget 2016; 6:7166-81. [PMID: 25704884 PMCID: PMC4466676 DOI: 10.18632/oncotarget.3347] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2014] [Accepted: 01/15/2015] [Indexed: 12/19/2022] Open
Abstract
Leptin, a hormone mainly produced from adipose tissue, has been shown to induce proliferation of cancer cells. However, the molecular mechanisms underlying leptin-induced tumor progression have not been clearly elucidated. In the present study, we investigated the role of autophagy in leptin-induced cancer cell proliferation using human hepatoma (HepG2) and breast cancer cells (MCF-7), and tumor growth in a xenograft model. Herein, we showed that leptin treatment caused autophagy induction as assessed by increase in expression of autophagy-related genes, including beclin-1, Atg5 and LC3 II, further induction of autophagosome formation and autophagic flux. Interestingly, inhibition of autophagic process by treatment with inhibitors and LC3B gene silencing blocked leptin-induced increase in cell number and suppression of apoptosis, indicating a crucial role of autophagy in leptin-induced tumor progression. Moreover, gene silencing of p53 or FoxO3A prevented leptin-induced LC3 II protein expression, suggesting an involvement of p53/FoxO3A axis in leptin-induced autophagy activation. Leptin administration also accelerated tumor growth in BALB/c nude mice, which was found to be autophagy dependent. Taken together, our results demonstrate that leptin-induced tumor growth is mediated by autophagy induction and autophagic process would be a promising target to regulate development of cancer caused by leptin production.
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Affiliation(s)
- Saroj Nepal
- College of Pharmacy, Yeungnam University, Gyeongsangbuk-do, Republic of Korea
| | - Mi Jin Kim
- College of Pharmacy, Yeungnam University, Gyeongsangbuk-do, Republic of Korea
| | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Sang Hyun Kim
- Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Dong-Hwan Sohn
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, Republic of Korea
| | - Sung Hee Lee
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, Republic of Korea
| | - Kyung Song
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, Republic of Korea
| | - Dong Young Choi
- College of Pharmacy, Yeungnam University, Gyeongsangbuk-do, Republic of Korea
| | - Eung Seok Lee
- College of Pharmacy, Yeungnam University, Gyeongsangbuk-do, Republic of Korea
| | - Pil-Hoon Park
- College of Pharmacy, Yeungnam University, Gyeongsangbuk-do, Republic of Korea
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