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Hu X, Jia F, Li L, Chen W, Zhang L, Pan J, Zhu S, Wang Z, Huang J. Single-Cell and Single-Nuclei transcriptomics profiling reveals dynamic cellular features in tumor-related adipose microenvironment of breast cancer patients with high BMI. Transl Oncol 2025; 57:102408. [PMID: 40344915 DOI: 10.1016/j.tranon.2025.102408] [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: 10/29/2024] [Revised: 04/21/2025] [Accepted: 05/04/2025] [Indexed: 05/11/2025] Open
Abstract
OBJECTIVES High body mass index (BMI), encompassing overweight and obesity, is a well-established risk factor for developing breast cancer (BC). The underlying mechanisms linking elevated BMI to increased BC risk involve metabolic reprogramming and chronic inflammatory microenvironments regulated by cellular networks within breast white adipose tissue (WAT). However, the complicated landscape and specific cell chat leading to BC-related adipose microenvironment remained unclear. MATERIALS AND METHODS We unveiled a comprehensive cell atlas by employing single-cell (N = 27) and single-nuclei (N = 6) transcriptomics to address dynamic changes of immune and stromal cell components within WAT in high BMI population. Bulk RNA-seq data sets were used for validation. RESULTS Characteristics of adipose-infiltrating tissue-resident macrophages (PVMs), APOD+γδ T cells, and mature FKBP5+ adipocytes in breast cancer women with high BMI were revealed, in terms of transcriptional genes, metabolism features, developmental trajectories and gene set enrichment analysis (GSEA). PVMs upregulated c-Maf combined with its co-activator CREB1 to increase TCA cycles. APOD+γδ T cells were found to elevate intracellular lipid metabolism, leading to poor clinical prognosis. Mature FKBP5+adipocytes served as an advanced adipogenesis mediator to promote tumor aggressiveness. In-depth analysis of cell-cell interactions uncovered a remodeling trend towards metabolic dysfunction and chronic inflammation in WAT with weight gain via EGF, CXCL, and CCL signalings. CONCLUSION These results provided a novel understanding of detailed and unbiased cellular landscape of WAT in breast cancer with high BMI from single-cell atlas perspective, uncovering interplays between breast adipose-infiltrating immune cells and stromal cells that promote progression of BC under high BMI conditions.
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Affiliation(s)
- Xiaoxiao Hu
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Fang Jia
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lili Li
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China; Department of Medical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang, China
| | - Wuzhen Chen
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Leyi Zhang
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jun Pan
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Sangsang Zhu
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zhen Wang
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
| | - Jian Huang
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
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Fallone F, Rebeaud M, Bouche C, Fontaine J, Arellano C, Ducoux-Petit M, Orgerit L, Deudon R, Nicolle R, Franchet C, Estève D, Mouton-Barbosa E, Dauvillier S, Moutahir M, Burlet-Schiltz O, Bouloumié A, Vaysse C, Muller C. Lack of fibro-inflammatory response in human mammary adipose tissue in obesity. Int J Obes (Lond) 2025; 49:809-818. [PMID: 39738492 DOI: 10.1038/s41366-024-01705-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 11/26/2024] [Accepted: 12/11/2024] [Indexed: 01/02/2025]
Abstract
BACKGROUND Understanding how obesity impacts human mammary adipose tissue (MAT) biology is crucial for deciphering its role in mammary epithelium during both physiological and pathophysiological processes, including breast cancer. Hypertrophic mammary adipocytes and Crown-Like Structures are present in MAT of patients with obesity but whether these changes initiate a fibro-inflammatory response at the tissue level remains insufficiently explored. OBJECTIVE We investigated the markers of adipose tissue dysfunction (immune cell infiltration, secretion pattern and fibrosis) in tumor-free MAT of patients with obesity versus patients who are lean. METHODS Tumor-free MAT were obtained from 96 women with (n = 43) or without (n = 53) obesity who underwent mastectomy for breast cancer risk reduction or treatment. Immune and non-immune cell infiltration were determined using flow cytometry. Bulk transcriptomic was used to characterize the phenotype of CD206+ macrophages whose infiltration is increased in patients with obesity. Conditioned-medium were prepared from MAT to characterize their secretome and dose adipokines and cytokines by ELISA assay. The extra-cellular matrix (ECM) deposition was evaluated by Masson trichrome staining on cross-stained sections, 3D imaging of red picrosirius-stained tissues and measure of hydroxyproline content. RESULTS We observed an increase of CD206+/HLA-DR+ macrophages in the stromal vascular fraction of MAT from patients with obesity compared to patients who are lean. Other immune cell infiltration and endothelial or adipose progenitor cell numbers were similar between groups. Bulk transcriptomics on CD206+ macrophages revealed a significant decrease in ECM component expression and processing in obesity. In addition, no heightened secretion of pro-inflammatory cytokines, TGF-β1 or MCP-1 was observed in the samples from patients with obesity. ECM characterization revealed an absence of fibrosis, with MAT of patients with obesity showing even a slightly reduced collagen secretion and deposition compared with their lean counterparts. CONCLUSIONS Obesity is not associated with inflammation nor fibrosis in MAT, highlighting its unique behavior.
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Affiliation(s)
- Frédérique Fallone
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UT3), Toulouse, France.
| | - Marie Rebeaud
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UT3), Toulouse, France
| | - Caroline Bouche
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UT3), Toulouse, France
- Département de Chirurgie Gynécologique Oncologique, CHU-Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
| | - Jessica Fontaine
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse, INSERM, UPS, Toulouse, France
| | - Carlo Arellano
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UT3), Toulouse, France
- Département de Chirurgie Gynécologique Oncologique, CHU-Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
| | - Manuelle Ducoux-Petit
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UT3), Toulouse, France
- Infrastructure Nationale de Protéomique, ProFI, FR 2048, Toulouse, France
| | - Lucyle Orgerit
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UT3), Toulouse, France
- Département de Chirurgie Gynécologique Oncologique, CHU-Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
| | - Rémi Deudon
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UT3), Toulouse, France
- Département de Chirurgie Gynécologique Oncologique, CHU-Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
| | - Rémy Nicolle
- Université Paris Cité, Centre de Recherche sur l'Inflammation (CRI), INSERM, U1149, CNRS, ERL 8252, F-75018, Paris, France
| | - Camille Franchet
- Département d'Anatomo-Pathologie, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
| | - David Estève
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UT3), Toulouse, France
| | - Emmanuelle Mouton-Barbosa
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UT3), Toulouse, France
- Infrastructure Nationale de Protéomique, ProFI, FR 2048, Toulouse, France
| | - Stéphanie Dauvillier
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UT3), Toulouse, France
| | - Mohamed Moutahir
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UT3), Toulouse, France
| | - Odile Burlet-Schiltz
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UT3), Toulouse, France
- Infrastructure Nationale de Protéomique, ProFI, FR 2048, Toulouse, France
| | - Anne Bouloumié
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse, INSERM, UPS, Toulouse, France
| | - Charlotte Vaysse
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UT3), Toulouse, France
- Département de Chirurgie Gynécologique Oncologique, CHU-Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
| | - Catherine Muller
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UT3), Toulouse, France.
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Illipse M, Gasparini A, Christoffersen B, Hall P, Czene K, Humphreys K. Studying the association between longitudinal nondense breast tissue measurements and the risk of breast cancer: a joint modeling approach. Am J Epidemiol 2025; 194:1065-1071. [PMID: 39004517 PMCID: PMC11978613 DOI: 10.1093/aje/kwae196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 05/25/2024] [Accepted: 07/08/2024] [Indexed: 07/16/2024] Open
Abstract
Conflicting results have appeared in the literature on whether the amount of nondense, adipose tissue in the breast is a risk factor or a protective factor for breast cancer (BC), and biological hypotheses supporting both have been proposed. We suggest here that limitations in study design and statistical methodology could potentially explain the inconsistent results. Specifically, we exploit recent advances in methodology and software developed for the joint analysis of multiple longitudinal outcomes and time-to-event data to jointly analyze dense and nondense tissue trajectories and the risk of BC in a large Swedish screening cohort. We also perform extensive sensitivity analyses by mimicking analyses/designs of previously published studies-for example, ignoring available longitudinal data. Overall, we do not find strong evidence supporting an association between nondense tissue and the risk of incident BC. We hypothesize that (1) previous studies have not been able to isolate the effect of nondense tissue from dense tissue or adipose tissue elsewhere in the body, that (2) estimates of the effect of nondense tissue on risk are strongly sensitive to modeling assumptions, or that (3) the effect size of nondense tissue on BC risk is likely to be small/not clinically relevant.
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Affiliation(s)
- Maya Illipse
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, SE-171 77 Stockholm, Sweden
| | - Alessandro Gasparini
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, SE-171 77 Stockholm, Sweden
| | - Benjamin Christoffersen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, SE-171 77 Stockholm, Sweden
| | - Per Hall
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, SE-171 77 Stockholm, Sweden
- Department of Oncology, Södersjukhuset, 11883 Stockholm, Sweden
| | - Kamila Czene
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, SE-171 77 Stockholm, Sweden
| | - Keith Humphreys
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, SE-171 77 Stockholm, Sweden
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Lv Y, Chen C, Han M, Tian C, Song F, Feng S, Xu M, Zhao Z, Zhou H, Su W, Zhong J. CXCL2: a key player in the tumor microenvironment and inflammatory diseases. Cancer Cell Int 2025; 25:133. [PMID: 40197328 PMCID: PMC11978139 DOI: 10.1186/s12935-025-03765-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Accepted: 03/26/2025] [Indexed: 04/10/2025] Open
Abstract
CXCL2 (C-X-C Motif Chemokine Ligand 2), a constituent of the C-X-C chemokine subfamily, serves as a powerful chemotactic factor for neutrophils, facilitating leukocyte recruitment and movement while initiating an inflammatory response. Recent investigations have demonstrated the pivotal involvement of CXCL2 in carcinogenesis. Within the tumor microenvironment, CXCL2 modulates cellular activity primarily via its interaction with the CXCR2 receptor. The activation of signaling pathways, including ERK/MAPK, NF-κB/MAPK, PI3K/AKT, and JAK/STAT3, highlights CXCL2's inclination to promote tumorigenesis. Furthermore, the role of CXCL2 encompasses inflammatory conditions like lung inflammation, atherosclerosis, and obesity. This article examines the structural characteristics, biological roles, and molecular foundation of CXCL2 in carcinogenesis and inflammatory disorders.
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Affiliation(s)
- Yuanhao Lv
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Caizheng Chen
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Miaomiao Han
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Chenfei Tian
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Fuyang Song
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Sijia Feng
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Miaoming Xu
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Ziyin Zhao
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Hongyan Zhou
- Xinxiang Key Laboratory of Precision Diagnosis and Treatment for Colorectal Cancer, Xinxiang First People's Hospital, Xinxiang, China
| | - Wei Su
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.
- Xinxiang Engineering Technology Research Center of Digestive Tumor Molecular Diagnosis, Xinxiang Medical University, Xinxiang, China.
| | - Jiateng Zhong
- Department of Pathology, Xinxiang Medical University, Xinxiang, China.
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.
- Xinxiang Key Laboratory of Precision Diagnosis and Treatment for Colorectal Cancer, Xinxiang First People's Hospital, Xinxiang, China.
- Xinxiang Engineering Technology Research Center of Digestive Tumor Molecular Diagnosis, Xinxiang Medical University, Xinxiang, China.
- Henan Province Engineering Technology Research Center of Tumor diagnostic biomarkers and RNA interference drugs, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.
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Gaber M, Quentel A, Holmes J, Lepetit C, Triki H, Wilson A, Payne V, Tenvooren I, Dehours C, Peoples A, Duet ML, Katz AJ, Pécot T, Bougras-Cartron G, Cartron PF, Cook KL, Vidi PA. Obesity increases DNA damage in the breast epithelium. Breast Cancer Res 2025; 27:11. [PMID: 39838489 PMCID: PMC11753040 DOI: 10.1186/s13058-025-01961-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 01/10/2025] [Indexed: 01/23/2025] Open
Abstract
Obesity is a modifiable risk factor for breast cancer. Yet, how obesity contributes to cancer initiation is not fully understood. The goal of this study was to determine if the body mass index (BMI) and metabolic hallmarks of obesity are related to DNA damage in normal breast tissue. In a mouse model of diet-induced obesity, weight gain was associated with elevated levels of DNA double-strand breaks in the mammary gland. We also found a positive correlation between BMI and DNA breaks in the breast epithelium of premenopausal women (but not postmenopausal women). High BMI was associated with elevated systemic and tissue-level oxidative DNA damage across the lifespan, and we propose that the breast epithelium undergoing menstruous proliferation waves is particularly prone to the generation of DNA breaks from oxidative lesions. Ancestry was an important modulator of the obesity-DNA break connection. Compared to non-Hispanic Whites, women identifying as African Americans had higher levels of DNA breaks, as well as elevated leptin and IGF-1. In 3D cultures of breast acini, both leptin and IGF-1 caused an accumulation of DNA damage. The results highlight a connection between premalignant genomic alterations in the breast epithelium and metabolic health modulated by obesity and ancestry. They call for attention on biological determinants of breast cancer risk disparities.
