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Lagarde CB, Thapa K, Cullen NM, Hawes ML, Salim K, Benz MC, Dietrich SR, Burow BE, Bunnell BA, Martin EC, Collins-Burow BM, Lynch RM, Hoang VT, Burow ME, Fang JS. Obesity and leptin in breast cancer angiogenesis. Front Endocrinol (Lausanne) 2024; 15:1465727. [PMID: 39439572 PMCID: PMC11493622 DOI: 10.3389/fendo.2024.1465727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 09/04/2024] [Indexed: 10/25/2024] Open
Abstract
At the time of breast cancer diagnosis, most patients meet the diagnostic criteria to be classified as obese or overweight. This can significantly impact patient outcome: breast cancer patients with obesity (body mass index > 30) have a poorer prognosis compared to patients with a lean BMI. Obesity is associated with hyperleptinemia, and leptin is a well-established driver of metastasis in breast cancer. However, the effect of hyperleptinemia on angiogenesis in breast cancer is less well-known. Angiogenesis is an important process in breast cancer because it is essential for tumor growth beyond 1mm3 in size as well as cancer cell circulation and metastasis. This review investigates the role of leptin in regulating angiogenesis, specifically within the context of breast cancer and the associated tumor microenvironment in obese patients.
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Affiliation(s)
- Courtney B. Lagarde
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Kapil Thapa
- Department of Cell and Molecular Biology, Tulane University School of Science and Engineering, New Orleans, LA, United States
| | - Nicole M. Cullen
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Mackenzie L. Hawes
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Khudeja Salim
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Megan C. Benz
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Sophie R. Dietrich
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
- United States Department of Agriculture Southern Regional Research Center, New Orleans, LA, United States
| | - Brandon E. Burow
- Department of Cell and Molecular Biology, Tulane University School of Science and Engineering, New Orleans, LA, United States
| | - Bruce A. Bunnell
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Elizabeth C. Martin
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Bridgette M. Collins-Burow
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Ronald M. Lynch
- Department of Physiology, College of Medicine, University of Arizona, Tucson, AZ, United States
| | - Van T. Hoang
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
| | - Matthew E. Burow
- Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, LA, United States
- Tulane University Cancer Center, New Orleans, LA, United States
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, United States
- Department of Surgery, Tulane University School of Medicine, New Orleans, LA, United States
| | - Jennifer S. Fang
- Department of Cell and Molecular Biology, Tulane University School of Science and Engineering, New Orleans, LA, United States
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
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Cook CE, Keter D, Cade WT, Winkelstein BA, Reed WR. Manual therapy and exercise effects on inflammatory cytokines: a narrative overview. FRONTIERS IN REHABILITATION SCIENCES 2024; 5:1305925. [PMID: 38745971 PMCID: PMC11091266 DOI: 10.3389/fresc.2024.1305925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 04/12/2024] [Indexed: 05/16/2024]
Abstract
Background Matching disease and treatment mechanisms is a goal of the Precision Medicine Initiative. Pro- and anti-inflammatory cytokines (e.g., Tumor Necrosis Factor-alpha, Transforming Growth Factor-beta, and Interleukin-2, 10, and 12) have gained a significant amount of interest in their potential role in persistent pain for musculoskeletal (MSK) conditions. Manual therapy (MT) and exercise are two guideline-recommended approaches for treating MSK conditions. The objective of this narrative overview was to investigate of the effects of MT and exercise on pro- and anti-inflammatory cytokines and determine the factors that lead to variability in results. Methods Two reviewers evaluated the direction and variabilities of MT and exercise literature. A red, yellow, and green light scoring system was used to define consistencies. Results Consistencies in responses were seen with acute and chronic exercise and both pro- and anti-inflammatory cytokines. Chronic exercise is associated with a consistent shift towards a more anti-inflammatory cytokine profile (Transforming Growth Factor-beta, and Interleukin-2 and 13, whereas acute bouts of intense exercise can transiently increase pro-inflammatory cytokine levels. The influence of MT on cytokines was less commonly studied and yielded more variable results. Conclusion Variability in findings is likely related to the subject and their baseline condition or disease, when measurement occurs, and the exercise intensity, duration, and an individual's overall health and fitness.
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Affiliation(s)
- Chad E. Cook
- Doctor of Physical Therapy Division, Department of Orthopaedics, Duke University, Durham, NC, United States
- Department of Population Health Sciences, Duke University, Durham, NC, United States
- Duke Clinical Research Institute, Duke University, Durham, NC, United States
| | - Damian Keter
- Department of Veterans Affairs Medical Center, Cleveland, OH, United States
| | - William Todd Cade
- Doctor of Physical Therapy Division, Department of Orthopaedics, Duke University, Durham, NC, United States
| | - Beth A. Winkelstein
- Departments of Bioengineering & Neurosurgery, University of Pennsylvania, Philadelphia, PA, United States
| | - William R. Reed
- Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, AL, United States
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Meneu A, Lavoué V, Guillermet S, Levêque J, Mathelin C, Brousse S. [How could physical activity decrease the risk of breast cancer development and recurrence?]. GYNECOLOGIE, OBSTETRIQUE, FERTILITE & SENOLOGIE 2024; 52:158-164. [PMID: 38244776 DOI: 10.1016/j.gofs.2024.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 01/10/2024] [Indexed: 01/22/2024]
Abstract
OBJECTIVES Breast cancer is the most frequent and deadly cancer among women. In France, 50% of adults are currently overweight, mostly as a result of a sedentary lifestyle. Numerous studies have highlighted overweight, obesity and lack of physical activity as risk factors for the occurrence and prognosis of cancers, particularly breast cancer. The aim of this study was to understand the extent to which physical activity can improve this prognosis, and what the pathophysiology is. METHODS The Senology Commission of the Collège national des gynécologues et obstétriciens français (CNGOF) based its responses on an analysis of the international literature using a Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) methodology conducted on the PubMed database between 1994 and 2023. RESULTS A total of 70 articles were selected, demonstrating the role of regular physical activity in reducing the risk of breast cancer occurrence and recurrence. This role in controlling carcinogenesis is mediated by metabolic factors such as leptin, adiponectin and insulin, sex hormones and inflammation. The signaling pathways deregulated by these molecules are known carcinogenic pathways which could be used as therapeutic targets adapted to this population, without replacing the essential hygienic-dietary recommendations. CONCLUSION Physical activity has a protective effect on breast cancer risk and prognosis. We must therefore continue to raise awareness in the general population and promote physical activity as a means of primary, secondary, and tertiary prevention.
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Affiliation(s)
- Alisée Meneu
- Service de chirurgie, centre Eugène-Marquis, avenue de la Bataille Flandres-Dunkerque, 35042 Rennes cedex, France
| | - Vincent Lavoué
- Service de chirurgie, centre Eugène-Marquis, avenue de la Bataille Flandres-Dunkerque, 35042 Rennes cedex, France; Service de gynécologie-obstétrique, CHU de Rennes, Rennes, France
| | - Sophie Guillermet
- Service de chirurgie, centre Eugène-Marquis, avenue de la Bataille Flandres-Dunkerque, 35042 Rennes cedex, France
| | - Jean Levêque
- Service de chirurgie, centre Eugène-Marquis, avenue de la Bataille Flandres-Dunkerque, 35042 Rennes cedex, France; Service de gynécologie-obstétrique, CHU de Rennes, Rennes, France
| | - Carole Mathelin
- Service de chirurgie, ICANS, CHRU avenue Molière, avenue Albert-Calmette, 67200 Strasbourg, France
| | - Susie Brousse
- Service de chirurgie, centre Eugène-Marquis, avenue de la Bataille Flandres-Dunkerque, 35042 Rennes cedex, France; Inserm UMR_S 1242, Chemistry Oncogenesis Stress Signaling, université de Rennes, Rennes, France.
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Haif SK, Al Kury LT, Talib WH. Combination of Thymoquinone and Intermittent Fasting as a Treatment for Breast Cancer Implanted in Mice. PLANTS (BASEL, SWITZERLAND) 2023; 13:35. [PMID: 38202341 PMCID: PMC10780740 DOI: 10.3390/plants13010035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/14/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024]
Abstract
Breast cancer stands out as a particularly challenging form of cancer to treat among various types. Traditional treatment methods have been longstanding approaches, yet their efficacy has diminished over time owing to heightened toxicity, adverse effects, and the emergence of multi-drug resistance. Nevertheless, a viable solution has emerged through the adoption of a complementary treatment strategy utilizing natural substances and the incorporation of intermittent fasting to enhance therapeutic outcomes. This study aimed to assess the anticancer activity of thymoquinone (TQ), intermittent fasting, and their combination using in vivo and in vitro methods. The anti-proliferative activity of TQ and fasting (glucose/serum restriction) were evaluated against the T47D, MDA-MB-231, and EMT6 cell lines and compared to normal cell lines (Vero) using the MTT colorimetric assay method. Additionally, this study aimed to determine the half-maximal inhibitory concentration (IC50) of TQ. For the in vivo experiment, the antitumor activity of TQ and intermittent fasting (IF) was assessed by measuring the tumor sizes using a digital caliper to determine the change in the tumor size and survival rates. At the molecular level, the serum levels of glucose, β-hydroxybutyrate (β-HB), leptin, and insulin growth factor-1 (IGF-1) were measured using standard kits. Additionally, the aspartate transaminase (AST), alanine transaminase (ALT), and creatinine serum levels were measured. The inhibition of the breast cancer cell lines was achieved by TQ. TQ and intermittent fasting both had an additional anticancer effect against breast tumors inoculated in mice. The combination therapy was evaluated and found to significantly reduce the tumor size, with a change in tumor size of -57.7%. Additionally, the combination of TQ and IF led to a decrease in the serum levels of glucose, IGF-1 (24.49 ng/mL) and leptin (1.77 ng/mL) while increasing β-hydroxybutyrate in the mice given combination therapy (200.86 nM) with no toxicity on the liver or kidneys. In the mice receiving combination therapy, TQ and IF treated breast cancer in an additive way without causing liver or kidney toxicity due to decreased levels of glucose, IGF-1, and leptin and increased levels of β-hydroxybutyrate. Further investigation is required to optimize the doses and determine the other possible mechanisms exhibited by the novel combination.
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Affiliation(s)
- Shatha Khaled Haif
- Department of Clinical Pharmacy and Therapeutics, Applied Science Private University, Amman 11931-166, Jordan;
| | - Lina T. Al Kury
- Department of Health Sciences, College of Natural and Health Sciences, Zayed University, Abu Dhabi 144534, United Arab Emirates
| | - Wamidh H. Talib
- Faculty of Allied Medical Sciences, Applied Science Private University, Amman 11931-166, Jordan
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Arvelo F, Sojo F. Transición epitelio – mesenquima y cáncer. INVESTIGACIÓN CLÍNICA 2023; 64:379-404. [DOI: 10.54817/ic.v64n3a10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Cancer cell migration and invasion are critical components of metastatic disease, the leading cause of death in cancer patients. The epithe-lium-mesenchyme-transition (EMT) and mesenchyme-epithelium-transition (MET) are pathways involved in cancer metastasis. This process involves the degradation of cell-cell and cell-extracellular matrix junctions and the subse-quent loss of regulation of binding proteins such as E-cadherin. Cells undergo a reorganization of the cytoskeleton. These alterations are associated with a change in cell shape from epithelial to mesenchymal morphology. Understand-ing EMT and MET’s molecular and cellular basis provides fundamental insights into cancer etiology and may lead to new therapeutic strategies. In this review, we discuss some of the regulatory mechanisms and pathological role of epitheli-al-mesenchymal plasticity, focusing on the knowledge about the complexity and dynamics of this phenomenon in cancer
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Affiliation(s)
- Francisco Arvelo
- Fundación Instituto de Estudios Avanzados-IDEA, Area Salud, Caracas-Venezuela. Laboratorio de Cultivo de Tejidos y Biología de Tumores, Instituto de Biología Experimental, Universidad Central de Venezuela, Caracas, Venezuela
| | - Felipe Sojo
- Fundación Instituto de Estudios Avanzados-IDEA, Area Salud, Caracas-Venezuela. Laboratorio de Cultivo de Tejidos y Biología de Tumores, Instituto de Biología Experimental, Universidad Central de Venezuela, Caracas, Venezuela
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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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ÖZYURT R, ERKASAP N, ÖZKURT M, ERKASAP S, DİMAS K, ÇAKIR GÜNDOĞDU A, ULUKAYA E. Targeting of Notch, IL-1, and leptin has therapeutic potential in xenograft colorectal cancer. Turk J Biol 2023; 47:290-300. [PMID: 38152619 PMCID: PMC10751088 DOI: 10.55730/1300-0152.2663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 08/31/2023] [Accepted: 08/10/2023] [Indexed: 12/29/2023] Open
Abstract
Background/aim Colorectal cancer (CRC) is a fatal malignancy type and its occurence still needs to be explored mechanistically. Notch, IL-1, and leptin crosstalk is reported to play a role in the proliferation, migration, and expression of proangiogenic molecules. In this study, we aimed to investigate the effect of inhibition of Notch, IL-1, and leptin on CRC. Materials and methods To generate colorectal cancer tumor xenografts, 1 × 107 cells from exponentially growing cultures of HCT-15 cells were injected subcutaneously, at the axillary region of the left and right rear flanks of forty NOD.CB17-Prkdcscid/J (NOD/SCID) female mice. The mice were then monitored for the development of tumors and were randomly divided into five groups when tumor sizes reached a volume of approximately 150 mm3. Mice were used to determine the effectiveness of the gamma-secretase inhibitor (DAPT, Notch inhibitor), the interleukin-1 receptor antagonist (Anakinra) and the leptin receptor antagonist (Allo aca) against tumor growth. The mice were euthanized by CO2 inhalation immediately after the treatments finished, and all efforts were made to minimize suffering. Tumors were excissed for RT-PCR and histological analysis. Results There is an intact Notch, IL-1, and leptin signaling axis, and in vivo antagonism of Notch, IL-1, and leptin affects mRNA and protein expression of inflammatory and angiogenic molecules. Conclusion Present data suggest that targeting Notch, IL-1, and leptin may be possesses therapeutic potential in CRC.