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Affiliation(s)
- Mohamed Gaber
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Arnaud Quentel
- Institut de Cancérologie de l'Ouest, Angers, F-49055, France
- Université d'Angers, Inserm UMR 1307, CNRS UMR 6075, Nantes Université, CRCI2NA, SFR ICAT, Angers, France
| | - Julia Holmes
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | | | - Hana Triki
- Université d'Angers, Inserm UMR 1307, CNRS UMR 6075, Nantes Université, CRCI2NA, SFR ICAT, Angers, France
- Institut de Cancérologie de l'Ouest, Saint Herblain, F-44805, France
- Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Nantes, France
| | - Adam Wilson
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Valerie Payne
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Iliana Tenvooren
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Cloé Dehours
- Institut de Cancérologie de l'Ouest, Angers, F-49055, France
- Université d'Angers, Inserm UMR 1307, CNRS UMR 6075, Nantes Université, CRCI2NA, SFR ICAT, Angers, France
| | - Abigail Peoples
- Department of Plastic and Reconstructive Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Mary L Duet
- Department of Plastic and Reconstructive Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Adam J Katz
- Department of Plastic and Reconstructive Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Thierry Pécot
- Biosit, UAR 3480 CNRS - US 18 Inserm, Rennes University, Rennes, F-35042, France
| | - Gwenola Bougras-Cartron
- Université d'Angers, Inserm UMR 1307, CNRS UMR 6075, Nantes Université, CRCI2NA, SFR ICAT, Angers, France
- Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Nantes, France
| | - Pierre-François Cartron
- Université d'Angers, Inserm UMR 1307, CNRS UMR 6075, Nantes Université, CRCI2NA, SFR ICAT, Angers, France
- Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Nantes, France
| | - Katherine L Cook
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Pierre-Alexandre Vidi
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
- Institut de Cancérologie de l'Ouest, Angers, F-49055, France.
- Université d'Angers, Inserm UMR 1307, CNRS UMR 6075, Nantes Université, CRCI2NA, SFR ICAT, Angers, France.
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Yang Y, Ma X, Li Y, Jin L, Zhou X. The evolving tumor-associated adipose tissue microenvironment in breast cancer: from cancer initiation to metastatic outgrowth. Clin Transl Oncol 2024:10.1007/s12094-024-03831-8. [PMID: 39720985 DOI: 10.1007/s12094-024-03831-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 12/09/2024] [Indexed: 12/26/2024]
Abstract
Adipocytes represent a significant proportion of breast tissue, comprising between 3.7 and 37% of stromal tissue. They play a pivotal role in metabolic regulation, energy supply, metabolic regulation, support effects, and cytokine release within the breast. In breast cancer (BC) tissue, adipocytes engage in intricate crosstalk with BC cells, playing a key role in tumor proliferation, invasion, metastasis formation, and metabolic remodeling. This is due to the provision of hormones, adipokines, and fatty acids to tumor cells by the adipocytes. With the initiation of metastatic outgrowth of BC, the peritumoral adipose tissue exhibits abundant and intricate changes based on its original construction and function, which convert it into a tumor-associated adipose tissue microenvironment (TAAME). It includes some specific adipocytes: adipose-derived stem cells (ASCs), cancer-associated adipocytes (CAAs), adipocyte-derived fibroblasts (ADFs), etc. From a mechanistic standpoint, specific adipocytes can facilitate the proliferation, invasion, metastasis, and angiogenesis of BC cells by secreting a multitude of cytokines (IL-6) and adipokines (leptin), which collectively create an environment conducive to BC progression. It is of paramount importance to recognize the TAAME as a crucial target for the diagnosis, treatment, and drug resistance of BC. Consequently, the review presents an overview of the characteristics and interactions of specific adipocytes within TAAME cell populations. This will facilitate the development of more effective personalized therapies against BC progression, relapse, and metastasis.
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Affiliation(s)
- Yang Yang
- College of Life Science, Northeast Forestry University, Harbin, 150000, China
- Central Laboratory, The Affiliated Hospital of Yanbian University, Yanji, 133000, China
- Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji, 133000, China
- Zhejiang Orient Gene Biotech Co., Ltd, Huzhou, 313300, China
| | - Xiao Ma
- Central Laboratory, The Affiliated Hospital of Yanbian University, Yanji, 133000, China
- Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji, 133000, China
| | - Yue Li
- Central Laboratory, The Affiliated Hospital of Yanbian University, Yanji, 133000, China
- Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji, 133000, China
| | - Lihua Jin
- College of Life Science, Northeast Forestry University, Harbin, 150000, China
| | - Xianchun Zhou
- Central Laboratory, The Affiliated Hospital of Yanbian University, Yanji, 133000, China.
- Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji, 133000, China.
- Central Laboratory, Yanbian University Hospital, Ju Zi Road No.1327, Yanji, 133002, China.
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Calabrese C, Miserocchi G, De Vita A, Spadazzi C, Cocchi C, Vanni S, Gabellone S, Martinelli G, Ranallo N, Bongiovanni A, Liverani C. Lipids and adipocytes involvement in tumor progression with a focus on obesity and diet. Obes Rev 2024; 25:e13833. [PMID: 39289899 DOI: 10.1111/obr.13833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 08/26/2024] [Accepted: 08/29/2024] [Indexed: 09/19/2024]
Abstract
The adipose tissue is a complex organ that can play endocrine, metabolic, and immune regulatory roles in cancer. In particular, adipocytes provide metabolic substrates for cancer cell proliferation and produce signaling molecules that can stimulate cell adhesion, migration, invasion, angiogenesis, and inflammation. Cancer cells, in turn, can reprogram adipocytes towards a more inflammatory state, resulting in a vicious cycle that fuels tumor growth and evolution. These mechanisms are enhanced in obesity, which is associated with the risk of developing certain tumors. Diet, an exogenous source of lipids with pro- or anti-inflammatory functions, has also been connected to cancer risk. This review analyzes how adipocytes and lipids are involved in tumor development and progression, focusing on the relationship between obesity and cancer. In addition, we discuss how diets with varying lipid intakes can affect the disease outcomes. Finally, we introduce novel metabolism-targeted treatments and adipocyte-based therapies in oncology.
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Affiliation(s)
- Chiara Calabrese
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Giacomo Miserocchi
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Alessandro De Vita
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Chiara Spadazzi
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Claudia Cocchi
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Silvia Vanni
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Sofia Gabellone
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Giovanni Martinelli
- Scientific Directorate, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Nicoletta Ranallo
- Clinical and Experimental Oncology, Immunotherapy, Rare Cancers and Biological Resource Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Alberto Bongiovanni
- Clinical and Experimental Oncology, Immunotherapy, Rare Cancers and Biological Resource Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Chiara Liverani
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
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8
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Bogdan RG, Helgiu A, Cimpean AM, Ichim C, Todor SB, Iliescu-Glaja M, Bodea IC, Crainiceanu ZP. Assessing Fat Grafting in Breast Surgery: A Narrative Review of Evaluation Techniques. J Clin Med 2024; 13:7209. [PMID: 39685668 DOI: 10.3390/jcm13237209] [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: 10/16/2024] [Revised: 11/19/2024] [Accepted: 11/25/2024] [Indexed: 12/18/2024] Open
Abstract
Fat grafting has gained prominence in reconstructive and aesthetic surgery, necessitating accurate assessment methods for evaluating graft volume retention. This paper reviews various techniques for assessing fat and fat grafts, including their benefits and limitations. Three-dimensional (3D) scanning offers highly accurate, non-invasive volumetric assessments with minimal interference from breathing patterns. Magnetic resonance imaging (MRI) is recognized as the gold standard, providing precise volumetric evaluations and sensitivity to complications like oil cysts and necrosis. Computed tomography (CT) is useful for fat volume assessment but may overestimate retention rates. Ultrasonography presents a reliable, non-invasive method for measuring subcutaneous fat thickness. Other methods, such as digital imaging, histological analysis, and weight estimation, contribute to fat graft quantification. The integration of these methodologies is essential for advancing fat graft assessment, promoting standardized practices, and improving patient outcomes in clinical settings.
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Affiliation(s)
- Razvan-George Bogdan
- Plastic Surgery Department, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
- County Clinical Emergency Hospital Pius Branzeu, 300723 Timisoara, Romania
| | - Alina Helgiu
- Faculty of Medicine, "Lucian Blaga" University of Sibiu, 550024 Sibiu, Romania
- County Clinical Emergency Hospital of Sibiu, 550245 Sibiu, Romania
| | - Anca-Maria Cimpean
- Plastic Surgery Department, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Cristian Ichim
- Faculty of Medicine, "Lucian Blaga" University of Sibiu, 550024 Sibiu, Romania
| | - Samuel Bogdan Todor
- Faculty of Medicine, "Lucian Blaga" University of Sibiu, 550024 Sibiu, Romania
| | - Mihai Iliescu-Glaja
- Plastic Surgery Department, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
- County Clinical Emergency Hospital Pius Branzeu, 300723 Timisoara, Romania
| | - Ioan Catalin Bodea
- General Surgery Department, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania
- Regional Institute of Gastroenterology and Hepatology Prof. Dr. Octavian Fodor, 400394 Cluj-Napoca, Romania
| | - Zorin Petrisor Crainiceanu
- Plastic Surgery Department, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
- County Clinical Emergency Hospital Pius Branzeu, 300723 Timisoara, Romania
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9
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Xue M, Liao Y, Jiang W. Insights into the molecular changes of adipocyte dedifferentiation and its future research opportunities. J Lipid Res 2024; 65:100644. [PMID: 39303983 PMCID: PMC11550672 DOI: 10.1016/j.jlr.2024.100644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 08/23/2024] [Accepted: 09/14/2024] [Indexed: 09/22/2024] Open
Abstract
Recent studies have challenged the traditional belief that mature fat cells are irreversibly differentiated and revealed they can dedifferentiate into fibroblast-like cells known as dedifferentiated fat (DFAT) cells. Resembling pluripotent stem cells, DFAT cells hold great potential as a cell source for stem cell therapy. However, there is limited understanding of the specific changes that occur following adipocyte dedifferentiation and the detailed regulation of this process. This review explores the epigenetic, genetic, and phenotypic alterations associated with DFAT cell dedifferentiation, identifies potential targets for clinical regulation and discusses the current applications and challenges in the field of DFAT cell research.
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Affiliation(s)
- Mingheng Xue
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yunjun Liao
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
| | - Wenqing Jiang
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
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10
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Wolf M, Brochhausen C, Ramakrishnan V, Iberl S, Roth J, Seitz S, Burkhardt R, Stadler SC. Histologic Characterization of Tumor-Adjacent Mammary Adipose Tissue in Normal-Weight and Overweight/Obese Patients with Triple-Negative Breast Cancer. Cancers (Basel) 2024; 16:3515. [PMID: 39456610 PMCID: PMC11506523 DOI: 10.3390/cancers16203515] [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: 09/03/2024] [Revised: 10/01/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024] Open
Abstract
Background: Obesity is a risk factor of several types of cancer, including breast cancer. In this study, we aimed to histologically characterize the adipose tissue of the tumor microenvironment (TME) of triple-negative breast cancer (TNBC) in overweight/obese versus normal-weight patients. Methods: TNBC tissue sections from normal-weight (BMI<25) and overweight/obese patients (BMI≥25) were stained with antibodies against CD68, CD163, CD31, CD34, and vimentin. At the invasive tumor front, positive cells were counted in tumor adjacent adipose tissue (AT) and within cancer tissue (CT). Further, the size of the tumor-adjacent and distant mammary adipocytes was determined in perilipin stained sections. Expression of ANGPTL4, CD36 and FABP4, proteins involved in fatty acid metabolism, was analyzed in marginal tumor cells using an immune reactive score. Results: Overweight/obese TNBC patients had significantly larger adipocytes, higher numbers of CD163+ macrophages (BMI<25: 2.80 vs. BMI≥25: 10.45; p = 0.011) and lower numbers of CD31+ (BMI<25: 4.20 vs. BMI≥25: 2.40; p = 0.018) and CD34+ (BMI<25: 14.60 vs. BMI≥25: 5.20; p = 0.045) cells as markers of angiogenesis in the AT as well as a higher frequency of cancer-associated-fibroblast-like cells in the AT and CT (BMI<25: 7.60 vs. BMI≥25: 25.39 in total; p = 0.001). Moreover, expression of CD36 (BMI<25: 2.15 vs. BMI≥25: 2.60; p = 0.041) and ANGPTL4 (BMI<25: 6.00 vs. BMI≥25: 9.80; p = 0.026) was elevated in the TNBC cells of overweight/obese patients. Conclusions: Our data suggest BMI-related changes in the TME of overweight/obese TNBC patients, including hypertrophied adipocytes, reduced vascularization, more M2-like macrophages and CAF-like cells, and an increase in the expression of fatty acid metabolizing proteins in marginal tumor cells, all contributing to a more tumor-promoting, immunosuppressive environment.
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Affiliation(s)
- Marietta Wolf
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, 93053 Regensburg, Germany (R.B.)
- Department of Operative Dentistry and Periodontology, Center for Dental Medicine, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg im Breisgau, Germany
| | - Christoph Brochhausen
- Institute of Pathology, Medical Faculty Mannheim, University Heidelberg, 69120 Mannheim, Germany
- Institute of Pathology, Regensburg University, 93053 Regensburg, Germany
| | | | - Sabine Iberl
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, 93053 Regensburg, Germany (R.B.)
| | - Jonas Roth
- Department of Gynecology and Obstetrics, University Medical Centre Regensburg, 93053 Regensburg, Germany
| | - Stephan Seitz
- Department of Gynecology and Obstetrics, University Medical Centre Regensburg, 93053 Regensburg, Germany
| | - Ralph Burkhardt
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, 93053 Regensburg, Germany (R.B.)
| | - Sonja C. Stadler
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, 93053 Regensburg, Germany (R.B.)
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11
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Cai J, Cheng H, Xu S. ABHD5 as a friend or an enemy in cancer biology? Front Oncol 2024; 14:1447509. [PMID: 39328203 PMCID: PMC11424376 DOI: 10.3389/fonc.2024.1447509] [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: 06/11/2024] [Accepted: 08/28/2024] [Indexed: 09/28/2024] Open
Abstract
Alpha beta hydrolase domain containing 5 (ABHD5) is an essential coactivator of adipose triglyceride lipase (ATGL), a rate-limiting enzyme in various cell types that promotes the hydrolysis of triacylglycerol (TG) into diacylglycerol (DG) and fatty acid (FA). It acts as a critical regulatory factor in cellular lipid metabolism. The reprogramming of lipid metabolism is one of the hallmarks of cancer, suggesting that altering lipid metabolism could become a new strategy for tumor treatment. Research has revealed a close association between ABHD5 and the development and progression of malignancies. This review summarizes the role of ABHD5 in various malignant tumors and explores the different signaling pathways and metabolic routes that may be involved, providing a comprehensive mechanistic understanding of ABHD5.
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Affiliation(s)
- Jianya Cai
- Department of Surgery, Quanzhou Medical College, Quanzhou, China
| | - Hongwei Cheng
- Zhuhai UM Science & Technology Research Institute, University of Macau, Macau, Macau SAR, China
| | - Shuangta Xu
- Department of Thyroid and Breast Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
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12
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Shang JR, Zhu J, Bai L, Kulabiek D, Zhai XX, Zheng X, Qian J. Adipocytes impact on gastric cancer progression: Prognostic insights and molecular features. World J Gastrointest Oncol 2024; 16:3011-3031. [PMID: 39072151 PMCID: PMC11271780 DOI: 10.4251/wjgo.v16.i7.3011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 03/17/2024] [Accepted: 05/28/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Adipocytes, especially adipocytes within tumor tissue known as cancer-associated adipocytes, have been increasingly recognized for their pivotal role in the tumor microenvironment of gastric cancer (GC). Their influence on tumor progression and patient prognosis has sparked significant interest in recent research. The main objectives of this study were to investigate adipocyte infiltration, assess its correlation with clinical pathological features, develop a prognostic prediction model based on independent prognostic factors, evaluate the impact of adipocytes on immune cell infiltration and tumor invasiveness in GC, and identify and validate genes associated with high adipocyte expression, exploring their potential diagnostic and prognostic value. AIM To explore the relationship between increased adipocytes within tumor tissue and prognosis in GC patients as well as the associated mechanisms and potential biomarkers, using public databases and clinical data. METHODS Using mRNA microarray datasets from the Gene Expression Omnibus database and clinical samples from Jiangsu Provincial Hospital, survival and regression analyses were conducted to determine the relevant prognostic factors in GC. Feature gene selection was performed using least absolute shrinkage and selection operator and support vector machine recursive feature elimination algorithms, followed by differential gene expression analysis, gene ontology, pathway analysis, and Gene Set Enrichment Analysis. Immune cell infiltration was analyzed using the CIBERSORT algorithm. RESULTS Tumor adipocyte infiltration correlated with poor prognosis in GC, leading to the development of a highly accurate and discriminative prognostic prediction model. Key genes, ADH1B, SFRP1, PLAC9, and FABP4, were identified as associated with high adipocyte expression in GC. The diagnostic and prognostic potential of these identified genes was validated using independent datasets. Downregulation of immune cells was observed in GC with high adipocyte expression. CONCLUSION GC with high intratumoral adipocyte expression demonstrated aggressive tumor biology and a poorer prognosis. The genes ADH1B, SFRP1, PLAC9, and FABP4 have been identified as holding diagnostic and prognostic significance in GC. These findings strongly support the use of adipocyte expression as a valuable indicator of tumor invasiveness and anticipated patient outcomes in GC.
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Affiliation(s)
- Jia-Rong Shang
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
| | - Jin Zhu
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
| | - Lu Bai
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
| | - Delida Kulabiek
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
| | - Xiao-Xue Zhai
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
| | - Xia Zheng
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
| | - Jun Qian
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
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13
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Habanjar O, Nehme R, Goncalves-Mendes N, Cueff G, Blavignac C, Aoun J, Decombat C, Auxenfans C, Diab-Assaf M, Caldefie-Chézet F, Delort L. The obese inflammatory microenvironment may promote breast DCIS progression. Front Immunol 2024; 15:1384354. [PMID: 39072314 PMCID: PMC11272476 DOI: 10.3389/fimmu.2024.1384354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 06/20/2024] [Indexed: 07/30/2024] Open
Abstract
Introduction Ductal carcinoma in situ (DCIS), characterized by a proliferation of neoplastic cells confined within the mammary ducts, is distinctly isolated from the surrounding stroma by an almost uninterrupted layer of myoepithelial cells (MECs) and by the basement membrane. Heightened interactions within the adipose microenvironment, particularly in obese patients, may play a key role in the transition from DCIS to invasive ductal carcinoma (IDC), which is attracting growing interest in scientific research. Adipose tissue undergoes metabolic changes in obesity, impacting adipokine secretion and promoting chronic inflammation. This study aimed to assess the interactions between DCIS, including in situ cancer cells and MECs, and the various components of its inflammatory adipose microenvironment (adipocytes and macrophages). Methods To this end, a 3D co-culture model was developed using bicellular bi-fluorescent DCIS-like tumoroids, adipose cells, and macrophages to investigate the influence of the inflammatory adipose microenvironment on DCIS progression. Results The 3D co-culture model demonstrated an inhibition of the expression of genes involved in apoptosis (BAX, BAG1, BCL2, CASP3, CASP8, and CASP9), and an increase in genes related to cell survival (TP53, JUN, and TGFB1), inflammation (TNF-α, PTGS2, IL-6R), invasion and metastasis (TIMP1 and MMP-9) in cancer cells of the tumoroids under inflammatory conditions versus a non-inflammatory microenvironment. On the contrary, it confirmed the compromised functionality of MECs, resulting in the loss of their protective effects against cancer cells. Adipocytes from obese women showed a significant increase in the expression of all studied myofibroblast-associated genes (myoCAFs), such as FAP and α-SMA. In contrast, adipocytes from normal-weight women expressed markers of inflammatory fibroblast phenotypes (iCAF) characterized by a significant increase in the expression of LIF and inflammatory cytokines such as TNF-α, IL-1β, IL-8, and CXCL-10. These changes also influenced macrophage polarization, leading to a pro-inflammatory M1 phenotype. In contrast, myoCAF-associated adipocytes, and the cancer-promoting microenvironment polarized macrophages towards an M2 phenotype, characterized by high CD163 receptor expression and IL-10 and TGF-β secretion. Discussion Reciprocal interactions between the tumoroid and its microenvironment, particularly in obesity, led to transcriptomic changes in adipocytes and macrophages, may participate in breast cancer progression while disrupting the integrity of the MEC layer. These results underlined the importance of adipose tissue in cancer progression.
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Affiliation(s)
- Ola Habanjar
- Université Clermont-Auvergne, INRAE, UNH, Clermont-Ferrand, France
| | - Rawan Nehme
- Université Clermont-Auvergne, INRAE, UNH, Clermont-Ferrand, France
| | | | - Gwendal Cueff
- Université Clermont-Auvergne, INRAE, UNH, Clermont-Ferrand, France
| | - Christelle Blavignac
- Université Clermont-Auvergne, Centre d’Imagerie Cellulaire Santé (CCIS), Clermont-Ferrand, France
| | - Jessy Aoun
- Université Clermont-Auvergne, INRAE, UNH, Clermont-Ferrand, France
| | | | - Céline Auxenfans
- Banque de tissus et de cellules, Hôpital Edouard-Herriot, Lyon, France
| | - Mona Diab-Assaf
- Equipe Tumorigénèse Moléculaire et Pharmacologie Anticancéreuse, Faculté des Sciences II, Université libanaise Fanar, Beirut, Lebanon
| | | | - Laetitia Delort
- Université Clermont-Auvergne, INRAE, UNH, Clermont-Ferrand, France
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14
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Kakkat S, Suman P, Turbat- Herrera EA, Singh S, Chakroborty D, Sarkar C. Exploring the multifaceted role of obesity in breast cancer progression. Front Cell Dev Biol 2024; 12:1408844. [PMID: 39040042 PMCID: PMC11260727 DOI: 10.3389/fcell.2024.1408844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 06/17/2024] [Indexed: 07/24/2024] Open
Abstract
Obesity is a multifaceted metabolic disorder characterized by excessive accumulation of adipose tissue. It is a well-established risk factor for the development and progression of breast cancer. Adipose tissue, which was once regarded solely as a passive energy storage depot, is now acknowledged as an active endocrine organ producing a plethora of bioactive molecules known as adipokines that contribute to the elevation of proinflammatory cytokines and estrogen production due to enhanced aromatase activity. In the context of breast cancer, the crosstalk between adipocytes and cancer cells within the adipose microenvironment exerts profound effects on tumor initiation, progression, and therapeutic resistance. Moreover, adipocytes can engage in direct interactions with breast cancer cells through physical contact and paracrine signaling, thereby facilitating cancer cell survival and invasion. This review endeavors to summarize the current understanding of the intricate interplay between adipocyte-associated factors and breast cancer progression. Furthermore, by discussing the different aspects of breast cancer that can be adversely affected by obesity, this review aims to shed light on potential avenues for new and novel therapeutic interventions.
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Affiliation(s)
- Sooraj Kakkat
- Department of Pathology, University of South Alabama, Mobile, AL, United States
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, United States
| | - Prabhat Suman
- Department of Pathology, University of South Alabama, Mobile, AL, United States
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, United States
| | - Elba A. Turbat- Herrera
- Department of Pathology, University of South Alabama, Mobile, AL, United States
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, United States
| | - Seema Singh
- Department of Pathology, University of South Alabama, Mobile, AL, United States
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, United States
- Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL, United States
| | - Debanjan Chakroborty
- Department of Pathology, University of South Alabama, Mobile, AL, United States
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, United States
- Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL, United States
| | - Chandrani Sarkar
- Department of Pathology, University of South Alabama, Mobile, AL, United States
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, United States
- Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL, United States
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15
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Gogg S, Nerstedt A, Smith U, Hansson E. Breast volume in non-obese females is related to breast adipose cell hypertrophy, inflammation, and COX2 expression. J Plast Surg Hand Surg 2024; 59:83-88. [PMID: 38967364 DOI: 10.2340/jphs.v59.40754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 06/13/2024] [Indexed: 07/06/2024]
Abstract
BACKGROUND Breast hypertrophy seems to be a risk factor for breast cancer and the amount and characteristics of breast adipose tissue may play important roles. The main aim of this study was to investigate associations between breast volume in normal weight women and hypertrophic adipose tissue and inflammation. METHODS Fifteen non-obese women undergoing breast reduction surgery were examined. Breast volume was measured with plastic cups and surgery was indicated if the breast was 800 ml or larger according to Swedish guidelines. We isolated adipose cells from the breasts and ambient subcutaneous tissue to measure cell size, cell inflammation and other known markers of risk of developing breast cancer including COX2 gene activation and MAPK, a cell proliferation regulator. RESULTS Breast adipose cell size was characterized by cell hypertrophy and closely related to breast volume. The breast adipose cells were also characterized by being pro-inflammatory with increased IL-6, IL-8, IL-1β, CCL-2, TNF-a and an increased marker of cell senescence GLB1/β-galactosidase, commonly increased in hypertrophic adipose tissue. The prostaglandin synthetic marker COX2 was also increased in the hypertrophic cells and COX2 has previously been shown to be an important marker of risk of developing breast cancer. Interestingly, the phosphorylation of the proliferation marker MAPK was also increased in the hypertrophic adipose cells. CONCLUSION Taken together, these findings show that increased breast volume in non-obese women is associated with adipose cell hypertrophy and dysfunction and characterized by increased inflammation and other markers of increased risk for developing breast cancer. TRIAL REGISTRATION Projektdatabasen FoU i VGR, project number: 249191 (https://www.researchweb.org/is/vgr/project/249191).