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Affiliation(s)
- Rumeysa ÖZYURT
- Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX,
USA
- Department of Physiology, Eskişehir Osmangazi University Medical Faculty, Eskişehir,
Turkiye
| | - Nilüfer ERKASAP
- Department of Physiology, Eskişehir Osmangazi University Medical Faculty, Eskişehir,
Turkiye
| | - Mete ÖZKURT
- Department of Physiology, Eskişehir Osmangazi University Medical Faculty, Eskişehir,
Turkiye
| | - Serdar ERKASAP
- Department of General Surgery, Eskişehir Osmangazi University Medical Faculty, Eskişehir,
Turkiye
| | - Konstantinos DİMAS
- Department of Pharmacology, School of Health Science, Thessaly University, Larissa,
Greece
| | - Ayşe ÇAKIR GÜNDOĞDU
- Department of Histology and Embrology, Kütahya Health Sciences University Medical Faculty, Kütahya,
Turkiye
| | - Engin ULUKAYA
- Department of Clinical Biochemistry, Faculty of Medicine, İstinye University, İstanbul,
Turkiye
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Faida P, Attiogbe MKI, Majeed U, Zhao J, Qu L, Fan D. Lung cancer treatment potential and limits associated with the STAT family of transcription factors. Cell Signal 2023:110797. [PMID: 37423343 DOI: 10.1016/j.cellsig.2023.110797] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/19/2023] [Accepted: 07/04/2023] [Indexed: 07/11/2023]
Abstract
Lung cancer is one of the mortal cancers and the leading cause of cancer-related mortality, with a cancer survival rate of fewer than 5% in developing nations. This low survival rate can be linked to things like late-stage detection, quick postoperative recurrences in patients receiving therapy, and chemoresistance developing against various lung cancer treatments. Signal transducer and activator of transcription (STAT) family of transcription factors are involved in lung cancer cell proliferation, metastasis, immunological control, and treatment resistance. By interacting with specific DNA sequences, STAT proteins trigger the production of particular genes, which in turn result in adaptive and incredibly specific biological responses. In the human genome, seven STAT proteins have been discovered (STAT1 to STAT6, including STAT5a and STAT5b). Many external signaling proteins can activate unphosphorylated STATs (uSTATs), which are found inactively in the cytoplasm. When STAT proteins are activated, they can increase the transcription of several target genes, which leads to unchecked cellular proliferation, anti-apoptotic reactions, and angiogenesis. The effects of STAT transcription factors on lung cancer are variable; some are either pro- or anti-tumorigenic, while others maintain dual, context-dependent activities. Here, we give a succinct summary of the various functions that each member of the STAT family plays in lung cancer and go into more detail about the advantages and disadvantages of pharmacologically targeting STAT proteins and their upstream activators in the context of lung cancer treatment.
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Affiliation(s)
- Paison Faida
- Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Mawusse K I Attiogbe
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Usman Majeed
- College of Food Science and Technology, Northwest University, Xi'an, Shaanxi 710069, China
| | - Jing Zhao
- Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Linlin Qu
- Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China
| | - Daidi Fan
- Shaanxi Key Laboratory of Degradable Biomedical Materials and Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China; Biotech. & Biomed. Research Institute, Northwest University, Taibai North Road 229, Xi'an, Shaanxi 710069, China.
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Xie J, Li F, Cai Y, Zhang J, Zhang Y, Zhai Z, Su Z, Chen X, Lei M, Liu R, Li W, Kang D, Chen X, Hong A. SAIF plays anti-angiogenesis via blocking VEGF-VEGFR2-ERK signal in tumor treatment. Heliyon 2023; 9:e18240. [PMID: 37539189 PMCID: PMC10395482 DOI: 10.1016/j.heliyon.2023.e18240] [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: 02/18/2023] [Revised: 07/06/2023] [Accepted: 07/12/2023] [Indexed: 08/05/2023] Open
Abstract
Shark cartilage was created as a cancer-fighting diet because it was believed to have an element that may suppress tumor growth. Due to overfishing, sharks have become endangered recently, making it impossible to harvest natural components from shark cartilage for therapeutic development research. Previously, we identified a peptide SAIF from shark cartilage with an-tiangiogenic and anti-tumor effects, successfully expressed it in Escherichia coli by using genetic engineering techniques. However, we did not elucidate the specific target of SAIF and its antiangiogenic molecular mechanism, which hindered its further drug development. Therefore, in this work, the exact mechanism of action was studied using various techniques, including cellular and in vivo animal models, computer-aided simulation, molecular target capture, and transcriptome sequencing analysis. With VEGF-VEGFR2 interaction and preventing the activation of VEGFR2/ERK signaling pathways, SAIF was discovered to decrease angiogenesis and hence significantly limit tumor development. The findings further demonstrated SAIF's strong safety and pharmaceutically potential. The evidence showed that SAIF, which is expressed by, is a potent and safe angiogenesis inhibitor and might be developed as a candidate peptide drug for the treatment of solid tumors such as hepatocellular carcinoma and other conditions linked with angiogenic overgrowth.
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Affiliation(s)
- Junye Xie
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center; National Engineering Research Center of Genetic Medicine, Ji'nan University, Guangzhou, 510632, China
| | - Fu Li
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center; National Engineering Research Center of Genetic Medicine, Ji'nan University, Guangzhou, 510632, China
| | - Yuling Cai
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center; National Engineering Research Center of Genetic Medicine, Ji'nan University, Guangzhou, 510632, China
| | - Jinting Zhang
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center; National Engineering Research Center of Genetic Medicine, Ji'nan University, Guangzhou, 510632, China
| | - Yibo Zhang
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center; National Engineering Research Center of Genetic Medicine, Ji'nan University, Guangzhou, 510632, China
| | - Zhaodong Zhai
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center; National Engineering Research Center of Genetic Medicine, Ji'nan University, Guangzhou, 510632, China
| | - Zijian Su
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center; National Engineering Research Center of Genetic Medicine, Ji'nan University, Guangzhou, 510632, China
| | - Xue Chen
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center; National Engineering Research Center of Genetic Medicine, Ji'nan University, Guangzhou, 510632, China
| | - Minghua Lei
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center; National Engineering Research Center of Genetic Medicine, Ji'nan University, Guangzhou, 510632, China
| | - Rongzhan Liu
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center; National Engineering Research Center of Genetic Medicine, Ji'nan University, Guangzhou, 510632, China
| | - Weicai Li
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center; National Engineering Research Center of Genetic Medicine, Ji'nan University, Guangzhou, 510632, China
| | - Dianlong Kang
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center; National Engineering Research Center of Genetic Medicine, Ji'nan University, Guangzhou, 510632, China
| | - Xiaojia Chen
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center; National Engineering Research Center of Genetic Medicine, Ji'nan University, Guangzhou, 510632, China
- The First Affiliated Hospital, Ji'nan University, Guangzhou, 510630, China
| | - An Hong
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center; National Engineering Research Center of Genetic Medicine, Ji'nan University, Guangzhou, 510632, China
- The First Affiliated Hospital, Ji'nan University, Guangzhou, 510630, China
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Yang J, He J, Feng Y, Xiang M. Obesity contributes to hepatocellular carcinoma development via immunosuppressive microenvironment remodeling. Front Immunol 2023; 14:1166440. [PMID: 37266440 PMCID: PMC10231659 DOI: 10.3389/fimmu.2023.1166440] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 05/05/2023] [Indexed: 06/03/2023] Open
Abstract
It is generally recognized that the initiation of obesity-related hepatocellular carcinoma (HCC) is closely associated with hepatic inflammation. However, the paradoxical role of inflammation in the initiation and progression of HCC is highlighted by the fact that the inflammatory HCC is accompanied by significant immune effector cells infiltration compared to non-inflammatory HCC and HCC with enhanced immune response exhibits better survival. Importantly, the cancer progression has been primarily attributed to the immunosuppression, which can also be induced by obesity. Furthermore, the increased risk of viral infection and thus viral-HCC in obese individuals supports the view that obesity contributes to HCC via immunosuppression. Here, we have reviewed the various mechanisms responsible for obesity-induced tumor immune microenvironment and immunosuppression in obesity-related HCC. We highlight that the obesity-induced immunosuppression originates from lipid disorder as well as metabolic reprogramming and propose potential therapeutic strategy for HCC based on the current success of immunotherapy.
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11
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Habanjar O, Bingula R, Decombat C, Diab-Assaf M, Caldefie-Chezet F, Delort L. Crosstalk of Inflammatory Cytokines within the Breast Tumor Microenvironment. Int J Mol Sci 2023; 24:4002. [PMID: 36835413 PMCID: PMC9964711 DOI: 10.3390/ijms24044002] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/10/2023] [Accepted: 02/14/2023] [Indexed: 02/18/2023] Open
Abstract
Several immune and immunocompetent cells, including dendritic cells, macrophages, adipocytes, natural killer cells, T cells, and B cells, are significantly correlated with the complex discipline of oncology. Cytotoxic innate and adaptive immune cells can block tumor proliferation, and others can prevent the immune system from rejecting malignant cells and provide a favorable environment for tumor progression. These cells communicate with the microenvironment through cytokines, a chemical messenger, in an endocrine, paracrine, or autocrine manner. These cytokines play an important role in health and disease, particularly in host immune responses to infection and inflammation. They include chemokines, interleukins (ILs), adipokines, interferons, colony-stimulating factors (CSFs), and tumor necrosis factor (TNF), which are produced by a wide range of cells, including immune cells, such as macrophages, B-cells, T-cells, and mast cells, as well as endothelial cells, fibroblasts, a variety of stromal cells, and some cancer cells. Cytokines play a crucial role in cancer and cancer-related inflammation, with direct and indirect effects on tumor antagonistic or tumor promoting functions. They have been extensively researched as immunostimulatory mediators to promote the generation, migration and recruitment of immune cells that contribute to an effective antitumor immune response or pro-tumor microenvironment. Thus, in many cancers such as breast cancer, cytokines including leptin, IL-1B, IL-6, IL-8, IL-23, IL-17, and IL-10 stimulate while others including IL-2, IL-12, and IFN-γ, inhibit cancer proliferation and/or invasion and enhance the body's anti-tumor defense. Indeed, the multifactorial functions of cytokines in tumorigenesis will advance our understanding of cytokine crosstalk pathways in the tumor microenvironment, such as JAK/STAT, PI3K, AKT, Rac, MAPK, NF-κB, JunB, cFos, and mTOR, which are involved in angiogenesis, cancer proliferation and metastasis. Accordingly, targeting and blocking tumor-promoting cytokines or activating and amplifying tumor-inhibiting cytokines are considered cancer-directed therapies. Here, we focus on the role of the inflammatory cytokine system in pro- and anti-tumor immune responses, discuss cytokine pathways involved in immune responses to cancer and some anti-cancer therapeutic applications.
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Affiliation(s)
- Ola Habanjar
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Rea Bingula
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Caroline Decombat
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Mona Diab-Assaf
- Equipe Tumorigénèse Pharmacologie Moléculaire et Anticancéreuse, Faculté des Sciences II, Université Libanaise Fanar, Beyrouth 1500, Lebanon
| | - Florence Caldefie-Chezet
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
| | - Laetitia Delort
- Université Clermont-Auvergne, INRAE, UNH, Unité de Nutrition Humaine, CRNH-Auvergne, 63000 Clermont-Ferrand, France
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12
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Su YH, Wu YZ, Ann DK, Chen JLY, Kuo CY. Obesity promotes radioresistance through SERPINE1-mediated aggressiveness and DNA repair of triple-negative breast cancer. Cell Death Dis 2023; 14:53. [PMID: 36681663 PMCID: PMC9867751 DOI: 10.1038/s41419-023-05576-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/08/2023] [Accepted: 01/09/2023] [Indexed: 01/22/2023]
Abstract
Obesity is a risk factor in various types of cancer, including breast cancer. The disturbance of adipose tissue in obesity highly correlates with cancer progression and resistance to standard treatments such as chemo- and radio-therapies. In this study, in a syngeneic mouse model of triple-negative breast cancer (TNBC), diet-induced obesity (DIO) not only promoted tumor growth, but also reduced tumor response to radiotherapy. Serpine1 (Pai-1) was elevated in the circulation of obese mice and was enriched within tumor microenvironment. In vitro co-culture of human white adipocytes-conditioned medium (hAd-CM) with TNBC cells potentiated the aggressive phenotypes and radioresistance of TNBC cells. Moreover, inhibition of both cancer cell autonomous and non-autonomous SERPINE1 by either genetic or pharmacological strategy markedly dampened the aggressive phenotypes and radioresistance of TNBC cells. Mechanistically, we uncovered a previously unrecognized role of SERPINE1 in DNA damage response. Ionizing radiation-induced DNA double-strand breaks (DSBs) increased the expression of SERPINE1 in cancer cells in an ATM/ATR-dependent manner, and promoted nuclear localization of SERPINE1 to facilitate DSB repair. By analyzing public clinical datasets, higher SERPINE1 expression in TNBC correlated with patients' BMI as well as poor outcomes. Elevated SERPINE1 expression and nuclear localization were also observed in radioresistant breast cancer cells. Collectively, we reveal a link between obesity and radioresistance in TNBC and identify SERPINE1 to be a crucial factor mediating obesity-associated tumor radioresistance.