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Affiliation(s)
- Silvia Gogg
- The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Institute of Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Annika Nerstedt
- The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Institute of Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ulf Smith
- The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Institute of Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Emma Hansson
- Department of Plastic Surgery, Institute of Clinical Sciences, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Region Västra Götaland, Sahlgrenska University Hospital, Department of Plastic Surgery, Gothenburg, Sweden.
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16
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Tedeschi G, Palomba F, Scipioni L, Digman MA. Multimodal Phasor Approach to study breast cancer cells invasion in 3D spheroid model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.10.598307. [PMID: 38915530 PMCID: PMC11195137 DOI: 10.1101/2024.06.10.598307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
We implemented a multimodal set of functional imaging techniques optimized for deep-tissue imaging to investigate how cancer cells invade surrounding tissues and how their physiological properties change in the process. As a model for cancer invasion of the extracellular matrix, we created 3D spheroids from triple-negative breast cancer cells (MDA-MB-231) and non-tumorigenic breast epithelial cells (MCF-10A). We analyzed multiple hallmarks of cancer within the same spheroid by combining a number of imaging techniques, such as metabolic imaging of NADH by Fluorescence Lifetime Imaging Microscopy (NADH-FLIM), hyperspectral imaging of a solvatochromic lipophilic dye (Nile Red) and extracellular matrix imaging by Second Harmonic Generation (SHG). We included phasor-based bioimage analysis of spheroids at three different time points, tracking both morphological and biological properties, including cellular metabolism, fatty acids storage, and collagen organization. Employing this multimodal deep-imaging framework, we observed and quantified cancer cell plasticity in response to changes in the environment composition.
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Affiliation(s)
- Giulia Tedeschi
- Laboratory for Fluorescence Dynamics, Biomedical Engineering Department, University of California, Irvine, Irvine, CA 92617 (USA)
| | - Francesco Palomba
- Laboratory for Fluorescence Dynamics, Biomedical Engineering Department, University of California, Irvine, Irvine, CA 92617 (USA)
| | - Lorenzo Scipioni
- Laboratory for Fluorescence Dynamics, Biomedical Engineering Department, University of California, Irvine, Irvine, CA 92617 (USA)
| | - Michelle A Digman
- Laboratory for Fluorescence Dynamics, Biomedical Engineering Department, University of California, Irvine, Irvine, CA 92617 (USA)
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17
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Rebeaud M, Lacombe M, Fallone F, Milhas D, Roumiguié M, Vaysse C, Attané C, Muller C. Specificities of mammary and periprostatic adipose tissues: A perspective from cancer research. ANNALES D'ENDOCRINOLOGIE 2024; 85:220-225. [PMID: 38871505 DOI: 10.1016/j.ando.2024.05.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]
Abstract
In addition to the major subcutaneous and visceral adipose tissues (AT), other adipose depots are dispersed throughout the body and are found in close interaction with proximal organs such as mammary and periprostatic AT (MAT and PPAT respectively). These ATs have an effect on proximal organ function during physiological processes and diseases such as cancer. We highlighted here some of their most distinctive features in terms of tissular organization and responses to external stimuli and discussed how obesity affects them based on our current knowledge.
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Affiliation(s)
- Marie Rebeaud
- UMR 5089, CNRS, équipe labélisée ligue nationale contre le cancer, institut de pharmacologie et de biologie structurale, université de Toulouse, 205, route de Narbonne, BP 64182, 31077 Toulouse, France
| | - Mathilde Lacombe
- UMR 5089, CNRS, équipe labélisée ligue nationale contre le cancer, institut de pharmacologie et de biologie structurale, université de Toulouse, 205, route de Narbonne, BP 64182, 31077 Toulouse, France
| | - Frédérique Fallone
- UMR 5089, CNRS, équipe labélisée ligue nationale contre le cancer, institut de pharmacologie et de biologie structurale, université de Toulouse, 205, route de Narbonne, BP 64182, 31077 Toulouse, France
| | - Delphine Milhas
- UMR 5089, CNRS, équipe labélisée ligue nationale contre le cancer, institut de pharmacologie et de biologie structurale, université de Toulouse, 205, route de Narbonne, BP 64182, 31077 Toulouse, France
| | - Mathieu Roumiguié
- UMR 5089, CNRS, équipe labélisée ligue nationale contre le cancer, institut de pharmacologie et de biologie structurale, université de Toulouse, 205, route de Narbonne, BP 64182, 31077 Toulouse, France; Département d'urologie, CHU de Toulouse, 1, avenue du Professeur-Jean-Poulhès, 31400 Toulouse, France
| | - Charlotte Vaysse
- UMR 5089, CNRS, équipe labélisée ligue nationale contre le cancer, institut de pharmacologie et de biologie structurale, université de Toulouse, 205, route de Narbonne, BP 64182, 31077 Toulouse, France; Département de chirurgie gynécologique-oncologique, institut universitaire du cancer de Toulouse-Oncopole, CHU de Toulouse, 1, avenue Irène-Joliot-Curie, 31059 Toulouse cedex 9, France
| | - Camille Attané
- UMR 5089, CNRS, équipe labélisée ligue nationale contre le cancer, institut de pharmacologie et de biologie structurale, université de Toulouse, 205, route de Narbonne, BP 64182, 31077 Toulouse, France
| | - Catherine Muller
- UMR 5089, CNRS, équipe labélisée ligue nationale contre le cancer, institut de pharmacologie et de biologie structurale, université de Toulouse, 205, route de Narbonne, BP 64182, 31077 Toulouse, France.
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18
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Navarro AS, Omalek D, Chaltiel L, Vaysse C, Meresse T, Gangloff D, Jouve E, Selmes G. Oncologic safety of autologous fat grafting in primary breast reconstruction after mastectomy for cancer. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024; 50:107998. [PMID: 38460246 DOI: 10.1016/j.ejso.2024.107998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 01/15/2024] [Accepted: 02/01/2024] [Indexed: 03/11/2024]
Abstract
INTRODUCTION Autologous fat transfer (AFT) is widely used to improve results of breast reconstructive surgery, but its safety is controversial. Our objective was to evaluate the oncologic safety of AFT in a homogeneous population of patients who underwent a total mastectomy with immediate reconstruction for breast cancer. METHODS We performed a retrospective cohort study by identifying all patients who underwent immediate breast reconstruction after mastectomy for breast cancer from 2007 to 2015 in our center. A patient group with AFT performed in the 24 months after mastectomy was compared to a control group. RESULTS Five hundred fifty cases were included, of whom 136 (24.7%) underwent at least one fat graft transfer. Median age was 51 years. Reconstruction was performed in 465 (84.5%) with an implant reconstruction. The median time from mastectomy to AFT was 13.8 months. The median follow up was 55.2 months. A total of 53 events were observed, including 10 (7.4%) in the AFT group and 43 (10.4%) in the control group. There was no difference in 5-year recurrence-free survival (RFS) between the groups. In the subgroup analysis, only lymph node involvement in patients who underwent AFT in the first 24 months after oncologic surgery appeared as a risk factor of recurrence. Among the 104 patients with lymph node involvement, 5-year RFS was 69.2% in patients with lipofilling vs 92.5% in patients without it (p = 0 0.0351). CONCLUSION Performing early lipofilling in primary breast reconstruction after mastectomy for cancer seems to be oncologically safe. Lymph node involvement increases the risk of recurrence in this population.
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Affiliation(s)
- Anne-Sophie Navarro
- Departement of Surgical Oncology, Institut Universitaire Du Cancer Toulouse Oncopole, Toulouse, France.
| | - Donia Omalek
- Departement of Surgical Oncology, Institut Universitaire Du Cancer Toulouse Oncopole, Toulouse, France
| | - Léonor Chaltiel
- Departement of Biostatistics, Institut Universitaire Du Cancer Toulouse Oncopole, Toulouse, France
| | - Charlotte Vaysse
- Departement of Gynecology and Surgical Oncology, Centre Hospitalier Universitaire de Toulouse, IUCT-Oncopôle de Toulouse, France
| | - Thomas Meresse
- Departement of Plastic and Reconstructive Surgery, Institut Universitaire Du Cancer Toulouse Oncopole, Toulouse, France
| | - Dimitri Gangloff
- Departement of Plastic and Reconstructive Surgery, Institut Universitaire Du Cancer Toulouse Oncopole, Toulouse, France
| | - Eva Jouve
- Departement of Surgical Oncology, Institut Universitaire Du Cancer Toulouse Oncopole, Toulouse, France
| | - Gabrielle Selmes
- Departement of Surgical Oncology, Institut Universitaire Du Cancer Toulouse Oncopole, Toulouse, France
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19
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Wu J, Li J, Xu H, Qiu N, Huang X, Li H. Periostin drives extracellular matrix degradation, stemness, and chemoresistance by activating the MAPK/ERK signaling pathway in triple-negative breast cancer cells. Lipids Health Dis 2023; 22:153. [PMID: 37716956 PMCID: PMC10504790 DOI: 10.1186/s12944-023-01912-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 08/29/2023] [Indexed: 09/18/2023] Open
Abstract
BACKGROUND Adipose tissue, which is mainly composed of adipocytes, is a crucial component of the tumor microenvironment, particularly in breast cancer. Adipocytes surround breast cancer cells and may participate in cell‒cell interactions in the breast microenvironment. However, little is currently known about how adipocytes influence the biological behavior of the surrounding breast cancer cells. Hence, this study sought to investigate the role and underlying mechanisms of periostin in triple-negative breast cancer (TNBC) cells cocultured with adipogenic conditioned medium (ACM) and palmitic acid (PA). METHODS Human TNBC cell lines (MDA‒MB‒231 and SUM159PT) were treated with ACM and PA, then the expression of periostin, matrix metalloproteinases (MMPs) and stemness-related molecules were assessed by Western blotting and RT‒qPCR. The cellular viability was assessed using CCK‒8 assay. Plasmid transfection, RNA sequencing, and pathway inhibitor were used to explore the specific mechanisms of periostin. RESULTS ACM and PA elevated the expression of both MMPs and stemness-related molecules in TNBCs. MMPs can promote tumor cell infiltration and migration by degrading the extracellular matrix, and stemness expression increases the development of tumor chemoresistance. Additionally, ACM and PA increased periostin expression, while inhibiting periostin disrupted the involvement of ACM and PA in promoting extracellular matrix degradation, stemness, and chemoresistance in TNBCs. Furthermore, this study found that periostin promoted TNBC progression by activating the MAPK/ERK signaling pathway and that inhibition of MAPK/ERK signaling reduced the phenotype caused by periostin upregulation in TNBCs treated with ACM or PA. Finally, the present results showed that the high expression of POSTN, which encodes periostin, was substantially related to worse survival in TNBC patients. CONCLUSIONS The results of the study elucidated for the first time how periostin is the key protein secreted in TNBCs in response to the adipocyte-regulated tumor microenvironment, while periostin-neutralizing antibodies may serve as potential therapeutic agents in relation to TNBC progression.
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Affiliation(s)
- Jinna Wu
- Department of Breast Oncology Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China
| | - Jia Li
- Department of Breast Oncology Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China
| | - Huiya Xu
- Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Ni Qiu
- Department of Breast Oncology Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China
| | - Xiaojia Huang
- Department of Breast Oncology Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China
| | - Hongsheng Li
- Department of Breast Oncology Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China.
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20
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Martino F, Lupi M, Giraudo E, Lanzetti L. Breast cancers as ecosystems: a metabolic perspective. Cell Mol Life Sci 2023; 80:244. [PMID: 37561190 PMCID: PMC10415483 DOI: 10.1007/s00018-023-04902-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/18/2023] [Accepted: 07/28/2023] [Indexed: 08/11/2023]
Abstract
Breast cancer (BC) is the most frequently diagnosed cancer and one of the major causes of cancer death. Despite enormous progress in its management, both from the therapeutic and early diagnosis viewpoints, still around 700,000 patients succumb to the disease each year, worldwide. Late recurrency is the major problem in BC, with many patients developing distant metastases several years after the successful eradication of the primary tumor. This is linked to the phenomenon of metastatic dormancy, a still mysterious trait of the natural history of BC, and of several other types of cancer, by which metastatic cells remain dormant for long periods of time before becoming reactivated to initiate the clinical metastatic disease. In recent years, it has become clear that cancers are best understood if studied as ecosystems in which the impact of non-cancer-cell-autonomous events-dependent on complex interaction between the cancer and its environment, both local and systemic-plays a paramount role, probably as significant as the cell-autonomous alterations occurring in the cancer cell. In adopting this perspective, a metabolic vision of the cancer ecosystem is bound to improve our understanding of the natural history of cancer, across space and time. In BC, many metabolic pathways are coopted into the cancer ecosystem, to serve the anabolic and energy demands of the cancer. Their study is shedding new light on the most critical aspect of BC management, of metastatic dissemination, and that of the related phenomenon of dormancy and fostering the application of the knowledge to the development of metabolic therapies.
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Affiliation(s)
- Flavia Martino
- Department of Oncology, University of Torino Medical School, Turin, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy
| | - Mariadomenica Lupi
- Department of Oncology, University of Torino Medical School, Turin, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy
| | - Enrico Giraudo
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy
- Department of Science and Drug Technology, University of Torino, Turin, Italy
| | - Letizia Lanzetti
- Department of Oncology, University of Torino Medical School, Turin, Italy.
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.
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21
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Meng X, Morita M, Kuba S, Hayashi H, Otsubo R, Matsumoto M, Yamanouchi K, Kobayashi K, Soyama A, Hidaka M, Kanetaka K, Nagayasu T, Eguchi S. Association of quantitative analysis of intratumoral reduced E-cadherin expression with lymph node metastasis and prognosis in patients with breast cancer. Sci Rep 2023; 13:10434. [PMID: 37369698 PMCID: PMC10300190 DOI: 10.1038/s41598-023-37012-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Loss of E-cadherin expression is a poor prognostic factor in patients with breast cancer. Breast cancer cells co-cultured with adipocytes reportedly promote E-cadherin attenuation and tumor progression. The current study aimed to investigate the association of reduced E-cadherin expression with adipose tissue invasion (ATI) and prognosis in breast cancer. Surgical specimens were collected from 188 women with invasive ductal carcinoma of the breast who had undergone surgery without neoadjuvant treatment. We compared E-cadherin expression in ATI and invasive front (IF) using immunohistochemistry with ImageJ. Reduced E-cadherin expression was detected not only in the ATI area but also in the IF, and the degree of reduced E-cadherin expression was positively correlated with both areas. In patients with lymph node metastasis compared to those without, E-cadherin expression was reduced and this reduction was associated with poor recurrence-free survival. We concluded that E-cadherin expression is reduced not only at the ATI area but also at the IF of the tumor. Reduced E-cadherin expression is a clear prognostic factor for breast cancer. Hence, future research is warranted for establishing an objective and quantitative E-cadherin staining assay that will allow clinical use of E-cadherin as a prognostic factor.
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Affiliation(s)
- Xiangyue Meng
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan
| | - Michi Morita
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan
| | - Sayaka Kuba
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan.
| | - Hiroko Hayashi
- Department of Pathology, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
| | - Ryota Otsubo
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
| | - Megumi Matsumoto
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
| | - Kosho Yamanouchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan
| | - Kazuma Kobayashi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan
| | - Kengo Kanetaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan
| | - Takeshi Nagayasu
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto-Machi, Nagasaki, 852-8501, Japan
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22
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Mertz DR, Parigoris E, Sentosa J, Lee JH, Lee S, Kleer CG, Luker G, Takayama S. Triple-negative breast cancer cells invade adipocyte/preadipocyte-encapsulating geometrically inverted mammary organoids. Integr Biol (Camb) 2023; 15:zyad004. [PMID: 37015816 PMCID: PMC10155781 DOI: 10.1093/intbio/zyad004] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 02/25/2023] [Indexed: 04/06/2023]
Abstract
This paper describes the manufacture of geometrically inverted mammary organoids encapsulating primary mammary preadipocytes and adipocytes. Material manipulation in an array of 192 hanging drops induces cells to self-assemble into inside-out organoids where an adipose tissue core is enveloped by a cell-produced basement membrane, indicated by laminin V staining and then a continuous layer of mammary epithelial cells. This inverted tissue structure enables investigation of multiple mammary cancer subtypes, with a significantly higher extent of invasion by triple-negative MDA-MB-231 breast cancer cells compared to MCF7 cells. By seeding cancer cells into co-culture around pre-formed organoids with encapsulated preadipocytes/adipocytes, invasion through the epithelium, then into the adipose core is observable through acquisition of confocal image stacks of whole mount specimens. Furthermore, in regions of the connective tissue core where invasion occurs, there is an accumulation of collagen in the microenvironment. Suggesting that this collagen may be conducive to increased invasiveness, the anti-fibrotic drug pirfenidone shows efficacy in this model by slowing invasion. Comparison of adipose tissue derived from three different donors shows method consistency as well as the potential to evaluate donor cell-based biological variability. Insight box Geometrically inverted mammary organoids encapsulating primary preadipocytes/adipocytes (P/As) are bioengineered using a minimal amount of Matrigel scaffolding. Use of this eversion-free method is key to production of adipose mammary organoids (AMOs) where not only the epithelial polarity but also the entire self-organizing arrangement, including adipose position, is inside-out. While an epithelial-only structure can analyze cancer cell invasion, P/As are required for invasion-associated collagen deposition and efficacy of pirfenidone to counteract collagen deposition and associated invasion. The methods described strike a balance between repeatability and preservation of biological variability: AMOs form consistently across multiple adipose cell donors while revealing cancer cell invasion differences.
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Affiliation(s)
- David R Mertz
- Wallace H. Coulter Department of Biomedical Engineering , Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA
| | - Eric Parigoris
- Wallace H. Coulter Department of Biomedical Engineering , Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA
| | - Jason Sentosa
- Wallace H. Coulter Department of Biomedical Engineering , Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA
| | - Ji-Hoon Lee
- Wallace H. Coulter Department of Biomedical Engineering , Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA
| | - Soojung Lee
- Wallace H. Coulter Department of Biomedical Engineering , Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA
| | - Celina G Kleer
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Gary Luker
- Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, MI, USA
| | - Shuichi Takayama
- Wallace H. Coulter Department of Biomedical Engineering , Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA
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23
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Munkácsy G, Santarpia L, Győrffy B. Therapeutic Potential of Tumor Metabolic Reprogramming in Triple-Negative Breast Cancer. Int J Mol Sci 2023; 24:ijms24086945. [PMID: 37108109 PMCID: PMC10138520 DOI: 10.3390/ijms24086945] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/28/2023] [Accepted: 04/05/2023] [Indexed: 04/29/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with clinical features of high metastatic potential, susceptibility to relapse, and poor prognosis. TNBC lacks the expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It is characterized by genomic and transcriptional heterogeneity and a tumor microenvironment (TME) with the presence of high levels of stromal tumor-infiltrating lymphocytes (TILs), immunogenicity, and an important immunosuppressive landscape. Recent evidence suggests that metabolic changes in the TME play a key role in molding tumor development by impacting the stromal and immune cell fractions, TME composition, and activation. Hence, a complex inter-talk between metabolic and TME signaling in TNBC exists, highlighting the possibility of uncovering and investigating novel therapeutic targets. A better understanding of the interaction between the TME and tumor cells, and the underlying molecular mechanisms of cell-cell communication signaling, may uncover additional targets for better therapeutic strategies in TNBC treatment. In this review, we aim to discuss the mechanisms in tumor metabolic reprogramming, linking these changes to potential targetable molecular mechanisms to generate new, physical science-inspired clinical translational insights for the cure of TNBC.
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Affiliation(s)
- Gyöngyi Munkácsy
- National Laboratory for Drug Research and Development, Magyar Tudósok Körútja 2, 1117 Budapest, Hungary
- Oncology Biomarker Research Group, Research Centre for Natural Sciences, Institute of Enzymology, Magyar Tudósok Körútja 2, 1117 Budapest, Hungary
| | | | - Balázs Győrffy
- Department of Bioinformatics, Semmelweis University, Tűzoltó u. 5-7, 1094 Budapest, Hungary
- Department of Pediatrics, Semmelweis University, Tűzoltó u. 5-7, 1094 Budapest, Hungary
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24
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Godina C, Tryggvadottir H, Bosch A, Borgquist S, Belting M, Isaksson K, Jernström H. Caveolin-1 genotypes as predictor for locoregional recurrence and contralateral disease in breast cancer. Breast Cancer Res Treat 2023; 199:335-347. [PMID: 37017811 PMCID: PMC10175335 DOI: 10.1007/s10549-023-06919-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 03/18/2023] [Indexed: 04/06/2023]
Abstract
PURPOSE Caveolin-1 (CAV1) has been implicated in breast cancer oncogenesis and metastasis and may be a potential prognosticator, especially for non-distant events. CAV1 functions as a master regulator of membrane transport and cell signaling. Several CAV1 SNPs have been linked to multiple cancers, but the prognostic impact of CAV1 SNPs in breast cancer remains unclear. Here, we investigated CAV1 polymorphisms in relation to clinical outcomes in breast cancer. METHODS A cohort of 1017 breast cancer patients (inclusion 2002-2012, Sweden) were genotyped using Oncoarray by Ilumina. Patients were followed for up to 15 years. Five out of six CAV1 SNPs (rs10256914, rs959173, rs3807989, rs3815412, and rs8713) passed quality control and were used for haplotype construction. CAV1 genotypes and haplotypes in relation to clinical outcomes were assessed with Cox regression and adjusted for potential confounders (age, tumor characteristics, and adjuvant treatments). RESULTS Only one SNP was associated with lymph node status, no other SNPs or haplotypes were associated with tumor characteristics. The CAV1 rs3815412 CC genotype (5.8% of patients) was associated with increased risk of contralateral breast cancer, adjusted hazard ratio (HRadj) 4.26 (95% CI 1.86-9.73). Moreover, the TTACA haplotype (13% of patients) conferred an increased risk for locoregional recurrence HRadj 2.24 (95% CI 1.24-4.04). No other genotypes or haplotypes were associated with clinical outcome. CONCLUSION CAV1 polymorphisms were associated with increased risk for locoregional recurrence and contralateral breast cancer. These findings may identify patients that could derive benefit from more tailored treatment to prevent non-distant events, if confirmed.
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Affiliation(s)
- Christopher Godina
- Division of Oncology, Department of Clinical Sciences in Lund, Lund University and Skåne University Hospital, Barngatan 4, 221 85, Lund, Sweden
| | - Helga Tryggvadottir
- Division of Oncology, Department of Clinical Sciences in Lund, Lund University and Skåne University Hospital, Barngatan 4, 221 85, Lund, Sweden
- Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund and Malmö, Sweden
| | - Ana Bosch
- Division of Oncology, Department of Clinical Sciences in Lund, Lund University and Skåne University Hospital, Barngatan 4, 221 85, Lund, Sweden
- Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund and Malmö, Sweden
| | - Signe Borgquist
- Division of Oncology, Department of Clinical Sciences in Lund, Lund University and Skåne University Hospital, Barngatan 4, 221 85, Lund, Sweden
- Department of Oncology, Aarhus University and Aarhus University Hospital, Aarhus, Denmark
| | - Mattias Belting
- Division of Oncology, Department of Clinical Sciences in Lund, Lund University and Skåne University Hospital, Barngatan 4, 221 85, Lund, Sweden
- Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund and Malmö, Sweden
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Karolin Isaksson
- Division of Surgery, Department of Clinical Sciences in Lund, Lund University and Kristianstad Hospital, Lund and Kristianstad, Sweden
| | - Helena Jernström
- Division of Oncology, Department of Clinical Sciences in Lund, Lund University and Skåne University Hospital, Barngatan 4, 221 85, Lund, Sweden.
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25
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Rebeaud M, Bouche C, Dauvillier S, Attané C, Arellano C, Vaysse C, Fallone F, Muller C. A novel 3D culture model for human primary mammary adipocytes to study their metabolic crosstalk with breast cancer in lean and obese conditions. Sci Rep 2023; 13:4707. [PMID: 36949082 PMCID: PMC10033714 DOI: 10.1038/s41598-023-31673-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 03/15/2023] [Indexed: 03/24/2023] Open
Abstract
Obesity is a negative prognosis factor for breast cancer. Yet, the biological mechanisms underlying this effect are still largely unknown. An emerging hypothesis is that the transfer of free fatty acids (FFA) between adipocytes and tumor cells might be altered under obese conditions, contributing to tumor progression. Currently there is a paucity of models to study human mammary adipocytes (M-Ads)-cancer crosstalk. As for other types of isolated white adipocytes, herein, we showed that human M-Ads die within 2-3 days by necrosis when grown in 2D. As an alternative, M-Ads were grown in a fibrin matrix, a 3D model that preserve their distribution, integrity and metabolic function for up to 5 days at physiological glucose concentrations (5 mM). Higher glucose concentrations frequently used in in vitro models promote lipogenesis during M-Ads culture, impairing their lipolytic function. Using transwell inserts, the matrix embedded adipocytes were cocultured with breast cancer cells. FFA transfer between M-Ads and cancer cells was observed, and this event was amplified by obesity. Together these data show that our 3D model is a new tool for studying the effect of M-Ads on tumor cells and beyond with all the components of the tumor microenvironment including the immune cells.