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Affiliation(s)
- Yong-Han Su
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Zhen Wu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - David K Ann
- Department of Diabetes Complications & Metabolism, City of Hope, Duarte, CA, USA
- Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA, USA
| | - Jenny Ling-Yu Chen
- Department of Radiology, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Radiation Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Ching-Ying Kuo
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
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13
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Pathophysiology of obesity and its associated diseases. Acta Pharm Sin B 2023. [DOI: 10.1016/j.apsb.2023.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
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14
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Ritter A, Kreis NN, Hoock SC, Solbach C, Louwen F, Yuan J. Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells, Obesity and the Tumor Microenvironment of Breast Cancer. Cancers (Basel) 2022; 14:3908. [PMID: 36010901 PMCID: PMC9405791 DOI: 10.3390/cancers14163908] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/01/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
Breast cancer is the most frequently diagnosed cancer and a common cause of cancer-related death in women. It is well recognized that obesity is associated with an enhanced risk of more aggressive breast cancer as well as reduced patient survival. Adipose tissue is the major microenvironment of breast cancer. Obesity changes the composition, structure, and function of adipose tissue, which is associated with inflammation and metabolic dysfunction. Interestingly, adipose tissue is rich in ASCs/MSCs, and obesity alters the properties and functions of these cells. As a key component of the mammary stroma, ASCs play essential roles in the breast cancer microenvironment. The crosstalk between ASCs and breast cancer cells is multilateral and can occur both directly through cell-cell contact and indirectly via the secretome released by ASC/MSC, which is considered to be the main effector of their supportive, angiogenic, and immunomodulatory functions. In this narrative review, we aim to address the impact of obesity on ASCs/MSCs, summarize the current knowledge regarding the potential pathological roles of ASCs/MSCs in the development of breast cancer, discuss related molecular mechanisms, underline the possible clinical significance, and highlight related research perspectives. In particular, we underscore the roles of ASCs/MSCs in breast cancer cell progression, including proliferation and survival, angiogenesis, migration and invasion, the epithelial-mesenchymal transition, cancer stem cell development, immune evasion, therapy resistance, and the potential impact of breast cancer cells on ASCS/MSCs by educating them to become cancer-associated fibroblasts. We conclude that ASCs/MSCs, especially obese ASCs/MSCs, may be key players in the breast cancer microenvironment. Targeting these cells may provide a new path of effective breast cancer treatment.
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Affiliation(s)
- Andreas Ritter
- Obstetrics and Prenatal Medicine, Gynecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany
| | | | | | | | | | - Juping Yuan
- Obstetrics and Prenatal Medicine, Gynecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany
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15
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Benot-Dominguez R, Cimini A, Barone D, Giordano A, Pentimalli F. The Emerging Role of Cyclin-Dependent Kinase Inhibitors in Treating Diet-Induced Obesity: New Opportunities for Breast and Ovarian Cancers? Cancers (Basel) 2022; 14:2709. [PMID: 35681689 PMCID: PMC9179653 DOI: 10.3390/cancers14112709] [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: 04/26/2022] [Revised: 05/26/2022] [Accepted: 05/26/2022] [Indexed: 12/24/2022] Open
Abstract
Overweight and obesity constitute the most impactful lifestyle-dependent risk factors for cancer and have been tightly linked to a higher number of tumor-related deaths nowadays. The excessive accumulation of energy can lead to an imbalance in the level of essential cellular biomolecules that may result in inflammation and cell-cycle dysregulation. Nutritional strategies and phytochemicals are gaining interest in the management of obesity-related cancers, with several ongoing and completed clinical studies that support their effectiveness. At the same time, cyclin-dependent kinases (CDKs) are becoming an important target in breast and ovarian cancer treatment, with various FDA-approved CDK4/6 inhibitors that have recently received more attention for their potential role in diet-induced obesity (DIO). Here we provide an overview of the most recent studies involving nutraceuticals and other dietary strategies affecting cell-cycle pathways, which might impact the management of breast and ovarian cancers, as well as the repurposing of already commercialized chemotherapeutic options to treat DIO.
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Affiliation(s)
- Reyes Benot-Dominguez
- Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA; (R.B.-D.); (A.G.)
| | - Annamaria Cimini
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy;
| | - Daniela Barone
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, 80131 Napoli, Italy;
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA; (R.B.-D.); (A.G.)
- Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
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16
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Shastri AA, Lombardo J, Okere SC, Higgins S, Smith BC, DeAngelis T, Palagani A, Hines K, Monti DA, Volpe S, Mitchell EP, Simone NL. Personalized Nutrition as a Key Contributor to Improving Radiation Response in Breast Cancer. Int J Mol Sci 2021; 23:175. [PMID: 35008602 PMCID: PMC8745527 DOI: 10.3390/ijms23010175] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/21/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Understanding metabolic and immune regulation inherent to patient populations is key to improving the radiation response for our patients. To date, radiation therapy regimens are prescribed based on tumor type and stage. Patient populations who are noted to have a poor response to radiation such as those of African American descent, those who have obesity or metabolic syndrome, or senior adult oncology patients, should be considered for concurrent therapies with radiation that will improve response. Here, we explore these populations of breast cancer patients, who frequently display radiation resistance and increased mortality rates, and identify the molecular underpinnings that are, in part, responsible for the radiation response and that result in an immune-suppressive tumor microenvironment. The resulting immune phenotype is discussed to understand how antitumor immunity could be improved. Correcting nutrient deficiencies observed in these populations should be considered as a means to improve the therapeutic index of radiation therapy.
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Affiliation(s)
- Anuradha A. Shastri
- Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (A.A.S.); (J.L.); (S.C.O.); (S.H.); (B.C.S.); (T.D.); (A.P.); (K.H.)
| | - Joseph Lombardo
- Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (A.A.S.); (J.L.); (S.C.O.); (S.H.); (B.C.S.); (T.D.); (A.P.); (K.H.)
| | - Samantha C. Okere
- Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (A.A.S.); (J.L.); (S.C.O.); (S.H.); (B.C.S.); (T.D.); (A.P.); (K.H.)
| | - Stephanie Higgins
- Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (A.A.S.); (J.L.); (S.C.O.); (S.H.); (B.C.S.); (T.D.); (A.P.); (K.H.)
| | - Brittany C. Smith
- Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (A.A.S.); (J.L.); (S.C.O.); (S.H.); (B.C.S.); (T.D.); (A.P.); (K.H.)
| | - Tiziana DeAngelis
- Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (A.A.S.); (J.L.); (S.C.O.); (S.H.); (B.C.S.); (T.D.); (A.P.); (K.H.)
| | - Ajay Palagani
- Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (A.A.S.); (J.L.); (S.C.O.); (S.H.); (B.C.S.); (T.D.); (A.P.); (K.H.)
| | - Kamryn Hines
- Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (A.A.S.); (J.L.); (S.C.O.); (S.H.); (B.C.S.); (T.D.); (A.P.); (K.H.)
| | - Daniel A. Monti
- Department of Integrative Medicine and Nutritional Sciences, Marcus Institute of Integrative Health, Thomas Jefferson University, Philadelphia, PA 19107, USA;
| | - Stella Volpe
- Department of Human Nutrition, Foods and Exercise, College of Agriculture and Life Sciences, Virginia Tech, Blacksburg, VA 24061, USA;
| | - Edith P. Mitchell
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA;
| | - Nicole L. Simone
- Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA; (A.A.S.); (J.L.); (S.C.O.); (S.H.); (B.C.S.); (T.D.); (A.P.); (K.H.)
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17
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Bahrami N, Jabeen S, Tahiri A, Sauer T, Ødegård HP, Geisler SB, Gravdehaug B, Reitsma LC, Selsås K, Kristensen V, Geisler J. Lack of cross-resistance between non-steroidal and steroidal aromatase inhibitors in breast cancer patients: the potential role of the adipokine leptin. Breast Cancer Res Treat 2021; 190:435-449. [PMID: 34554372 PMCID: PMC8558290 DOI: 10.1007/s10549-021-06399-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 09/11/2021] [Indexed: 11/01/2022]
Abstract
PURPOSE The aromatase inactivator exemestane may cause clinical disease stabilization following progression on non-steroidal aromatase inhibitors like letrozole in patients with metastatic breast cancer, indicating that additional therapeutic effects, not necessarily related to estrogen-suppression, may be involved in this well-known "lack of cross-resistance". METHODS Postmenopausal women with ER positive, HER-2 negative, locally advanced breast cancer were enrolled in the NEOLETEXE-trial and randomized to sequential treatment starting with either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) followed by the alternative aromatase inhibitor. Serum levels of 54 cytokines, including 12 adipokines were assessed using Luminex xMAP technology (multiple ELISA). RESULTS Serum levels of leptin were significantly decreased during treatment with exemestane (p < 0.001), regardless whether exemestane was given as first or second neoadjuvant therapy. In contrast, letrozole caused a non-significant increase in serum leptin levels in vivo. CONCLUSIONS Our findings suggest an additional and direct effect of exemestane on CYP-19 (aromatase) synthesis presumably due to effects on the CYP19 promoter use that is not present during therapy with the non-steroidal aromatase inhibitor letrozole. Our findings provide new insights into the influence of clinically important aromatase inhibitors on cytokine levels in vivo that contribute to the understanding of the clinically observed lack of cross-resistance between non-steroidal and steroidal aromatase inhibitors in breast cancer patients. TRIAL REGISTRATION Registered on March 23rd 2015 in the National trial database of Norway (Registration number: REK-SØ-84-2015).
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Affiliation(s)
- Nazli Bahrami
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway.,Department of Breast and Endocrine Surgery, Akershus University Hospital, Lørenskog, Norway
| | - Shakila Jabeen
- Department of Clinical Molecular Biology (EPIGEN), Akershus University Hospital, Lørenskog, Norway.,Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Andliena Tahiri
- Department of Clinical Molecular Biology (EPIGEN), Akershus University Hospital, Lørenskog, Norway.,Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Torill Sauer
- Department of Pathology, Akershus University Hospital, Lørenskog, Norway.,Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, University of Oslo, Oslo, Norway
| | | | | | - Berit Gravdehaug
- Department of Breast and Endocrine Surgery, Akershus University Hospital, Lørenskog, Norway
| | | | - Knut Selsås
- Department of Breast and Endocrine Surgery, Akershus University Hospital, Lørenskog, Norway
| | - Vessela Kristensen
- Department of Clinical Molecular Biology (EPIGEN), Akershus University Hospital, Lørenskog, Norway.,Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Jürgen Geisler
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway. .,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
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18
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Batty MJ, Chabrier G, Sheridan A, Gage MC. Metabolic Hormones Modulate Macrophage Inflammatory Responses. Cancers (Basel) 2021; 13:cancers13184661. [PMID: 34572888 PMCID: PMC8467249 DOI: 10.3390/cancers13184661] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/31/2021] [Accepted: 09/13/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Macrophages are a type of immune cell which play an important role in the development of cancer. Obesity increases the risk of cancer and obesity also causes disruption to the normal levels of hormones that are produced to coordinate metabolism. Recent research now shows that these metabolic hormones also play important roles in macrophage immune responses and so through macrophages, disrupted metabolic hormone levels may promote cancer. This review article aims to highlight and summarise these recent findings so that the scientific community may better understand how important this new area of research is, and how these findings can be capitalised on for future scientific studies. Abstract Macrophages are phagocytotic leukocytes that play an important role in the innate immune response and have established roles in metabolic diseases and cancer progression. Increased adiposity in obese individuals leads to dysregulation of many hormones including those whose functions are to coordinate metabolism. Recent evidence suggests additional roles of these metabolic hormones in modulating macrophage inflammatory responses. In this review, we highlight key metabolic hormones and summarise their influence on the inflammatory response of macrophages and consider how, in turn, these hormones may influence the development of different cancer types through the modulation of macrophage functions.