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Affiliation(s)
- Marie Rebeaud
- Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR 5089, 205 route de Narbonne, BP 64182, 31077, Toulouse, France
| | - Caroline Bouche
- Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR 5089, 205 route de Narbonne, BP 64182, 31077, Toulouse, France
- Département de Chirurgie Gynécologique oncologique, CHU-Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, 1 avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France
| | - Stéphanie Dauvillier
- Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR 5089, 205 route de Narbonne, BP 64182, 31077, Toulouse, France
| | - Camille Attané
- Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR 5089, 205 route de Narbonne, BP 64182, 31077, Toulouse, France
| | - Carlo Arellano
- Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR 5089, 205 route de Narbonne, BP 64182, 31077, Toulouse, France
- Département de Chirurgie Gynécologique oncologique, CHU-Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, 1 avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France
| | - Charlotte Vaysse
- Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR 5089, 205 route de Narbonne, BP 64182, 31077, Toulouse, France
- Département de Chirurgie Gynécologique oncologique, CHU-Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, 1 avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France
| | - Frédérique Fallone
- Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR 5089, 205 route de Narbonne, BP 64182, 31077, Toulouse, France
| | - Catherine Muller
- Institut de Pharmacologie et de Biologie Structurale, CNRS/Université de Toulouse UMR 5089, 205 route de Narbonne, BP 64182, 31077, Toulouse, France.
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26
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Bobiński R, Dutka M, Pizon M, Waksmańska W, Pielesz A. Ferroptosis, Acyl Starvation, and Breast Cancer. Mol Pharmacol 2023; 103:132-144. [PMID: 36750321 DOI: 10.1124/molpharm.122.000607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 10/31/2022] [Indexed: 12/14/2022] Open
Abstract
To maintain their growth rate, cancer cells must secure a supply of fatty acids, which are necessary for building cell membranes and maintaining energy processes. This is one of the reasons why tissues with intensive fatty acid metabolism, such as the mammary gland, are more likely to develop tumors. One natural or induced defense process against cancer is ferroptosis, which interferes with normal fatty acid metabolism. This leads to the oxidation of polyunsaturated fatty acids, which causes a rearrangement of the metabolism and damages cell membranes. As a consequence of this oxidation, there is a shortage of normal polyunsaturated fatty acids, which disturbs the complicated metabolism of fatty acids. This imbalance in metabolism, resulting from the deficiency of properly structured fatty acids, is called, by these authors, "acyl starvation." When cancer cells are exposed to alternating hypoxia and reoxygenation, they often develop resistance to neoadjuvant therapies. Blocking the stearoyl-CoA desaturase - fatty acid-binding protein 4 - fatty acid translocase axis appears to be a promising pathway in the treatment of breast cancer. On the one hand, the inhibition of desaturase leads to the formation of toxic phospholipid hydroperoxides in ferroptosis, whereas on the other hand, the inhibition of fatty acid-binding protein 4 and translocase leads to a reduced uptake of fatty acids and disruption of the cellular transport of fatty acids, resulting in intracellular acyl starvation. The disruption in the metabolism of fatty acids in cancer cells may augment the effectiveness of neoadjuvant therapy. SIGNIFICANCE STATEMENT: Regulation of the metabolism of fatty acids in cancer cells seems to be a promising therapeutic direction. Studies show that the induction of ferroptosis in cancer cells, combined with use of neoadjuvant therapies, effectively inhibits the proliferation of these cells. We link the process of ferroptosis with apoptosis and SCD1-FABP4-CD36 axis and propose the term "acyl starvation" for the processes leading to FA deficiency, dysregulation of FA metabolism in cancer cells, and, most importantly, the appearance of incorrect proportions FAs.
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Affiliation(s)
- Rafał Bobiński
- Department of Biochemistry and Molecular Biology (R.B., M.D., W.W.) and Department of Microbiology and Environmental Technology, Institute of Engineering and Environmental Protection (A.P.), University of Bielsko-Biala, Bielsko-Biala, Poland; and Department of Research and Development, Transfusion Center Bayreuth, Bayreuth, Germany (M.P.)
| | - Mieczysław Dutka
- Department of Biochemistry and Molecular Biology (R.B., M.D., W.W.) and Department of Microbiology and Environmental Technology, Institute of Engineering and Environmental Protection (A.P.), University of Bielsko-Biala, Bielsko-Biala, Poland; and Department of Research and Development, Transfusion Center Bayreuth, Bayreuth, Germany (M.P.)
| | - Monika Pizon
- Department of Biochemistry and Molecular Biology (R.B., M.D., W.W.) and Department of Microbiology and Environmental Technology, Institute of Engineering and Environmental Protection (A.P.), University of Bielsko-Biala, Bielsko-Biala, Poland; and Department of Research and Development, Transfusion Center Bayreuth, Bayreuth, Germany (M.P.)
| | - Wioletta Waksmańska
- Department of Biochemistry and Molecular Biology (R.B., M.D., W.W.) and Department of Microbiology and Environmental Technology, Institute of Engineering and Environmental Protection (A.P.), University of Bielsko-Biala, Bielsko-Biala, Poland; and Department of Research and Development, Transfusion Center Bayreuth, Bayreuth, Germany (M.P.)
| | - Anna Pielesz
- Department of Biochemistry and Molecular Biology (R.B., M.D., W.W.) and Department of Microbiology and Environmental Technology, Institute of Engineering and Environmental Protection (A.P.), University of Bielsko-Biala, Bielsko-Biala, Poland; and Department of Research and Development, Transfusion Center Bayreuth, Bayreuth, Germany (M.P.)
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The Tumor Microenvironment in Tumorigenesis and Therapy Resistance Revisited. Cancers (Basel) 2023; 15:cancers15020376. [PMID: 36672326 PMCID: PMC9856874 DOI: 10.3390/cancers15020376] [Citation(s) in RCA: 76] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/28/2022] [Accepted: 01/04/2023] [Indexed: 01/09/2023] Open
Abstract
Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis, and highlight various ways through which tumor cells reprogram normal cells into phenotypes that are pro-tumorigenic, including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to the transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells, including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic, but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to the formation of new vascular networks in order to actively promote and sustain tumor growth via the supply of oxygen and nutrients, whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to the targeting of tumor cells. The reprogramming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centered therapies under investigation.
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Pagnotta P, Gantov M, Fletcher S, Lombardi A, Crosbie ML, Santiso N, Ursino A, Frascarolli C, Amato A, Dreszman R, Calvo JC, Toneatto J. Peritumoral adipose tissue promotes lipolysis and white adipocytes browning by paracrine action. Front Endocrinol (Lausanne) 2023; 14:1144016. [PMID: 37181035 PMCID: PMC10170974 DOI: 10.3389/fendo.2023.1144016] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 04/07/2023] [Indexed: 05/16/2023] Open
Abstract
Background Stromal adipocytes and tumor breast epithelial cells undergo a mutual metabolic adaptation within tumor microenvironment. Therefore, browning and lipolysis occur in cancer associated adipocytes (CAA). However, the paracrine effects of CAA on lipid metabolism and microenvironment remodeling remain poorly understood. Methods To analyze these changes, we evaluated the effects of factors in conditioned media (CM) derived from explants of human breast adipose tissue from tumor (hATT) or normal (hATN) on morphology, degree of browning, the levels of adiposity, maturity, and lipolytic-related markers in 3T3-L1 white adipocytes by Western blot, indirect immunofluorescence and lipolytic assay. We analyzed subcellular localization of UCP1, perilipin 1 (Plin1), HSL and ATGL in adipocytes incubated with different CM by indirect immunofluorescence. Additionally, we evaluated changes in adipocyte intracellular signal pathways. Results We found that adipocytes incubated with hATT-CM displayed characteristics that morphologically resembled beige/brown adipocytes with smaller cell size and higher number of small and micro lipid droplets (LDs), with less triglyceride content. Both, hATT-CM and hATN-CM, increased Pref-1, C/EBPβ LIP/LAP ratio, PPARγ, and caveolin 1 expression in white adipocytes. UCP1, PGC1α and TOMM20 increased only in adipocytes that were treated with hATT-CM. Also, hATT-CM increased the levels of Plin1 and HSL, while decreased ATGL. hATT-CM modified the subcellular localization of the lipolytic markers, favoring their relative content around micro-LDs and induced Plin1 segregation. Furthermore, the levels of p-HSL, p-ERK and p-AKT increased in white adipocytes after incubation with hATT-CM. Conclusions In summary, these findings allow us to conclude that adipocytes attached to the tumor could induce white adipocyte browning and increase lipolysis as a means for endocrine/paracrine signaling. Thus, adipocytes from the tumor microenvironment exhibit an activated phenotype that could have been induced not only by secreted soluble factors from tumor cells but also by paracrine action from other adipocytes present in this microenvironment, suggesting a "domino effect".
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Affiliation(s)
- Priscila Pagnotta
- Institute of Biology and Experimental Medicine (IBYME), CONICET, Buenos Aires, Argentina
- Department of Biological Chemistry, Faculty of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina
| | - Mariana Gantov
- Institute of Biology and Experimental Medicine (IBYME), CONICET, Buenos Aires, Argentina
| | - Sabrina Fletcher
- Institute of Biology and Experimental Medicine (IBYME), CONICET, Buenos Aires, Argentina
| | - Antonella Lombardi
- Institute of Neurosciences (INEU) FLENI-CONICET, Buenos Aires, Argentina
| | - María Lujan Crosbie
- Breast Surgery Section, Churruca-Visca Police Medical Centre, Buenos Aires, Argentina
| | - Natalia Santiso
- Breast Surgery Section, Churruca-Visca Police Medical Centre, Buenos Aires, Argentina
| | - Anabela Ursino
- Breast Surgery Section, Churruca-Visca Police Medical Centre, Buenos Aires, Argentina
| | - Celeste Frascarolli
- Breast Surgery Section, Churruca-Visca Police Medical Centre, Buenos Aires, Argentina
| | - Alicia Amato
- Breast Surgery Section, Churruca-Visca Police Medical Centre, Buenos Aires, Argentina
| | | | - Juan Carlos Calvo
- Institute of Biology and Experimental Medicine (IBYME), CONICET, Buenos Aires, Argentina
- Department of Biological Chemistry, Faculty of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina
| | - Judith Toneatto
- Institute of Biology and Experimental Medicine (IBYME), CONICET, Buenos Aires, Argentina
- *Correspondence: Judith Toneatto,
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Zaoui M, Morel M, Louadj L, Ferrand N, Lamazière A, Uzan C, Canlorbe G, Atlan M, Sabbah M. Adipocytes secretome from normal and tumor breast favor breast cancer invasion by metabolic reprogramming. Clin Transl Oncol 2022; 25:1389-1401. [PMID: 36520383 DOI: 10.1007/s12094-022-03035-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 11/29/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND Adipose tissue is a major component of breast stroma. This study focused on delineating the effects of adipose stem cells (ASCs) derived from breast of healthy women and cancer patients with normal or tumor breast cells. METHODS The ASCs were induced to differentiate into adipocytes, and the subsequent adipocyte conditioned media (ACM) were evaluated for their fatty acid profile, adipokine secretion and influence on proliferation, migration and invasion on tumoral (MCF-7 and SUM159) and normal (HMEC) human breast cell lines. RESULTS An enrichment of arachidonic acid was observed in ACM from tumor tissues. Adipose tissues from tumor free secrete twice as much leptin than those from proximal or distal to the tumor. All ACMs display proliferative activity and favor invasiveness of SUM159 cells compared to MCF-7 and HMEC. All ACMs induced lipid droplets accumulation in MCF-7 cells and increased CD36 expression in tumor cells. CONCLUSION We conclude that among secreted factors analyzed, only arachidonic acid and leptin levels did discriminate ASCs from tumor-bearing and tumor-free breasts emphasizing the importance that other cell types could contribute to the adipose tissue secretome in a tumor context.
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Affiliation(s)
- Maurice Zaoui
- Team Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie, Sorbonne University, INSERM UMR_S 938, 75012, Paris, France
| | - Mehdi Morel
- Team Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie, Sorbonne University, INSERM UMR_S 938, 75012, Paris, France
| | - Lila Louadj
- Team Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie, Sorbonne University, INSERM UMR_S 938, 75012, Paris, France
| | - Nathalie Ferrand
- Team Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie, Sorbonne University, INSERM UMR_S 938, 75012, Paris, France
| | - Antonin Lamazière
- UMR 70203, Laboratory of Biomolecules, Institut National de La Santé Et de La Recherche Médicale (INSERM), École Normale Supérieure, AP-HP, 75012, Paris, France
| | - Catherine Uzan
- Team Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie, Sorbonne University, INSERM UMR_S 938, 75012, Paris, France
- Department of Gynecological and Breast Surgery and Oncology, Assistance Publique des Hôpitaux de Paris (AP-HP)Pitié-Salpêtrière University Hospital, 75013, Paris, France
| | - Geoffroy Canlorbe
- Team Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie, Sorbonne University, INSERM UMR_S 938, 75012, Paris, France
- Department of Gynecological and Breast Surgery and Oncology, Assistance Publique des Hôpitaux de Paris (AP-HP)Pitié-Salpêtrière University Hospital, 75013, Paris, France
| | - Michael Atlan
- Department of Plastic Surgery, Reconstructive, Aesthetic, Microsurgery and Tissue Regeneration, Tenon Hospital, Institut Universitaire de Cancérologie, AP-HP, 75020, Paris, France
| | - Michèle Sabbah
- Team Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie, Sorbonne University, INSERM UMR_S 938, 75012, Paris, France.