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Blaszczak AM, Quiroga D, Jalilvand A, Torres Matias GS, Wright VP, Liu J, Yu L, Bradley D, Hsueh WA, Carson WE. Characterization of inflammatory changes in the breast cancer associated adipose tissue and comparison to the unaffected contralateral breast. Surg Oncol 2021; 39:101659. [PMID: 34534729 DOI: 10.1016/j.suronc.2021.101659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 09/06/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND Adipose tissue has emerged as an important window into cancer pathophysiology, revealing potential targets for novel therapeutic interventions. The goal of this study was to compare the breast adipose tissue (BrAT) immune milieu surrounding breast carcinoma and contralateral unaffected breast tissue obtained from the same patient. MATERIALS AND METHODS Patients undergoing bilateral mastectomy for unilateral breast cancer were enrolled for bilateral BrAT collection at the time of operation. After BrAT was processed, adipocyte and stromal vascular fraction (SVF) gene expression was quantified by PCR. SVF cells were also processed for flow cytometric immune cell characterization. RESULTS Twelve patients underwent bilateral mastectomy for unilateral ductal carcinoma. BrAT adipocyte CXCL2 gene expression trended higher in the tumor-affected breast as compared to the unaffected breast. Macrophage MCP-1 and PPARγ gene expression also tended to be higher in the tumor-affected breasts. T cell gene expression of FOXP3 (p = 0.0370) were significantly greater in tumor-affected breasts than unaffected breasts. Affected BrAT contained higher numbers of Th2 CD4+ cells (p = 0.0165) and eosinophils (p = 0.0095) while trending towards increased macrophage and lower Th1 CD4+ cells infiltration than tumor-affected BrAT. CONCLUSION This preliminary study aimed to identify the immunologic environment present within BrAT and is the first to directly compare this in individual patients' tumor-associated and unaffected BrAT. These findings suggest that cancer-affected BrAT had increased levels of T cell specific FOXP3 and higher levels of anti-inflammatory/regulatory cells compared to the contralateral BrAT.
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Affiliation(s)
- Alecia M Blaszczak
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Dionisia Quiroga
- The Ohio State University Comprehensive Cancer Center, The Ohio State University, 410 W 12th Avenue, Columbus, OH, 43210, USA; Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Starling Loving Hall, 320 W10th Ave, Columbus, OH, 43210, USA
| | - Anahita Jalilvand
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Gina S Torres Matias
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Valerie P Wright
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Joey Liu
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Lianbo Yu
- Center for Biostatistics, The Ohio State University, 2012 Kenny Rd, Columbus, OH, 43221, USA
| | - David Bradley
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - Willa A Hsueh
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA
| | - William E Carson
- The Ohio State University Comprehensive Cancer Center, The Ohio State University, 410 W 12th Avenue, Columbus, OH, 43210, USA; Department of Surgery, The Ohio State University, 410 W 10th Ave, N911 Doan Hall, Columbus, OH, 43210, USA.
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20
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Nidamanuri AL, Prince LLL, Mahapatra RK, Murugesan S. Effect on physiological and production parameters upon supplementation of fermented yeast culture to Nicobari chickens during and post summer. J Anim Physiol Anim Nutr (Berl) 2021; 106:284-295. [PMID: 34110055 DOI: 10.1111/jpn.13579] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 04/26/2021] [Accepted: 05/07/2021] [Indexed: 12/11/2022]
Abstract
Nicobari is an indigenous bird reared for meat and eggs. This study evaluated the effect of heat stress on plasma levels of leptin, growth hormone and their receptors, liver AMP kinase, plasma cholesterol and lipid peroxide (MDA). The laying period coincided with the post summer period. The birds were equally divided into three groups, control group was offered ad libitum feed and treatment groups were supplemented with fermented yeast culture at 700 mg (T1) and 1.4 g/kg (T2) of feed/day. The levels of plasma Leptin and GH hormones were higher (p < 0.05) in the control group when compared to the treatment groups. The expression of the hormone receptors was higher in the brain, and MMP3 gene expression in the magnum was lower in the treatment group. Plasma cholesterol, MDA and AMP kinase were significantly higher (p < 0.05) in the control group. Fermented yeast culture supplementation decreased feed intake and increased egg production parameters, which indicates a greater efficiency of supplementation. Supplementation reduced the severity of necrosis of villi in the jejunum when compared to control. In conclusion, higher ambient temperature during summer had negative effect on production parameters through modulation of physiological parameters which could be ameliorated by supplementation of FYC.
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Wang L, Li J, Qiao J, Guo X, Bian X, Guo L, Liu Z, Lu Z. Establishment of a model for predicting sentinel lymph node metastasis in early breast cancer based on contrast-enhanced ultrasound and clinicopathological features. Gland Surg 2021; 10:1701-1712. [PMID: 34164314 DOI: 10.21037/gs-21-245] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background Sentinel lymph node (SLN) biopsy (SLNB) is the standard procedure for axillary staging in clinically node-negative (cN0) breast cancer patients. However, the positive rate of SLNs among cN0 stage patients is 26-35%. The identification of appropriate candidates for SLNB is quite challenging. This study aimed to establish and verify a predictive model of SLN metastasis using contrast-enhanced ultrasound (CEUS) and other clinicopathological indicators. Methods The clinicopathological data of 224 patients who had undergone SLNB at the Affiliated Cancer Hospital of Zhengzhou University from June 2018 to July 2019 were analyzed retrospectively. The risk prediction model of SLN metastasis was established by logistic regression analysis. According to the β value of each variable in the model, a risk score system of SLN metastasis was established and verified using the internal population. The predictive model was prospectively applied to 73 patients from July 2019 to September 2019 to evaluate the clinical value of the model in patients with early breast cancer. Results Multivariate analysis confirmed that body mass index (BMI), SLN aspect ratio of CEUS mode, SLN aspect ratio of mammography, lympho-vascular invasion, and cytokeratin (CK)5/6 were independent risk factors for SLN metastasis. A scoring system was established according to the above risk factors, and a receiver operating characteristic (ROC) curve was drawn. After internal- and external verification, a corrected ROC curve was drawn, respectively. The ROC curve of the modeling group, internal verification group, and external verification group was 0.9075 (95% CI: 0.8616-0.9534), 0.8766 (95% CI: 0.8192-0.9341), and 0.8505 (95% CI: 0.7333-0.9676), respectively. Conclusions We constructed and verified a prediction model of SLN metastasis in early breast cancer. The model has a specific predictive value for preoperative evaluation of SLN status.
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Affiliation(s)
- Lina Wang
- Department of Breast Surgery, Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital), Zhengzhou, China
| | - Juntao Li
- Department of Breast Surgery, Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital), Zhengzhou, China
| | - Jianghua Qiao
- Department of Breast Surgery, Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital), Zhengzhou, China
| | - Xiaoxia Guo
- Department of Ultrasound, Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital), Zhengzhou, China
| | - Xiaolin Bian
- Department of Ultrasound, Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital), Zhengzhou, China
| | - Lanwei Guo
- Henan Office for Cancer Control and Research, Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital), Zhengzhou, China
| | - Zhenzhen Liu
- Department of Breast Surgery, Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital), Zhengzhou, China
| | - Zhenduo Lu
- Department of Breast Surgery, Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital), Zhengzhou, China
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Unraveling the Role of Leptin in Liver Function and Its Relationship with Liver Diseases. Int J Mol Sci 2020; 21:ijms21249368. [PMID: 33316927 PMCID: PMC7764544 DOI: 10.3390/ijms21249368] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/19/2020] [Accepted: 12/04/2020] [Indexed: 02/06/2023] Open
Abstract
Since its discovery twenty-five years ago, the fat-derived hormone leptin has provided a revolutionary framework for studying the physiological role of adipose tissue as an endocrine organ. Leptin exerts pleiotropic effects on many metabolic pathways and is tightly connected with the liver, the major player in systemic metabolism. As a consequence, understanding the metabolic and hormonal interplay between the liver and adipose tissue could provide us with new therapeutic targets for some chronic liver diseases, an increasing problem worldwide. In this review, we assess relevant literature regarding the main metabolic effects of leptin on the liver, by direct regulation or through the central nervous system (CNS). We draw special attention to the contribution of leptin to the non-alcoholic fatty liver disease (NAFLD) pathogenesis and its progression to more advanced stages of the disease as non-alcoholic steatohepatitis (NASH). Likewise, we describe the contribution of leptin to the liver regeneration process after partial hepatectomy, the mainstay of treatment for certain hepatic malignant tumors.
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Boothby-Shoemaker W, Benham V, Paithankar S, Shankar R, Chen B, Bernard JJ. The Relationship between Leptin, the Leptin Receptor and FGFR1 in Primary Human Breast Tumors. Cells 2020; 9:E2224. [PMID: 33019728 PMCID: PMC7600295 DOI: 10.3390/cells9102224] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 09/23/2020] [Accepted: 09/28/2020] [Indexed: 01/09/2023] Open
Abstract
Obesity is associated with increased breast cancer risk and poorer cancer outcomes; however, the precise etiology of these observations has not been fully identified. Our previous research suggests that adipose tissue-derived fibroblast growth factor-2 (FGF2) promotes the malignant transformation of epithelial cells through the activation of fibroblast growth factor receptor-1 (FGFR1). FGF2 is increased in the context of obesity, and increased sera levels have been associated with endocrine-resistant breast cancer. Leptin is a marker of obesity and promotes breast carcinogenesis through several mechanisms. In this study, we leverage public gene expression datasets to evaluate the associations between FGFR1, leptin, and the leptin receptor (LepR) in breast cancer. We show a positive association between FGFR1 and leptin protein copy number in primary breast tumors. These observations coincided with a positive association between Janus kinase 2 (Jak2) mRNA with both leptin receptor (LepR) mRNA and FGFR1 mRNA. Moreover, two separate Jak2 inhibitors attenuated both leptin+FGF2-stimulated and mouse adipose tissue-stimulated MCF-10A transformation. These results demonstrate how elevated sera FGF2 and leptin in obese patients may promote cancer progression in tumors that express elevated FGFR1 and LepR through Jak2 signaling. Therefore, Jak2 is a potential therapeutic target for FGFR1 amplified breast cancer, especially in the context of obesity.
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Affiliation(s)
- Wyatt Boothby-Shoemaker
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA; (W.B.-S.); (V.B.); (B.C.)
| | - Vanessa Benham
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA; (W.B.-S.); (V.B.); (B.C.)
| | - Shreya Paithankar
- Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, USA; (S.P.); (R.S.)
| | - Rama Shankar
- Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, USA; (S.P.); (R.S.)
| | - Bin Chen
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA; (W.B.-S.); (V.B.); (B.C.)
- Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, USA; (S.P.); (R.S.)
| | - Jamie J. Bernard
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA; (W.B.-S.); (V.B.); (B.C.)
- Nicolas V. Perricone Division of Dermatology, Department of Medicine, Michigan State University, East Lansing, MI 48824, USA
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Pérez-Pérez A, Sánchez-Jiménez F, Vilariño-García T, Sánchez-Margalet V. Role of Leptin in Inflammation and Vice Versa. Int J Mol Sci 2020; 21:E5887. [PMID: 32824322 PMCID: PMC7460646 DOI: 10.3390/ijms21165887] [Citation(s) in RCA: 174] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/07/2020] [Accepted: 08/14/2020] [Indexed: 12/15/2022] Open
Abstract
Inflammation is an essential immune response for the maintenance of tissue homeostasis. In a general sense, acute and chronic inflammation are different types of adaptive response that are called into action when other homeostatic mechanisms are insufficient. Although considerable progress has been made in understanding the cellular and molecular events that are involved in the acute inflammatory response to infection and tissue injury, the causes and mechanisms of systemic chronic inflammation are much less known. The pathogenic capacity of this type of inflammation is puzzling and represents a common link of the multifactorial diseases, such as cardiovascular diseases and type 2 diabetes. In recent years, interest has been raised by the discovery of novel mediators of inflammation, such as microRNAs and adipokines, with different effects on target tissues. In the present review, we discuss the data emerged from research of leptin in obesity as an inflammatory mediator sustaining multifactorial diseases and how this knowledge could be instrumental in the design of leptin-based manipulation strategies to help restoration of abnormal immune responses. On the other direction, chronic inflammation, either from autoimmune or infectious diseases, or impaired microbiota (dysbiosis) may impair the leptin response inducing resistance to the weight control, and therefore it may be a cause of obesity. Thus, we are reviewing the published data regarding the role of leptin in inflammation, and the other way around, the role of inflammation on the development of leptin resistance and obesity.
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Affiliation(s)
- Antonio Pérez-Pérez
- Department of Medical Biochemistry and Molecular Biology, and Immunology, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain; (F.S.-J.); (T.V.-G.)
| | | | | | - Víctor Sánchez-Margalet
- Department of Medical Biochemistry and Molecular Biology, and Immunology, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain; (F.S.-J.); (T.V.-G.)
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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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Gelsomino L, Naimo GD, Malivindi R, Augimeri G, Panza S, Giordano C, Barone I, Bonofiglio D, Mauro L, Catalano S, Andò S. Knockdown of Leptin Receptor Affects Macrophage Phenotype in the Tumor Microenvironment Inhibiting Breast Cancer Growth and Progression. Cancers (Basel) 2020; 12:cancers12082078. [PMID: 32727138 PMCID: PMC7464041 DOI: 10.3390/cancers12082078] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/17/2020] [Accepted: 07/23/2020] [Indexed: 12/12/2022] Open
Abstract
Aberrant leptin (Ob) signaling, a hallmark of obesity, has been recognized to influence breast cancer (BC) biology within the tumor microenvironment (TME). Here, we evaluated the impact of leptin receptor (ObR) knockdown in affecting BC phenotype and in mediating the interaction between tumor cells and macrophages, the most abundant immune cells within the TME. The stable knockdown of ObR (ObR sh) in ERα-positive and ERα-negative BC cells turned the tumor phenotype into a less aggressive one, as evidenced by in vitro and in vivo models. In xenograft tumors and in co-culture experiments between circulating monocytes and BC cells, the absence of ObR reduced the recruitment of macrophages, and also affected their cytokine mRNA expression profile. This was associated with a decreased expression and secretion of monocyte chemoattractant protein-1 in ObR sh clones. The loss of Ob/ObR signaling modulated the immunosuppressive TME, as shown by a reduced expression of programmed death ligand 1/programmed cell death protein 1/arginase 1. In addition, we observed increased phagocytic activity of macrophages compared to control Sh clones in the presence of ObR sh-derived conditioned medium. Our findings, addressing an innovative role of ObR in modulating immune TME, may open new avenues to improve BC patient health care.