- Centre National de la Recherche Scientifique (CNRS), 75012, Paris, France.
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Macrophage-Conditioned Media Promotes Adipocyte Cancer Association, Which in Turn Stimulates Breast Cancer Proliferation and Migration. Biomolecules 2022; 12:biom12121757. [PMID: 36551185 PMCID: PMC9775594 DOI: 10.3390/biom12121757] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/18/2022] [Accepted: 11/20/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Breast cancer is the most common cancer in women and the leading cause of female cancer deaths worldwide. Obesity causes chronic inflammation and is a risk factor for post-menopausal breast cancer and poor prognosis. Obesity triggers increased infiltration of macrophages into adipose tissue, yet little research has focused on the effects of macrophages in early stages of breast tumor development in obese patients. In this study, the effects of pro-inflammatory macrophages on breast cancer-adipocyte crosstalk were investigated. METHODS An innovative human cell co-culture system was built and used to model the paracrine interactions among adipocytes, macrophages, and breast cancer cells and how they facilitate tumor progression. The effects on cancer cells were examined using cell counts and migration assays. Quantitative reverse-transcription polymerase chain reaction was used to measure the expression levels of several cytokines and proteases to analyze adipocyte cancer association. RESULTS Macrophage-conditioned media intensified the effects of breast cancer-adipocyte crosstalk. Adipocytes became delipidated and increased production of pro-inflammatory cytokines, even in the absence of cancer cells, although the expression levels were highest with all three cell components. As a result, co-cultured breast cancer cells became more aggressive, with increased proliferation and migration compared to adipocyte-breast cancer co-cultures treated with unconditioned media. CONCLUSIONS A novel co-culture model was built to evaluate the crosstalk among human macrophages, adipocytes, and breast cancer cells. We found that macrophages may contribute to adipocyte inflammation and cancer association and thus promote breast cancer progression.
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Potential Pro-Tumorigenic Effect of Bisphenol A in Breast Cancer via Altering the Tumor Microenvironment. Cancers (Basel) 2022; 14:cancers14123021. [PMID: 35740686 PMCID: PMC9221131 DOI: 10.3390/cancers14123021] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 06/14/2022] [Accepted: 06/16/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Bisphenol A (BPA) is primarily used to produce polycarbonate plastics, such as water bottles. Exposure to BPA has been shown to increase the growth of breast cancer cells that depend on estrogen for growth due to its ability to mimic estrogen. More recent studies have suggested that BPA also affects the cellular and non-cellular components that compose tumor microenvironments (TMEs), namely the environment around a tumor, thereby potentially promoting breast cancer growth via altering the TME. The TME plays an essential role in cancer development and promotion. Therefore, it is crucial to understand the effect of BPA on breast TMEs to assess its role in the risk of breast cancer adequately. This review examines the potential effects of BPA on immune cells, fibroblasts, extracellular matrices, and adipocytes to highlight their roles in mediating the carcinogenic effect of BPA, and thereby proposes considerations for the risk assessment of BPA exposure. Abstract BPA, a chemical used in the preparation of polycarbonate plastics, is an endocrine disruptor. Exposure to BPA has been suggested to be a risk factor for breast cancer because of its potential to induce estrogen receptor signaling in breast cancer cells. More recently, it has been recognized that BPA also binds to the G protein-coupled estrogen receptor and other nuclear receptors, in addition to estrogen receptors, and acts on immune cells, adipocytes, and fibroblasts, potentially modulating the TME. The TME significantly impacts the behavior of cancer cells. Therefore, understanding how BPA affects stromal components in breast cancer is imperative to adequately assess the association between exposure to BPA and the risk of breast cancer. This review examines the effects of BPA on stromal components of tumors to highlight their potential role in the carcinogenic effect of BPA. As a result, I propose considerations for the risk assessment of BPA exposure and studies needed to improve understanding of the TME-mediated, breast cancer-promoting effect of BPA.
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Roumiguié M, Estève D, Manceau C, Toulet A, Gilleron J, Belles C, Jia Y, Houël C, Pericart S, LeGonidec S, Valet P, Cormont M, Tanti JF, Malavaud B, Bouloumié A, Milhas D, Muller C. Periprostatic Adipose Tissue Displays a Chronic Hypoxic State that Limits Its Expandability. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:926-942. [PMID: 35358473 DOI: 10.1016/j.ajpath.2022.03.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/15/2022] [Accepted: 03/08/2022] [Indexed: 06/14/2023]
Abstract
White adipose tissue accumulates at various sites throughout the body, some adipose tissue depots exist near organs whose function they influence in a paracrine manner. Prostate gland is surrounded by a poorly characterized adipose depot called periprostatic adipose tissue (PPAT), which plays emerging roles in prostate-related disorders. Unlike all other adipose depots, PPAT secretes proinflammatory cytokines even in lean individuals and does not increase in volume during obesity. These unique features remain unexplained because of the poor structural and functional characterization of this tissue. This study characterized the structural organization of PPAT in patients compared with abdominopelvic adipose tissue (APAT), an extraperitoneal adipose depot, the accumulation of which is correlated to body mass index. Confocal microscopy followed by three-dimensional reconstructions showed a sparse vascular network in PPAT when compared with that in APAT, suggesting that this tissue is hypoxic. Unbiased comparisons of PPAT and APAT transcriptomes found that most differentially expressed genes were related to the hypoxia response. High levels of the hypoxia-inducible factor 2α confirmed the presence of an adaptive response to hypoxia in PPAT. This chronic hypoxic state was associated with inflammation and fibrosis, which were not further up-regulated by obesity. This fibrosis and inflammation explain the failure of PPAT to expand in obesity and open new mechanistic avenues to explain its role in prostate-related disorders, including cancer.
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Affiliation(s)
- Mathieu Roumiguié
- Institut de Pharmacologie et Biologie Structurale (Equipe Labélisée Ligue Nationale contre le Cancer), Université de Toulouse, Centre national de la recherche scientifique, Toulouse, France; Département d'Urologie, Institut Universitaire du Cancer, Toulouse, France
| | - David Estève
- Institut de Pharmacologie et Biologie Structurale (Equipe Labélisée Ligue Nationale contre le Cancer), Université de Toulouse, Centre national de la recherche scientifique, Toulouse, France
| | - Cécile Manceau
- Institut de Pharmacologie et Biologie Structurale (Equipe Labélisée Ligue Nationale contre le Cancer), Université de Toulouse, Centre national de la recherche scientifique, Toulouse, France; Département d'Urologie, Institut Universitaire du Cancer, Toulouse, France
| | - Aurélie Toulet
- Institut de Pharmacologie et Biologie Structurale (Equipe Labélisée Ligue Nationale contre le Cancer), Université de Toulouse, Centre national de la recherche scientifique, Toulouse, France
| | - Jérôme Gilleron
- Université Côte d'Azur, INSERM, Centre Méditerranéen de Médecine Moléculaire, Team Cellular and Molecular Pathophysiology of Obesity, Nice, France
| | - Chloé Belles
- Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, INSERM, Toulouse, France
| | - Yiyue Jia
- Institut de Pharmacologie et Biologie Structurale (Equipe Labélisée Ligue Nationale contre le Cancer), Université de Toulouse, Centre national de la recherche scientifique, Toulouse, France
| | - Cynthia Houël
- Institut de Pharmacologie et Biologie Structurale (Equipe Labélisée Ligue Nationale contre le Cancer), Université de Toulouse, Centre national de la recherche scientifique, Toulouse, France
| | - Sarah Pericart
- Département d'Anatomo-Pathologie, Institut Universitaire du Cancer, Toulouse, France
| | - Sophie LeGonidec
- Institut RESTORE, Université de Toulouse, Centre national de la recherche scientifique U-5070, Etablissement Français du Sang, Ecole Nationale Vétérinaire de Toulouse, INSERM U1301, Toulouse, France
| | - Philippe Valet
- Institut RESTORE, Université de Toulouse, Centre national de la recherche scientifique U-5070, Etablissement Français du Sang, Ecole Nationale Vétérinaire de Toulouse, INSERM U1301, Toulouse, France
| | - Mireille Cormont
- Université Côte d'Azur, INSERM, Centre Méditerranéen de Médecine Moléculaire, Team Cellular and Molecular Pathophysiology of Obesity, Nice, France
| | - Jean-François Tanti
- Université Côte d'Azur, INSERM, Centre Méditerranéen de Médecine Moléculaire, Team Cellular and Molecular Pathophysiology of Obesity, Nice, France
| | - Bernard Malavaud
- Département d'Urologie, Institut Universitaire du Cancer, Toulouse, France
| | - Anne Bouloumié
- Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, INSERM, Toulouse, France
| | - Delphine Milhas
- Institut de Pharmacologie et Biologie Structurale (Equipe Labélisée Ligue Nationale contre le Cancer), Université de Toulouse, Centre national de la recherche scientifique, Toulouse, France.
| | - Catherine Muller
- Institut de Pharmacologie et Biologie Structurale (Equipe Labélisée Ligue Nationale contre le Cancer), Université de Toulouse, Centre national de la recherche scientifique, Toulouse, France.
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Winkler NS, Tran A, Kwok AC, Freer PE, Fajardo LL. Autologous Fat Grafting to the Breast: An Educational Review. JOURNAL OF BREAST IMAGING 2022; 4:209-221. [PMID: 38422423 DOI: 10.1093/jbi/wbab055] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Indexed: 03/02/2024]
Abstract
Autologous fat grafting (AFG) is a technique that is increasingly utilized in breast cosmetic and reconstructive surgery. In this procedure, fat is aspirated by liposuction from one area of the body and injected into the breast. The procedure and process of AFG has evolved over the last few decades, leading to more widespread use, though there is no standard method. Autologous fat grafting is generally considered a safe procedure but may result in higher utilization of diagnostic imaging due to development of palpable lumps related to fat necrosis. Imaging findings depend on surgical technique but typically include bilateral, symmetric, retromammary oil cysts and scattered dystrophic and/or coarse calcifications when AFG is used for primary breast augmentation. More focal findings occur when AFG is used to improve specific areas of cosmetic deformity, scarring, or pain following breast cancer surgery. As with any cause of fat necrosis, imaging features tend to appear more benign over time, with development of rim calcifications associated with oil cysts and a shift in echogenicity of oil cyst contents on ultrasound towards anechoic in some cases. This article reviews the AFG procedure, uses, complications, and imaging findings.
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Affiliation(s)
- Nicole S Winkler
- University of Utah and Huntsman Cancer Institute, Department of Radiology and Imaging Sciences, Salt Lake City, UT, USA
| | - Alexander Tran
- University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Alvin C Kwok
- University of Utah and Huntsman Cancer Institute, Department of Plastic Surgery, Salt Lake City, UT, USA
| | - Phoebe E Freer
- University of Utah and Huntsman Cancer Institute, Department of Radiology and Imaging Sciences, Salt Lake City, UT, USA
| | - Laurie L Fajardo
- University of Utah and Huntsman Cancer Institute, Department of Radiology and Imaging Sciences, Salt Lake City, UT, USA
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Thromboinflammatory Processes at the Nexus of Metabolic Dysfunction and Prostate Cancer: The Emerging Role of Periprostatic Adipose Tissue. Cancers (Basel) 2022; 14:cancers14071679. [PMID: 35406450 PMCID: PMC8996963 DOI: 10.3390/cancers14071679] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/03/2022] [Accepted: 03/04/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary As overweight and obesity increase among the population worldwide, a parallel increase in the number of individuals diagnosed with prostate cancer was observed. There appears to be a relationship between both diseases where the increase in the mass of fat tissue can lead to inflammation. Such a state of inflammation could produce many factors that increase the aggressiveness of prostate cancer, especially if this inflammation occurred in the fat stores adjacent to the prostate. Another important observation that links obesity, fat tissue inflammation, and prostate cancer is the increased production of blood clotting factors. In this article, we attempt to explain the role of these latter factors in the effect of increased body weight on the progression of prostate cancer and propose new ways of treatment that act by affecting how these clotting factors work. Abstract The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it becomes pivotal to elucidate the thromboinflammatory processes occurring in the periprostatic adipose tissue (PPAT), a fundamental microenvironmental niche of the prostate. Here, we highlight key findings linking thromboinflammation and the pleiotropic effects of coagulation factors and their inhibitors in metabolic diseases, PCa, and their crosstalk. We also propose several novel therapeutic targets and therapeutic interventions possibly modulating the interaction between these pathological states.