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Affiliation(s)
- Luca Gelsomino
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (L.G.); (G.D.N.); (R.M.); (G.A.); (S.P.); (C.G.); (I.B.); (D.B.); (L.M.); (S.C.)
| | - Giuseppina Daniela Naimo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (L.G.); (G.D.N.); (R.M.); (G.A.); (S.P.); (C.G.); (I.B.); (D.B.); (L.M.); (S.C.)
| | - Rocco Malivindi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (L.G.); (G.D.N.); (R.M.); (G.A.); (S.P.); (C.G.); (I.B.); (D.B.); (L.M.); (S.C.)
| | - Giuseppina Augimeri
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (L.G.); (G.D.N.); (R.M.); (G.A.); (S.P.); (C.G.); (I.B.); (D.B.); (L.M.); (S.C.)
| | - Salvatore Panza
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (L.G.); (G.D.N.); (R.M.); (G.A.); (S.P.); (C.G.); (I.B.); (D.B.); (L.M.); (S.C.)
| | - Cinzia Giordano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (L.G.); (G.D.N.); (R.M.); (G.A.); (S.P.); (C.G.); (I.B.); (D.B.); (L.M.); (S.C.)
- Centro Sanitario, University of Calabria, 87036 Rende (CS), Italy
| | - Ines Barone
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (L.G.); (G.D.N.); (R.M.); (G.A.); (S.P.); (C.G.); (I.B.); (D.B.); (L.M.); (S.C.)
| | - Daniela Bonofiglio
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (L.G.); (G.D.N.); (R.M.); (G.A.); (S.P.); (C.G.); (I.B.); (D.B.); (L.M.); (S.C.)
- Centro Sanitario, University of Calabria, 87036 Rende (CS), Italy
| | - Loredana Mauro
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (L.G.); (G.D.N.); (R.M.); (G.A.); (S.P.); (C.G.); (I.B.); (D.B.); (L.M.); (S.C.)
| | - Stefania Catalano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (L.G.); (G.D.N.); (R.M.); (G.A.); (S.P.); (C.G.); (I.B.); (D.B.); (L.M.); (S.C.)
- Centro Sanitario, University of Calabria, 87036 Rende (CS), Italy
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; (L.G.); (G.D.N.); (R.M.); (G.A.); (S.P.); (C.G.); (I.B.); (D.B.); (L.M.); (S.C.)
- Centro Sanitario, University of Calabria, 87036 Rende (CS), Italy
- Correspondence: ; Tel.: +39-0984-496201; Fax: +39-0984-496203
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Panza S, Russo U, Giordano F, Leggio A, Barone I, Bonofiglio D, Gelsomino L, Malivindi R, Conforti FL, Naimo GD, Giordano C, Catalano S, Andò S. Leptin and Notch Signaling Cooperate in Sustaining Glioblastoma Multiforme Progression. Biomolecules 2020; 10:biom10060886. [PMID: 32526957 PMCID: PMC7356667 DOI: 10.3390/biom10060886] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/27/2020] [Accepted: 06/06/2020] [Indexed: 12/21/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most malignant form of glioma, which represents one of the commonly occurring tumors of the central nervous system. Despite the continuous development of new clinical therapies against this malignancy, it still remains a deadly disease with very poor prognosis. Here, we demonstrated the existence of a biologically active interaction between leptin and Notch signaling pathways that sustains GBM development and progression. We found that the expression of leptin and its receptors was significantly higher in human glioblastoma cells, U-87 MG and T98G, than in a normal human glial cell line, SVG p12, and that activation of leptin signaling induced growth and motility in GBM cells. Interestingly, flow cytometry and real-time RT-PCR assays revealed that GBM cells, grown as neurospheres, displayed stem cell-like properties (CD133+) along with an enhanced expression of leptin receptors. Leptin treatment significantly increased the neurosphere forming efficiency, self-renewal capacity, and mRNA expression levels of the stemness markers CD133, Nestin, SOX2, and GFAP. Mechanistically, we evidenced a leptin-mediated upregulation of Notch 1 receptor and the activation of its downstream effectors and target molecules. Leptin-induced effects on U-87 MG and T98G cells were abrogated by the selective leptin antagonist, the peptide LDFI (Leu-Asp-Phe-Ile), as well as by the specific Notch signaling inhibitor, GSI (Gamma Secretase Inhibitor) and in the presence of a dominant-negative of mastermind-like-1. Overall, these findings demonstrate, for the first time, a functional interaction between leptin and Notch signaling in GBM, highlighting leptin/Notch crosstalk as a potential novel therapeutic target for GBM treatment.
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Affiliation(s)
- Salvatore Panza
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
| | - Umberto Russo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
| | - Francesca Giordano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
| | - Antonella Leggio
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
| | - Ines Barone
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
| | - Daniela Bonofiglio
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
- Centro Sanitario, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy
| | - Luca Gelsomino
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
| | - Rocco Malivindi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
| | - Francesca Luisa Conforti
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
- Centro Sanitario, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy
| | - Giuseppina Daniela Naimo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
| | - Cinzia Giordano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
- Centro Sanitario, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy
| | - Stefania Catalano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
- Centro Sanitario, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy
- Correspondence: (S.C.); (S.A.); Tel.: +39-0984-496207 (S.C.); +39-0984-496201 (S.A.)
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy; (S.P.); (U.R.); (F.G.); (A.L.); (I.B.); (D.B.); (L.G.); (R.M.); (F.L.C.); (G.D.N.); (C.G.)
- Centro Sanitario, University of Calabria, Via P. Bucci, 87036 Arcavacata di Rende (CS), Italy
- Correspondence: (S.C.); (S.A.); Tel.: +39-0984-496207 (S.C.); +39-0984-496201 (S.A.)
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Sabol RA, Villela VA, Denys A, Freeman BT, Hartono AB, Wise RM, Harrison MAA, Sandler MB, Hossain F, Miele L, Bunnell BA. Obesity-Altered Adipose Stem Cells Promote Radiation Resistance of Estrogen Receptor Positive Breast Cancer through Paracrine Signaling. Int J Mol Sci 2020; 21:ijms21082722. [PMID: 32326381 PMCID: PMC7216284 DOI: 10.3390/ijms21082722] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 04/10/2020] [Accepted: 04/10/2020] [Indexed: 12/17/2022] Open
Abstract
Obesity is associated with poorer responses to chemo- and radiation therapy for breast cancer, which leads to higher mortality rates for obese women who develop breast cancer. Adipose stem cells (ASCs) are an integral stromal component of the tumor microenvironment (TME). In this study, the effects of obesity-altered ASCs (obASCs) on estrogen receptor positive breast cancer cell’s (ER+BCCs) response to radiotherapy (RT) were evaluated. We determined that BCCs had a decreased apoptotic index and increased surviving fraction following RT when co-cultured with obASCs compared to lnASCs or non-co-cultured cells. Further, obASCs reduced oxidative stress and induced IL-6 expression in co-cultured BCCs after radiation. obASCs produce increased levels of leptin relative to ASCs from normal-weight individuals (lnASCs). obASCs upregulate the expression of IL-6 compared to non-co-cultured BCCs, but BCCs co-cultured with leptin knockdown obASCs did not upregulate IL-6. The impact of shLeptin obASCs on radiation resistance of ER+BCCs demonstrate a decreased radioprotective ability compared to shControl obASCs. Key NOTCH signaling players were enhanced in ER+BBCs following co-culture with shCtrl obASCs but not shLep obASCs. This work demonstrates that obesity-altered ASCs, via enhanced secretion of leptin, promote IL-6 and NOTCH signaling pathways in ER+BCCs leading to radiation resistance.
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Affiliation(s)
- Rachel A. Sabol
- Center for Stem Cell Research, Tulane University School of Medicine, New Orleans, LA 70112, USA; (R.A.S.); (V.A.V.); (A.D.); (R.M.W.); (M.A.A.H.); (M.B.S.)
| | - Vidal A. Villela
- Center for Stem Cell Research, Tulane University School of Medicine, New Orleans, LA 70112, USA; (R.A.S.); (V.A.V.); (A.D.); (R.M.W.); (M.A.A.H.); (M.B.S.)
| | - Alexandra Denys
- Center for Stem Cell Research, Tulane University School of Medicine, New Orleans, LA 70112, USA; (R.A.S.); (V.A.V.); (A.D.); (R.M.W.); (M.A.A.H.); (M.B.S.)
| | - Benjamin T. Freeman
- Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA 70112, USA;
| | - Alifiani B. Hartono
- Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA;
| | - Rachel M. Wise
- Center for Stem Cell Research, Tulane University School of Medicine, New Orleans, LA 70112, USA; (R.A.S.); (V.A.V.); (A.D.); (R.M.W.); (M.A.A.H.); (M.B.S.)
| | - Mark A. A. Harrison
- Center for Stem Cell Research, Tulane University School of Medicine, New Orleans, LA 70112, USA; (R.A.S.); (V.A.V.); (A.D.); (R.M.W.); (M.A.A.H.); (M.B.S.)
| | - Maxwell B. Sandler
- Center for Stem Cell Research, Tulane University School of Medicine, New Orleans, LA 70112, USA; (R.A.S.); (V.A.V.); (A.D.); (R.M.W.); (M.A.A.H.); (M.B.S.)
| | - Fokhrul Hossain
- Louisiana State University Health Sciences Center (LSUHSC), Department of Genetics, New Orleans, LA 70112, USA; (F.H.); (L.M.)
- Louisiana Cancer Research Center (LCRC), Stanley S. Scott Cancer Center, LSUSHC, New Orleans, LA 70112, USA
| | - Lucio Miele
- Louisiana State University Health Sciences Center (LSUHSC), Department of Genetics, New Orleans, LA 70112, USA; (F.H.); (L.M.)
- Louisiana Cancer Research Center (LCRC), Stanley S. Scott Cancer Center, LSUSHC, New Orleans, LA 70112, USA
| | - Bruce A. Bunnell
- Center for Stem Cell Research, Tulane University School of Medicine, New Orleans, LA 70112, USA; (R.A.S.); (V.A.V.); (A.D.); (R.M.W.); (M.A.A.H.); (M.B.S.)
- Department of Pharmacology, Tulane University, New Orleans, LA 70112, USA
- Division of Regenerative Medicine, Tulane National Primate Research Center, Covington, LA 70433, USA
- Correspondence: ; Tel.: +1-504-988-7071
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Le Guennec D, Rossary A. The interrelationship between physical activity and metabolic regulation of breast cancer progression in obesity via cytokine control. Cytokine Growth Factor Rev 2020; 52:76-87. [DOI: 10.1016/j.cytogfr.2020.02.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 02/03/2020] [Accepted: 02/03/2020] [Indexed: 12/20/2022]
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Atoum MF, Alzoughool F, Al-Hourani H. Linkage Between Obesity Leptin and Breast Cancer. BREAST CANCER-BASIC AND CLINICAL RESEARCH 2020; 14:1178223419898458. [PMID: 31975779 PMCID: PMC6956603 DOI: 10.1177/1178223419898458] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Accepted: 12/12/2019] [Indexed: 12/22/2022]
Abstract
Many cancers might be influenced by obesity, including breast cancer, the leading cause of cancer death among women. Obesity is a complex state associated with multiple physiological and molecular changes capable of modulating the behavior of breast tumor cells and the surrounding microenvironment. This review discussed the inverse association between obesity and breast cancer among premenopausal breast cancer females and the positive association among postmenopausal. Four mechanisms may link obesity and breast cancer including leptin and leptin receptor expression, adipose chronic inflammation, sex hormone alternation, and insulin and insulinlike growth factor 1 (IGF-1) signaling. Leptin has been involved in breast cancer initiation, development, and progression through signaling transduction network. Leptin functions are strengthened through cross talk with multiple oncogenes, cytokines, and growth factors. Adipose chronic inflammation promotes cancer growth and angiogenesis and modifies the immune responses. A pro-inflammatory microenvironment at tumor site promotes cytokines and pro-inflammatory mediators adjacent to the tumor. Leptin stimulates pro-inflammatory cytokines and promotes T-helper 1 responses. Obesity is common of chronic inflammation. In obese patients, white adipose tissue (WAT) will promote pro-inflammatory mediators that will encourage tumor growth and WAT inflammation. Sex hormone alternation of estrogens is associated with increased risk for hormone-sensitive breast cancers. Estrogens cause tumorigenesis by its effect on signaling pathways that lead to DNA damage, stimulation angiogenesis, mutagenesis, and cell proliferation. In postmenopausal females, and due to termination of ovarian function, estrogens were produced extra gonadally, mainly in peripheral adipose tissues where adrenal-produced androgen precursors are converted to estrogens. Active estradiol leads to breast cancer development by binding to ERα, which is modified by receptor’s interaction of various signal transduction pathways. Hyperinsulinemia and IGF-1 activate the MAPK and PI3K pathways, leading to cancer-promoting effects. Cross talk between insulin/IGF and estrogen signaling pathways promotes hormone-sensitive breast cancer development. Hyperinsulinemia is a risk factor for breast cancer that explains the obesity-breast cancer association. Controlling IGF-1 level and targeting IGF-1 receptors among different breast cancer subtypes may be useful for breast cancer treatment. This review discussed several leptin signaling pathways, highlighting the potential advantage of targeting leptin as a potential target of the novel therapeutic strategies for breast cancer treatment.
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Affiliation(s)
- Manar Fayiz Atoum
- Faculty of Allied Health Sciences, Hashemite University, Zarqa, Jordan
| | - Foad Alzoughool
- Faculty of Allied Health Sciences, Hashemite University, Zarqa, Jordan
| | - Huda Al-Hourani
- Department of Clinical Nutrition and Dietetics, Hashemite University, Zarqa, Jordan
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Martínez-Rodríguez OP, Thompson-Bonilla MDR, Jaramillo-Flores ME. Association between obesity and breast cancer: Molecular bases and the effect of flavonoids in signaling pathways. Crit Rev Food Sci Nutr 2020; 60:3770-3792. [PMID: 31899947 DOI: 10.1080/10408398.2019.1708262] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Obesity is an abnormal or excessive accumulation of fat that leads to different health problems, such as cancer, where the adipocytes promote the proliferation, migration, and invasion of cancer cells, especially in the breast, where the epithelial cells are immersed in a fatty environment, and the interactions between these two types of cells involve, not only adipokines but also local pro-inflammatory mechanisms and hypoxic processes generating anti-apoptotic signals, which are a common result in leptin signaling. The expression of the Vascular Endothelial Growth Factor (VEGF) and cyclin D1, results in the decrease in phosphorylation of AMPK, increasing the activity of the aromatase enzyme; alternatively, the adiponectin activates AMPK to reduce inflammation. Nevertheless, alterations of the JAK/STAT pathways contribute to mammary carcinogenesis, while the PI3K/AKT/mTOR pathway controls most of the cancer's characteristics such as the cell cycle, survival, differentiation, proliferation, motility, metabolism, and genetic stability. Therefore, the purpose of the present review is, through the accumulated scientific evidence, to find the concordance between the signaling pathways involved among obesity and breast cancer, which can be modulated by using flavonoids.
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Affiliation(s)
- Oswaldo Pablo Martínez-Rodríguez
- Departamento de Ingeniería Bioquímica, Instituto Politécnico Nacional, Escuela Nacional de Ciencias Biológicas, Ciudad de México, México
| | - María Del Rocío Thompson-Bonilla
- Laboratorio de Medicina Genómica, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado ISSSTE, Ciudad de México, México
| | - María Eugenia Jaramillo-Flores
- Departamento de Ingeniería Bioquímica, Instituto Politécnico Nacional, Escuela Nacional de Ciencias Biológicas, Ciudad de México, México
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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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Becerril S, Rodríguez A, Catalán V, Ramírez B, Unamuno X, Portincasa P, Gómez-Ambrosi J, Frühbeck G. Functional Relationship between Leptin and Nitric Oxide in Metabolism. Nutrients 2019; 11:2129. [PMID: 31500090 PMCID: PMC6769456 DOI: 10.3390/nu11092129] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/23/2019] [Accepted: 09/02/2019] [Indexed: 12/28/2022] Open
Abstract
Leptin, the product of the ob gene, was originally described as a satiety factor, playing a crucial role in the control of body weight. Nevertheless, the wide distribution of leptin receptors in peripheral tissues supports that leptin exerts pleiotropic biological effects, consisting of the modulation of numerous processes including thermogenesis, reproduction, angiogenesis, hematopoiesis, osteogenesis, neuroendocrine, and immune functions as well as arterial pressure control. Nitric oxide (NO) is a free radical synthesized from L-arginine by the action of the NO synthase (NOS) enzyme. Three NOS isoforms have been identified: the neuronal NOS (nNOS) and endothelial NOS (eNOS) constitutive isoforms, and the inducible NOS (iNOS). NO mediates multiple biological effects in a variety of physiological systems such as energy balance, blood pressure, reproduction, immune response, or reproduction. Leptin and NO on their own participate in multiple common physiological processes, with a functional relationship between both factors having been identified. The present review describes the functional relationship between leptin and NO in different physiological processes.
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Affiliation(s)
- Sara Becerril
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008 Pamplona, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
| | - Amaia Rodríguez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008 Pamplona, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
| | - Victoria Catalán
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008 Pamplona, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
| | - Beatriz Ramírez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008 Pamplona, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
| | - Xabier Unamuno
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008 Pamplona, Spain.
- Medical Engineering Laboratory, University of Navarra, 31008 Pamplona, Spain.
| | - Piero Portincasa
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Policlinico Hospital, 70124 Bari, Italy.
| | - Javier Gómez-Ambrosi
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008 Pamplona, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
| | - Gema Frühbeck
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008 Pamplona, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
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Sánchez-Jiménez F, Pérez-Pérez A, de la Cruz-Merino L, Sánchez-Margalet V. Obesity and Breast Cancer: Role of Leptin. Front Oncol 2019; 9:596. [PMID: 31380268 PMCID: PMC6657346 DOI: 10.3389/fonc.2019.00596] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 06/17/2019] [Indexed: 01/08/2023] Open
Abstract
Obesity-related breast cancer is an important threat that affects especially post-menopausal women. The link between obesity and breast cancer seems to be relying on the microenvironment generated at adipose tissue level, which includes inflammatory cytokines. In addition, its association with systemic endocrine changes, including hyperinsulinemia, increased estrogens levels, and hyperleptinemia may be key factors for tumor development. These factors may promote tumor initiation, tumor primary growth, tissue invasion, and metastatic progression. Although the relationship between obesity and breast cancer is already established, the different pathophysiological mechanisms involved are not clear. Obesity-related insulin resistance is a well-known risk factor for breast cancer development in post-menopausal women. However, the role of inflammation and other adipokines, especially leptin, is less studied. Leptin, like insulin, appears to be a growth factor for breast cancer cells. There exists a link between leptin and metabolism of estrogens and between leptin and other factors in a more complex network. As a result, obesity-associated hyperleptinemia has been suggested as an important mediator in the pathophysiology of breast cancer. On the other hand, recent data on the paradoxical effect of obesity on cancer immunotherapy efficacy has brought some controversy, since the proinflammatory effect of leptin may help the effect of immune checkpoint inhibitors. Therefore, a better knowledge of the molecular mechanisms that mediate leptin action may be helpful to understand the underlying processes which link obesity to breast cancer in post-menopausal women, as well as the possible role of leptin in the response to immunotherapy in obese patients.
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Affiliation(s)
- Flora Sánchez-Jiménez
- Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, Virgen Macarena University Hospital, University of Seville, Seville, Spain
| | - Antonio Pérez-Pérez
- Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, Virgen Macarena University Hospital, University of Seville, Seville, Spain
| | - Luis de la Cruz-Merino
- Department of Clinical Oncology, Virgen Macarena University Hospital, University of Seville, Seville, Spain
| | - Víctor Sánchez-Margalet
- Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, Virgen Macarena University Hospital, University of Seville, Seville, Spain
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Daley-Brown D, Harbuzariu A, Kurian AA, Oprea-Ilies G, Gonzalez-Perez RR. Leptin-induced Notch and IL-1 signaling crosstalk in endometrial adenocarcinoma is associated with invasiveness and chemoresistance. World J Clin Oncol 2019; 10:222-233. [PMID: 31367531 PMCID: PMC6657217 DOI: 10.5306/wjco.v10.i6.222] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 03/14/2019] [Accepted: 03/28/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Obesity is a recognized risk factor for endometrial cancer (EmCa) and other cancer types. Leptin levels are significantly increased in obese individuals. Leptin-induced signaling crosstalk [Notch, Interleukin-1 (IL-1) and leptin outcome, NILCO] has been associated with breast cancer progression. This complex signaling crosstalk affects cancer cell proliferation, migration, invasion, angiogenesis, apoptosis and chemoresistance. NILCO expression was previously detected in human EmCa. However, it is unknown whether leptin regulates NILCO and alters EmCa’s response to chemotherapeutics. It is hypothesized that leptin induces NILCO and increases aggressiveness and chemoresistance in EmCa cells.
AIM To determine whether leptin induces NILCO molecules in EmCa affecting cell proliferation, aggressiveness and chemoresistance.
METHODS Leptin’s effects on the expression of NILCO molecules [mRNAs and proteins for Notch receptors (Notch1-4), ligands (JAG1 and DLL4) and downstream effectors (survivin, Hey2), and leptin (OB-R) and IL-1 (IL-1R tI) receptors] was examined in EmCa cells (type I: Ishikawa, and HEC-1A, and type II: An3Ca and KLE) using Real-time PCR and Western blot analysis, respectively. In addition, the effects of leptin on cell cycle, proliferation and cell invasion were determined using cytometric analysis (Cellometer Vision CBA system), MTT cell proliferation and Matrigel-based invasion assays, respectively. Inhibitors of leptin (nanoparticle-bound leptin peptide receptor antagonist-2, IONP-LPrA2), IL-1 (anti-IL-1R tI antibody) and Notch (siRNA interference RNA) were used to investigate NILCO’s effects on cell proliferation and invasion. Leptin’s effects on Paclitaxel cytotoxicity in EmCa cells was determined by the CCK8 and Cellometer-based Annexin V assays.
RESULTS For the first time it was shown that leptin is an inducer of Notch in EmCa. Experimental data suggest that leptin induced the expression of NILCO molecules, promoted proliferation and S- phase progression, and reduced Paclitaxel cytotoxicity on EmCa cells. Leptin’s effects were higher in type II EmCa cells. The progression of this more aggressive form of the disease is associated with obesity. Remarkably, the use of the leptin signaling antagonist, IONP-LPrA2, re-sensitized EmCa cells to Paclitaxel.
CONCLUSION Present data suggest the notion that leptin-induced NILCO could be a link between obesity and EmCa progression and chemoresistance. Most aggressive type II EmCa cells were higher sensitive to leptin, which appears to increase proliferation, cell cycle progression, aggressiveness, and chemoresistance to Paclitaxel. Therefore, leptin and NILCO could be novel therapeutic targets for type II EmCa, which does not have targeted therapy. Overall, IONP-LPrA2 has a potential as a novel adjuvant drug to enhance the effectiveness of type II EmCa chemotherapy.
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Affiliation(s)
- Danielle Daley-Brown
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, United States
| | - Adriana Harbuzariu
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, United States
| | - Ann Anu Kurian
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, United States
| | - Gabriela Oprea-Ilies
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, 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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Sun J, Chen J, Wang Z, Deng Y, Liu L, Liu X. [Expression of NUF2 in breast cancer and its clinical significance]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2019; 39:591-597. [PMID: 31140425 DOI: 10.12122/j.issn.1673-4254.2019.05.15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVE To investigate the expression of the cell division- associated gene NUF2 in breast cancer and its clinical significance. METHODS The expression of NUF2 in breast cancer tissues was analyzed using Oncomine database. The relationship between the expression of NUF2 and the prognosis of breast cancer was analyzed using the Kaplan-Meier Plotter database. Gene set enrichment analysis (GSEA) and GEO database were used to investigate the effect of NUF2 on gene enrichment. The String database was utilized to analyze the proteins associated with NUF2. The TIMER database was analyzed to assess the correlations of NUF2 with BUB1, MAD2L1 and MYC. The expressions of NUF2 mRNA in 8 pairs of breast cancer tissues and adjacent tissues were verified by q-PCR. RESULTS Compared with that in normal breast tissue, NUF2 was significantly overexpressed in breast cancer (P < 0.001). The overall survival time (HR = 1.52, P = 0.015) and the recurrence-free survival time (HR = 1.85, P = 3.2e-14) of the patients with high NUF2 expression were significantly shorter than those of patients with low NUF2 expression. In patients with high NUF2 expression, the enriched genes were involved mainly in cell cycle, P53, G2/M, DNA repair, MYC, and PI3K-AKT-MTOR signaling pathways, which were associated with tumor proliferation, invasion, metastasis and stemness. Combination of the results of String database, gene enrichment and TIMER database analyses suggested that NUF2 interacted directly with BUB1, MAD2L1, and MYC, which could promote the progression of breast cancer. The results of q-PCR showed that NUF2 expression was up-regulated in 6 cancer tissues and down-regulated in 2 cancer tissues. CONCLUSIONS NUF2 gene is overexpressed in breast cancer, and its expression level is important in predicting the prognosis of breast cancer.
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Affiliation(s)
- Jingbo Sun
- Department of General Surgery, Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Jiawei Chen
- Southern Medical University, Guangzhou 510515, China
| | - Zhizhi Wang
- Southern Medical University, Guangzhou 510515, China
| | - Yunyao Deng
- Department of General Surgery, Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Lixin Liu
- Department of General Surgery, Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Xiaolong Liu
- Department of General Surgery, Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
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Fogg KC, Olson WR, Miller JN, Khan A, Renner C, Hale I, Weisman PS, Kreeger PK. Alternatively activated macrophage-derived secretome stimulates ovarian cancer spheroid spreading through a JAK2/STAT3 pathway. Cancer Lett 2019; 458:92-101. [PMID: 31129149 DOI: 10.1016/j.canlet.2019.05.029] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 05/18/2019] [Accepted: 05/21/2019] [Indexed: 10/26/2022]
Abstract
High-grade serous ovarian cancer (HGSOC) metastasizes when tumor spheroids detach from the primary tumor and re-attach throughout the peritoneal cavity. Once the cancer cells have implanted in these new sites, the development of metastatic lesions is dependent on the disaggregation of cancer cells from the spheroids and subsequent expansion across the collagenous extracellular matrix (ECM). As HGSOC progresses an increase in alternatively activated macrophages (AAMs) in the surrounding ascites fluid has been observed and AAMs have been shown to enhance tumor invasion and growth in a wide range of cancers. We hypothesized that soluble factors from AAMs in the peritoneal microenvironment promote the disaggregation of ovarian cancer spheroids across the underlying ECM. We determined that co-culture with AAMs significantly increased HGSOC spheroid spreading across a collagen matrix. Multivariate modeling identified AAM-derived factors that correlated with enhanced spread of HGSOC spheroids and experimental validation showed that each individual cell line responded to a distinct AAM-derived factor (FLT3L, leptin, or HB-EGF). Despite this ligand-level heterogeneity, we determined that the AAM-derived factors utilized a common signaling pathway to induce spheroid spreading: JAK2/STAT3 activation followed by MMP-9 mediated spreading. Furthermore, immunostaining demonstrated that FLT3, LEPR, EGFR, and pSTAT3 were upregulated in metastases in HGSOC patients, with substantial patient-to-patient heterogeneity. These results suggest that inhibiting individual soluble factors will not inhibit AAM-induced effects across a broad group of patients; instead, the downstream JAK2/STAT3/MMP-9 pathway should be examined as potential therapeutic targets to slow metastasis in ovarian cancer.
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Affiliation(s)
- Kaitlin C Fogg
- Department of Biomedical Engineering, University of Wisconsin - Madison, Madison, WI, USA
| | - Will R Olson
- Department of Biomedical Engineering, University of Wisconsin - Madison, Madison, WI, USA
| | - Jamison N Miller
- Department of Biomedical Engineering, University of Wisconsin - Madison, Madison, WI, USA
| | - Aisha Khan
- Department of Biomedical Engineering, University of Wisconsin - Madison, Madison, WI, USA
| | - Carine Renner
- Department of Biomedical Engineering, University of Wisconsin - Madison, Madison, WI, USA
| | - Isaac Hale
- Department of Biomedical Engineering, University of Wisconsin - Madison, Madison, WI, USA
| | - Paul S Weisman
- Department of Pathology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Pamela K Kreeger
- Department of Biomedical Engineering, University of Wisconsin - Madison, Madison, WI, USA; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Department of Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
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Foglesong GD, Queen NJ, Huang W, Widstrom KJ, Cao L. Enriched environment inhibits breast cancer progression in obese models with intact leptin signaling. Endocr Relat Cancer 2019; 26:483-495. [PMID: 30856610 PMCID: PMC6717689 DOI: 10.1530/erc-19-0075] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 03/11/2019] [Indexed: 12/11/2022]
Abstract
Obesity is becoming a global epidemic and is a risk factor for breast cancer. Environmental enrichment (EE), a model recapitulating an active lifestyle, leads to leanness, resistance to diet-induced obesity (DIO) and cancer. One mechanism is the activation of the hypothalamic-sympathoneural-adipocyte (HSA) axis. This results in the release of norepinephrine onto adipose tissue inducing a drop of leptin. This study aimed to test the effects of EE on breast cancer onset and progression while considering the effect of leptin by utilizing the transgenic MMTV-PyMT model as well as several models of varied leptin signaling. EE was highly effective at reducing weight gain, regardless of the presence of leptin. However, the effects of EE on tumor progression were dependent on leptin signaling. EE decreased leptin and reduced mammary tumor growth rate in MMTV-PyMT spontaneous and DIO transplantation models; in contrast, the absence of leptin in ob/ob mice resulted in increased tumor growth likely due to elevated norepinephrine levels. Our results suggest that the microenvironment is critical in breast tumorigenesis and that the drop in leptin is an important peripheral mediator of the EE anti-breast cancer effects, offsetting the potential pro-tumorigenic effects of norepinephrine responding to a complex environment.
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Affiliation(s)
- Grant D Foglesong
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Nicholas J Queen
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Wei Huang
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Kyle J Widstrom
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Lei Cao
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
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The Nutritional Cytokine Leptin Promotes NSCLC by Activating the PI3K/AKT and MAPK/ERK Pathways in NSCLC Cells in a Paracrine Manner. BIOMED RESEARCH INTERNATIONAL 2019; 2019:2585743. [PMID: 31119158 PMCID: PMC6500706 DOI: 10.1155/2019/2585743] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 03/26/2019] [Accepted: 04/08/2019] [Indexed: 12/02/2022]
Abstract
Purpose Leptin is a nutritional cytokine encoded by the obesity gene whose concentration in the tumor microenvironment is closely related to the occurrence and progression of cancer. However, previous evidence has suggested that there is no clear relationship between serum leptin concentrations and lung cancer progression. Cancer-associated fibroblasts (CAFs), the most abundant component of the tumor microenvironment in a variety of solid tumors, were recently reported to produce leptin. Therefore, it was inferred that leptin is most likely to affect non-small-cell lung cancer (NSCLC) through an autocrine and paracrine mechanism. In the current study, we investigated the paracrine effect and mechanism of leptin produced by CAFs on NSCLC by establishing a novel in vitro cell coculture system. Methods A noncontact coculture device was designed and made by 3D printing. CAFs and paired normal lung fibroblasts (NLFs) from 5 patients were successfully isolated and cocultured with two NSCLC cell lines in a coculture system. The background expression of leptin was detected by western blot. The in situ expression of leptin and its receptor (Ob-R) in NSCLC tissues and paired normal lung tissues was analyzed by immunohistochemistry. Furthermore, we downregulated the expression of leptin in CAFs and assessed changes in its promotion on NSCLC cells in the coculture system. Finally, changes in the phosphorylation of ERK1/2 and AKT were examined to investigate the molecular mechanisms responsible for the paracrine promotion of NSCLC cells by leptin. Results Leptin was overexpressed in nearly all five primary CAF lines compared with its expression in paired NLFs. IHC staining showed that the expression of leptin was high in NSCLC cells, slightly lower in CAF, and negative in normal lung tissue. Ob-R was strongly expressed in NSCLC cells. The ability of A549 and H1299 cells to proliferate and migrate was enhanced by high leptin levels in both the cocultured fibroblasts and the culture medium. Furthermore, western blot assays suggested that the MAPK/ERK1/2 and PI3K/AKT signaling pathways were activated by leptin produced by CAFs, which demonstrated that the functions of paracrine leptin in NSCLC are as those of the serum leptin to other cancers. Conclusion Leptin produced by CAF promotes proliferation and migration of NSCLC cells probably via PI3K/AKT and MAPK/ERK1/2 signaling pathways in a paracrine manner.
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Engin AB, Engin A, Gonul II. The effect of adipocyte-macrophage crosstalk in obesity-related breast cancer. J Mol Endocrinol 2019; 62:R201-R222. [PMID: 30620711 DOI: 10.1530/jme-18-0252] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 01/07/2019] [Indexed: 12/11/2022]
Abstract
Adipose tissue is the primary source of many pro-inflammatory cytokines in obesity. Macrophage numbers and pro-inflammatory gene expression are positively associated with adipocyte size. Free fatty acid and tumor necrosis factor-α involve in a vicious cycle between adipocytes and macrophages aggravating inflammatory changes. Thereby, M1 macrophages form a characteristic 'crown-like structure (CLS)' around necrotic adipocytes in obese adipose tissue. In obese women, CLSs of breast adipose tissue are responsible for both increase in local aromatase activity and aggressive behavior of breast cancer cells. Interlinked molecular mechanisms between adipocyte-macrophage-breast cancer cells in obesity involve seven consecutive processes: Excessive release of adipocyte- and macrophage-derived inflammatory cytokines, TSC1-TSC2 complex-mTOR crosstalk, insulin resistance, endoplasmic reticulum (ER) stress and excessive oxidative stress generation, uncoupled respiration and hypoxia, SIRT1 controversy, the increased levels of aromatase activity and estrogen production. Considering elevated risks of estrogen receptor (E2R)-positive postmenopausal breast cancer growth in obesity, adipocyte-macrophage crosstalk is important in the aforementioned issues. Increased mTORC1 signaling in obesity ensures the strong activation of oncogenic signaling in E2Rα-positive breast cancer cells. Since insulin and insulin-like growth factors have been identified as tumor promoters, hyperinsulinemia is an independent risk factor for poor prognosis in breast cancer despite peripheral insulin resistance. The unpredictable effects of adipocyte-derived leptin-estrogen-macrophage axis, and sirtuin 1 (SIRT1)-adipose-resident macrophage axis in obese postmenopausal patients with breast cancer are unresolved mechanistic gaps in the molecular links between the tumor growth and adipocytokines.
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Affiliation(s)
- Ayse Basak Engin
- Department of Toxicology, Faculty of Pharmacy, Gazi University, Ankara, Turkey
| | - Atilla Engin
- Department of General Surgery, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Ipek Isik Gonul
- Department of Pathology, Faculty of Medicine, Gazi University, Ankara, Turkey
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Ghasemi A, Saeidi J, Azimi-Nejad M, Hashemy SI. Leptin-induced signaling pathways in cancer cell migration and invasion. Cell Oncol (Dordr) 2019; 42:243-260. [PMID: 30877623 DOI: 10.1007/s13402-019-00428-0] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Increasing evidence indicates that obesity is associated with tumor development and progression. Leptin is an adipocyte-related hormone with a key role in energy metabolism and whose circulating levels are elevated in obesity. The effect of leptin on cancer progression and metastasis and its underlying mechanisms are still unclear. Leptin can impact various steps in tumor metastasis, including epithelial-mesenchymal transition, cell adhesion to the extracellular matrix (ECM), and proteolysis of ECM components. To do so, leptin binds to its receptor (OB-Rb) to activate signaling pathways and downstream effectors that participate in tumor cell invasion as well as distant metastasis. CONCLUSIONS In this review, we describe metastasis steps in detail and characterize metastasis-related molecules activated by leptin, which may help to develop a roadmap that guides future work. In addition, we conclude that a profound understanding of the fundamental molecular processes that contribute to leptin-induced metastasis may pave the way for the development of new prognostic molecules and appropriate approaches to the treatment of obesity-related cancers.
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Affiliation(s)
- Ahmad Ghasemi
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Jafar Saeidi
- Department of Physiology, School of Basic Science, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran
| | - Mohsen Azimi-Nejad
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Department of Genetic, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Isaac Hashemy
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Interleukin-8 Activates Breast Cancer-Associated Adipocytes and Promotes Their Angiogenesis- and Tumorigenesis-Promoting Effects. Mol Cell Biol 2019; 39:MCB.00332-18. [PMID: 30397072 DOI: 10.1128/mcb.00332-18] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 10/25/2018] [Indexed: 01/23/2023] Open
Abstract
Increasing evidence supports the critical role of active stromal adipocytes in breast cancer development and spread. However, the mediators and the mechanisms of action are still elusive. We show here that cancer-associated adipocytes (CAAs) isolated from 10 invasive breast carcinomas are proinflammatory and exhibit active phenotypes, including higher proliferative, invasive, and migratory capacities compared to their adjacent tumor-counterpart adipocytes (TCAs). Furthermore, all CAAs secreted higher level of interleukin-8 (IL-8), which is critical in mediating the paracrine procarcinogenic effects of these cells. Importantly, ectopic expression of IL-8 in TCA cells activated them and enhanced their procarcinogenic effects both in vitro, in a STAT3-dependent manner, and in vivo In contrast, inhibition of the IL-8 signaling using specific short hairpin RNA, anti-IL-8 antibody, or reparixin suppressed the active features of CAAs, including their non-cell-autonomous tumor-promoting activities both on breast luminal cells and in orthotopic tumor xenografts in mice. IL-8 played also an important role in enhancing the proangiogenic effects of breast adipocytes. These results provide clear indication that IL-8 plays key roles in the activation of breast CAAs and acts as a major mediator for their paracrine protumorigenic effects. Thus, targeting CAAs by inhibiting the IL-8 pathway could have great therapeutic value.
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Chen W, Qin Y, Liu S. Cytokines, breast cancer stem cells (BCSCs) and chemoresistance. Clin Transl Med 2018; 7:27. [PMID: 30175384 PMCID: PMC6119679 DOI: 10.1186/s40169-018-0205-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 07/20/2018] [Indexed: 02/06/2023] Open
Abstract
Chemotherapy resistance of breast cancer poses a great challenge to the survival of patients. During breast cancer treatment, the development of intrinsic and acquired drug resistance tends to further induce adverse prognosis, such as metastasis. In recent years, the progress of research on cytokine-modulated tumor microenvironment and breast cancer stem cells (BCSCs) has shed light on defining the mechanisms of drug resistance gradually. In this review, we have discussed cytokine regulation on breast cancer chemoresistance. Cytokines can affect tumor cell behavior or reprogram tumor niche through specific signaling pathways, thereby regulating the progress of drug resistance. In addition, we summarized the mutually regulatory networks between cytokines and BCSCs in mediating chemoresistance. Cytokines in the tumor microenvironment can regulate the self-renewal and survival of BCSCs in a variety of ways, sequentially promoting chemotherapeutic resistance. Therefore, the combinational treatment of BCSC targeting and cytokine blockade may have a positive effect on the clinical treatment of breast cancer.
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Affiliation(s)
- Weilong Chen
- School of Life Science, The CAS Key Laboratory of Innate Immunity and Chronic Disease, University of Science & Technology of China, Hefei, 230027, Anhui, China
| | - Yuanyuan Qin
- School of Life Science, The CAS Key Laboratory of Innate Immunity and Chronic Disease, University of Science & Technology of China, Hefei, 230027, Anhui, China
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Key Laboratory of Medical Epigenetics and Metabolism; Innovation Center for Cell Signaling Network, Shanghai Medical College; Fudan University, Shanghai, 200032, China.
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Nwadozi E, Ng A, Strömberg A, Liu HY, Olsson K, Gustafsson T, Haas TL. Leptin is a physiological regulator of skeletal muscle angiogenesis and is locally produced by PDGFRα and PDGFRβ expressing perivascular cells. Angiogenesis 2018; 22:103-115. [DOI: 10.1007/s10456-018-9641-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 08/06/2018] [Indexed: 12/20/2022]
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Colombo M, Mirandola L, Chiriva-Internati M, Basile A, Locati M, Lesma E, Chiaramonte R, Platonova N. Cancer Cells Exploit Notch Signaling to Redefine a Supportive Cytokine Milieu. Front Immunol 2018; 9:1823. [PMID: 30154786 PMCID: PMC6102368 DOI: 10.3389/fimmu.2018.01823] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Accepted: 07/24/2018] [Indexed: 12/19/2022] Open
Abstract
Notch signaling is a well-known key player in the communication between adjacent cells during organ development, when it controls several processes involved in cell differentiation. Notch-mediated communication may occur through the interaction of Notch receptors with ligands on adjacent cells or by a paracrine/endocrine fashion, through soluble molecules that can mediate the communication between cells at distant sites. Dysregulation of Notch pathway causes a number of disorders, including cancer. Notch hyperactivation may be caused by mutations of Notch-related genes, dysregulated upstream pathways, or microenvironment signals. Cancer cells may exploit this aberrant signaling to "educate" the surrounding microenvironment cells toward a pro-tumoral behavior. This may occur because of key cytokines secreted by tumor cells or it may involve the microenvironment through the activation of Notch signaling in stromal cells, an event mediated by a direct cell-to-cell contact and resulting in the increased secretion of several pro-tumorigenic cytokines. Up to now, review articles were mainly focused on Notch contribution in a specific tumor context or immune cell populations. Here, we provide a comprehensive overview on the outcomes of Notch-mediated pathological interactions in different tumor settings and on the molecular and cellular mediators involved in this process. We describe how Notch dysregulation in cancer may alter the cytokine network and its outcomes on tumor progression and antitumor immune response.
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Affiliation(s)
- Michela Colombo
- Department of Health Sciences, Università degli Studi di Milano, Milano, Italy
| | | | - Maurizio Chiriva-Internati
- Kiromic Biopharma Inc., Houston, TX, United States.,Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.,Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Andrea Basile
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milano, Italy
| | - Massimo Locati
- Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Milano, Italy.,Humanitas Clinical and Research Center, Rozzano, Italy
| | - Elena Lesma
- Department of Health Sciences, Università degli Studi di Milano, Milano, Italy
| | | | - Natalia Platonova
- Department of Health Sciences, Università degli Studi di Milano, Milano, Italy
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Simone BA, Palagani A, Strickland K, Ko K, Jin L, Lim MK, Dan TD, Sarich M, Monti DA, Cristofanilli M, Simone NL. Caloric restriction counteracts chemotherapy-induced inflammation and increases response to therapy in a triple negative breast cancer model. Cell Cycle 2018; 17:1536-1544. [PMID: 29912618 DOI: 10.1080/15384101.2018.1471314] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Triple negative breast cancer (TNBC) is a heterogeneous disease that has no available targeted therapies. Previously, we have shown that caloric restriction (CR) can augment the effects of radiation therapy in a TNBC mouse model. To build upon this, we now present data regarding the combination of chemotherapy and CR in the same 4T1 model. Chemotherapy can induce inflammation that breeds resistance to therapy. We propose CR as a mechanism to decrease chemotherapy-induced inflammation and increase efficacy of therapy. 12-week old Balb/c mice were orthotopically injected with a syngeneic triple negative breast cancer cell line (4T1) and were treated in one of six cohorts: ad lib fed (AL), 30% reduction in calorie intake (CR), cisplatin or docetaxol alone or a combination CR+cisplatin/docetaxol. Mice in the cohorts receiving chemotherapy+CR had longer overall survival (12 ± 2 days) as compared to the AL group. These mice also demonstrated less lung metastases at the final time point of in vivo imaging. In addition, downregulation of the IGF-1R and IRS signaling pathways were noted most significantly in those mice receiving combination therapy. Lastly, serum from these mice demonstrated an increase in inflammatory cytokines TNF-α and IL-1β in response to chemotherapy alone. This increase was dampened by the addition of CR. Taken together, these data suggest that while chemotherapy is effective in TNBC, it can cause inflammation, which can be a driver of resistance to therapy. This chemotherapy-induced inflammation can be reversed with the use of CR as a nontoxic adjunct to treatment.
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Affiliation(s)
- Brittany A Simone
- a Radiation Oncology Department , Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia , PA , USA
| | - Ajay Palagani
- a Radiation Oncology Department , Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia , PA , USA
| | - Kimberly Strickland
- b Department of Medical Oncology , SKMC, Thomas Jefferson University , Philadelphia , PA , USA
| | - Kevin Ko
- a Radiation Oncology Department , Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia , PA , USA
| | - Lianjin Jin
- a Radiation Oncology Department , Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia , PA , USA
| | - Meng Kieng Lim
- a Radiation Oncology Department , Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia , PA , USA
| | - Tu D Dan
- c Department of Radiation Oncology , UT Southwestern Medical Center at Dallas , Dallas , TX , USA
| | - Mak Sarich
- a Radiation Oncology Department , Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia , PA , USA
| | - Daniel A Monti
- d Myrna Brynd Center for Integrative Medicine, Thomas Jefferson University , Philadelphia , PA , USA
| | - Massimo Cristofanilli
- e Department of Medical Oncology , Lurie Cancer Center at the Feinberg School of Medicine, Northwestern University , Chicago , IL , USA
| | - Nicole L Simone
- a Radiation Oncology Department , Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia , PA , USA
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Chen SI, Hsieh CC. Why are women with obesity more likely to develop breast cancer. Future Oncol 2018; 14:1523-1526. [PMID: 29938526 DOI: 10.2217/fon-2018-0125] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Affiliation(s)
- Sheng-I Chen
- Department of Industrial Engineering & Management, National Chiao Tung University, Hsinchu, Taiwan
| | - Chia-Chien Hsieh
- Department of Human Development & Family Studies, National Taiwan Normal University, Taipei, Taiwan
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Harbuzariu A, Gonzalez-Perez RR. Leptin-Notch axis impairs 5-fluorouracil effects on pancreatic cancer. Oncotarget 2018; 9:18239-18253. [PMID: 29719602 PMCID: PMC5915069 DOI: 10.18632/oncotarget.24435] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 01/30/2018] [Indexed: 12/15/2022] Open
Abstract
5-FU chemotherapy is a current strategy to treat pancreatic cancer (PC), but unfortunately chemoresistance is eventually developed in most patients. Obesity is a risk factor for PC that could affect 5-FU effectiveness through the adipokine leptin, which is a known proliferation, survival factor and Notch inducer. We investigated whether leptin signaling affects 5-FU cytotoxicity on PC. To this end, tumorspheres developed from BxPC-3 and MiaPaCa-2 PC cells were treated with 5-FU, leptin, inhibitors for Notch (DAPT) and leptin signaling (IONP-LPrA2) and ATP-binding cassette of proteins (Probenecid). Leptin treatment decreased 5-FU cytotoxicity, and increased cell proliferation, colony forming ability, stem cell, pluripotency, EMT markers, drug efflux proteins (ABCC5, ABCC11) and Notch. In addition, leptin reduced the 5-FU effects on apoptosis by decreasing pro-apoptotic (Bax, Caspase-3 activation and PARP degradation) and increasing anti-apoptotic factors (RIP and Bcl-XL). Leptin's effects on PC tumorspheres treated with 5-FU were reduced by IONP-LPrA2 and were mainly Notch signaling- dependent and more evident in MiaPaCa-2-derived tumorspheres. Present results suggest that leptin could impair 5-FU cytotoxicity and promote chemoresistance. Therefore, targeting the leptin-Notch axis could be a novel way to improve 5-FU therapy for PC patients, especially in obesity context.
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Affiliation(s)
- Adriana Harbuzariu
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - Ruben Rene Gonzalez-Perez
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA
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49
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Harbuzariu A, Rampoldi A, Daley-Brown DS, Candelaria P, Harmon TL, Lipsey CC, Beech DJ, Quarshie A, Ilies GO, Gonzalez-Perez RR. Leptin-Notch signaling axis is involved in pancreatic cancer progression. Oncotarget 2018; 8:7740-7752. [PMID: 27999190 PMCID: PMC5352357 DOI: 10.18632/oncotarget.13946] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 12/07/2016] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer (PC) shows a high death rate. PC incidence and prognosis are affected by obesity, a pandemic characterized by high levels of leptin. Notch is upregulated by leptin in breast cancer. Thus, leptin and Notch crosstalk could influence PC progression. Here we investigated in PC cell lines (BxPC-3, MiaPaCa-2, Panc-1, AsPC-1), derived tumorspheres and xenografts whether a functional leptin-Notch axis affects PC progression and expansion of pancreatic cancer stem cells (PCSC). PC cells and tumorspheres were treated with leptin and inhibitors of Notch (gamma-secretase inhibitor, DAPT) and leptin (iron oxide nanoparticle-leptin peptide receptor antagonist 2, IONP-LPrA2). Leptin treatment increased cell cycle progression and proliferation, and the expression of Notch receptors, ligands and targeted molecules (Notch1-4, DLL4, JAG1, Survivin and Hey2), PCSC markers (CD24/CD44/ESA, ALDH, CD133, Oct-4), ABCB1 protein, as well as tumorsphere formation. Leptin-induced effects on PC and tumorspheres were decreased by IONP-LPrA2 and DAPT. PC cells secreted leptin and expressed the leptin receptor, OB-R, which indicates a leptin autocrine/paracrine signaling loop could also affect tumor progression. IONP-LPrA2 treatment delayed the onset of MiaPaCa-2 xenografts, and decreased tumor growth and the expression of proliferation and PCSC markers. Present data suggest that leptin-Notch axis is involved in PC. PC has no targeted therapy and is mainly treated with chemotherapy, whose efficiency could be decreased by leptin and Notch activities. Thus, the leptin-Notch axis could be a novel therapeutic target, particularly for obese PC patients.
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Affiliation(s)
- Adriana Harbuzariu
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA
| | - Antonio Rampoldi
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA
| | - Danielle S Daley-Brown
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA
| | - Pierre Candelaria
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA
| | - Tia L Harmon
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA
| | - Crystal C Lipsey
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA
| | - Derrick J Beech
- Department of Surgery, Morehouse School of Medicine, Atlanta, GA, 30310 USA
| | - Alexander Quarshie
- Biomedical Informatics Program and Master of Science in Clinical Research Program, Clinical Research Center, Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - Gabriela Oprea Ilies
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Grady Memorial Hospital, Atlanta, GA, 30303 USA
| | - Ruben R Gonzalez-Perez
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, 30310 USA
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Abstract
Cytokines are required for normal growth and development of the mammary gland and TGF-β prominently represents an established effector of apoptosis, e.g., during involution of the mammary gland. By the control of intracellular signaling pathways, including JAK/STAT, MAPK, PI-3K, and NF-κB, cytokines efficiently regulate cell proliferation and inflammation in the breast. Therefore, cytokines are discussed also in a context of malignant mammary growth. As a group of tissue hormones produced by somatic cells or by cells from the immune system, cytokines are defined by their immunomodulatory potential. Over the past 40 years, multiple cytokines were identified in colostrum and milk. Importantly, cytokines derived from mammary secretions after birth are required for maturation of the immune system in the developing gastrointestinal tract from the suckling. Moreover, recent studies have further assessed the particular interactions between probiotic bacterial strains and cytokines. In light of the increasing prevalence of inflammatory diseases of the gastrointestinal system, the effects of probiotic microorganisms during milk fermentation may have immunotherapeutic potential in the future.
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Affiliation(s)
- Julia Brenmoehl
- Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Daniela Ohde
- Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Elisa Wirthgen
- Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Andreas Hoeflich
- Leibniz Institute for Farm Animal Biology (FBN), Dummerstorf, Germany.
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