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Lian X, Yang K, Li R, Li M, Zuo J, Zheng B, Wang W, Wang P, Zhou S. Immunometabolic rewiring in tumorigenesis and anti-tumor immunotherapy. Mol Cancer 2022; 21:27. [PMID: 35062950 PMCID: PMC8780708 DOI: 10.1186/s12943-021-01486-5] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 12/20/2021] [Indexed: 12/22/2022] Open
Abstract
Cellular metabolism constitutes a fundamental process in biology. During tumor initiation and progression, each cellular component in the cancerous niche undergoes dramatic metabolic reprogramming, adapting to a challenging microenvironment of hypoxia, nutrient deprivation, and other stresses. While the metabolic hallmarks of cancer have been extensively studied, the metabolic states of the immune cells are less well elucidated. Here we review the metabolic disturbance and fitness of the immune system in the tumor microenvironment (TME), focusing on the impact of oncometabolites to the function of immune cells and the clinical significance of targeting metabolism in anti-tumor immunotherapy. Metabolic alterations in the immune system of TME offer novel therapeutic insight into cancer treatment.
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Adipose Tissue-Breast Cancer Crosstalk Leads to Increased Tumor Lipogenesis Associated with Enhanced Tumor Growth. Int J Mol Sci 2021; 22:ijms222111881. [PMID: 34769312 PMCID: PMC8585035 DOI: 10.3390/ijms222111881] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/12/2022] Open
Abstract
We sought to identify therapeutic targets for breast cancer by investigating the metabolic symbiosis between breast cancer and adipose tissue. To this end, we compared orthotopic E0771 breast cancer tumors that were in direct contact with adipose tissue with ectopic E0771 tumors in mice. Orthotopic tumors grew faster and displayed increased de novo lipogenesis compared to ectopic tumors. Adipocytes release large amounts of lactate, and we found that both lactate pretreatment and adipose tissue co-culture augmented de novo lipogenesis in E0771 cells. Continuous treatment with the selective FASN inhibitor Fasnall dose-dependently decreased the E0771 viability in vitro. However, daily Fasnall injections were effective only in 50% of the tumors, while the other 50% displayed accelerated growth. These opposing effects of Fasnall in vivo was recapitulated in vitro; intermittent Fasnall treatment increased the E0771 viability at lower concentrations and suppressed the viability at higher concentrations. In conclusion, our data suggest that adipose tissue enhances tumor growth by stimulating lipogenesis. However, targeting lipogenesis alone can be deleterious. To circumvent the tumor's ability to adapt to treatment, we therefore believe that it is necessary to apply an aggressive treatment, preferably targeting several metabolic pathways simultaneously, together with conventional therapy.
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Gyamfi J, Yeo JH, Kwon D, Min BS, Cha YJ, Koo JS, Jeong J, Lee J, Choi J. Interaction between CD36 and FABP4 modulates adipocyte-induced fatty acid import and metabolism in breast cancer. NPJ Breast Cancer 2021; 7:129. [PMID: 34561446 PMCID: PMC8463699 DOI: 10.1038/s41523-021-00324-7] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 08/09/2021] [Indexed: 01/09/2023] Open
Abstract
Adipocytes influence breast cancer behaviour via fatty acid release into the tumour microenvironment. Co-culturing human adipocytes and breast cancer cells increased CD36 expression, with fatty acid import into breast cancer cells. Genetic ablation of CD36 attenuates adipocyte-induced epithelial-mesenchymal transition (EMT) and stemness. We show a feedforward loop between CD36 and STAT3; where CD36 activates STAT3 signalling and STAT3 binds to the CD36 promoter, regulating its expression. CD36 expression results in metabolic reprogramming, with a shift towards fatty acid oxidation. CD36 inhibition induces de novo lipogenesis in breast cancer cells. Increased CD36 expression occurs with increased FABP4 expression. We showed that CD36 directly interacts with FABP4 to regulate fatty acid import, transport, and metabolism. CD36 and FABP4 inhibition induces apoptosis in tumour cells. These results indicate that CD36 mediates fatty acid import from adipocytes into cancer cells and activates signalling pathways that drive tumour progression. Targeting CD36 may have a potential for therapy, which will target the tumour microenvironment.
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Affiliation(s)
- Jones Gyamfi
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea.,Department of Medical Laboratory Science, University of Health and Allied Sciences, Ho, Ghana
| | - Joo Hye Yeo
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea
| | - Doru Kwon
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea
| | - Byung Soh Min
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yoon Jin Cha
- Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Ja Seung Koo
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Joon Jeong
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jinu Lee
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea
| | - Junjeong Choi
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea.
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Ren J, Kong W, Lu F, Li Y. Adipose-derived stem cells (ADSCs) inhibit the expression of anti-apoptosis proteins through up-regulation of ATF4 on breast cancer cells. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1300. [PMID: 34532437 PMCID: PMC8422111 DOI: 10.21037/atm-21-3746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 08/06/2021] [Indexed: 12/09/2022]
Abstract
Background While current basic studies indicate adipose-derived stem cells (ADSCs) can promote cell proliferation, clinical trials have shown no significant difference in breast cancer recurrence rates for patients with or without autologous fat grafting (AFG). In this study we attempted to explore the underlying mechanism for these contradictory results. Methods ADSCs and umbilical mesenchymal stem cells (UMSCs) were co-cultured with breast cancer cells (MCF-7 and MDA-MB-231), and the cell viability analyzed by CCK-8 cell proliferation assay, TUNEL assay and immunofluorescence assay. In addition, real-time quantitative polymerase chain reaction (RT-qPCR) experiments and Western blot analysis were used to detect the mRNA and protein expression of activating transcription factor 4 (ATF4) and its downstream gene (MCL1 & BCL2), respectively. Results Co-cultured ADSCs could promote cell proliferation and cell apoptosis, and up-regulate ATF4 expression both in MCF-7 and MDA-MB-231. While co-cultured UMSCs could only promote cell apoptosis in MCF-7. Interestingly, we found that when co-cultured ADSCs, the expression of MCL1 and BCL2 protein was decreased, even if their mRNA expression was up-regulated both in MCF-7 and MDA-MB-231. Conclusions Co-cultured ADSCs can up-regulate ATF4 expression, then interfere with the translation process of MCL1 and BCL2 mRNA and induce cell apoptosis. These data provide insight into the safety characteristics of AFG.
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Affiliation(s)
- Jing Ren
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | | | - Feng Lu
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ye Li
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Mehraj U, Ganai RA, Macha MA, Hamid A, Zargar MA, Bhat AA, Nasser MW, Haris M, Batra SK, Alshehri B, Al-Baradie RS, Mir MA, Wani NA. The tumor microenvironment as driver of stemness and therapeutic resistance in breast cancer: New challenges and therapeutic opportunities. Cell Oncol (Dordr) 2021; 44:1209-1229. [PMID: 34528143 DOI: 10.1007/s13402-021-00634-9] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2021] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Breast cancer (BC), the second most common cause of cancer-related deaths, remains a significant threat to the health and wellness of women worldwide. The tumor microenvironment (TME), comprising cellular components, such as cancer-associated fibroblasts (CAFs), immune cells, endothelial cells and adipocytes, and noncellular components such as extracellular matrix (ECM), has been recognized as a critical contributor to the development and progression of BC. The interplay between TME components and cancer cells promotes phenotypic heterogeneity, cell plasticity and cancer cell stemness that impart tumor dormancy, enhanced invasion and metastasis, and the development of therapeutic resistance. While most previous studies have focused on targeting cancer cells with a dismal prognosis, novel therapies targeting stromal components are currently being evaluated in preclinical and clinical studies, and are already showing improved efficacies. As such, they may offer better means to eliminate the disease effectively. CONCLUSIONS In this review, we focus on the evolving concept of the TME as a key player regulating tumor growth, metastasis, stemness, and the development of therapeutic resistance. Despite significant advances over the last decade, several clinical trials focusing on the TME have failed to demonstrate promising effectiveness in cancer patients. To expedite clinical efficacy of TME-directed therapies, a deeper understanding of the TME is of utmost importance. Secondly, the efficacy of TME-directed therapies when used alone or in combination with chemo- or radiotherapy, and the tumor stage needs to be studied. Likewise, identifying molecular signatures and biomarkers indicating the type of TME will help in determining precise TME-directed therapies.
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Affiliation(s)
- Umar Mehraj
- Department of Bioresources, University of Kashmir, Srinagar, Jammu & Kashmir, India
| | - Rais A Ganai
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science & Technology , Awantipora, Jammu & Kashmir, India
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science & Technology , Awantipora, Jammu & Kashmir, India
| | - Abid Hamid
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India
| | - Mohammed A Zargar
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India
| | - Ajaz A Bhat
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Mohd Wasim Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Mohammad Haris
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar.,Laboratory of Animal Research, Qatar University, Doha, Qatar
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska, Lincoln, NE, USA.,Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Bader Alshehri
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Almajmaah, Kingdom of Saudi Arabia
| | - Raid Saleem Al-Baradie
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Almajmaah, Kingdom of Saudi Arabia
| | - Manzoor A Mir
- Department of Bioresources, University of Kashmir, Srinagar, Jammu & Kashmir, India.
| | - Nissar Ahmad Wani
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India.
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Nam K, Jeong CB, Kim H, Ahn M, Ahn S, Hur H, Kim DU, Jang J, Gwon H, Lim Y, Cho D, Lee K, Bae JY, Chang KS. Quantitative Photothermal Characterization with Bioprinted 3D Complex Tissue Constructs for Early-Stage Breast Cancer Therapy Using Gold Nanorods. Adv Healthc Mater 2021; 10:e2100636. [PMID: 34235891 PMCID: PMC11468621 DOI: 10.1002/adhm.202100636] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/18/2021] [Indexed: 11/12/2022]
Abstract
Plasmonic photothermal therapy (PPTT) using gold nanoparticles (AuNPs) has shown great potential for use in selective tumor treatment, because the AuNPs can generate destructive heat preferentially upon irradiation. However, PPTT using AuNPs has not been added to practice, owing to insufficient heating methods and tissue temperature measurement techniques, leading to unreliable and inaccurate treatments. Because the photothermal properties of AuNPs vary with laser power, particle optical density, and tissue depth, the accurate prediction of heat generation is indispensable for clinical treatment. In this report, bioprinted 3D complex tissue constructs comprising processed gel obtained from porcine skin and human decellularized adipose tissue are presented for characterization of the photothermal properties of gold nanorods (AuNRs) having an aspect ratio of 3.7 irradiated by a near-infrared laser. Moreover, an analytical function is suggested for achieving PPTT that can cause thermal damage selectively on early-stage human breast cancer by regulating the heat generation of the AuNRs in the tissue.
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Affiliation(s)
- Ki‐Hwan Nam
- Center for Scientific InstrumentationDivision of Scientific Instrumentation and ManagementKorea Basic Science Institute (KBSI)Daejeon34133Republic of Korea
| | - Chan Bae Jeong
- Center for Scientific InstrumentationDivision of Scientific Instrumentation and ManagementKorea Basic Science Institute (KBSI)Daejeon34133Republic of Korea
| | - HyeMi Kim
- Center for Scientific InstrumentationDivision of Scientific Instrumentation and ManagementKorea Basic Science Institute (KBSI)Daejeon34133Republic of Korea
| | - Minjun Ahn
- Department of Mechanical EngineeringPohang University of Science and Technology (POSTECH)PohangKyungbuk37673Republic of Korea
| | - Sung‐Jun Ahn
- Research Division for Industry and EnvironmentKorea Atomic Energy Research Institute (KAERI)JeongeupJeollabuk‐do56212Republic of Korea
| | - Hwan Hur
- Center for Scientific InstrumentationDivision of Scientific Instrumentation and ManagementKorea Basic Science Institute (KBSI)Daejeon34133Republic of Korea
| | - Dong Uk Kim
- Center for Scientific InstrumentationDivision of Scientific Instrumentation and ManagementKorea Basic Science Institute (KBSI)Daejeon34133Republic of Korea
| | - Jinah Jang
- Department of Creative IT EngineeringSchool of Interdisciplinary Bioscience and BioengineeringPohang University of Science and Technology (POSTECH)PohangKyungbuk37673Republic of Korea
| | - Hui‐Jeong Gwon
- Research Division for Industry and EnvironmentKorea Atomic Energy Research Institute (KAERI)JeongeupJeollabuk‐do56212Republic of Korea
| | - Youn‐Mook Lim
- Research Division for Industry and EnvironmentKorea Atomic Energy Research Institute (KAERI)JeongeupJeollabuk‐do56212Republic of Korea
| | - Dong‐Woo Cho
- Department of Mechanical EngineeringPohang University of Science and Technology (POSTECH)PohangKyungbuk37673Republic of Korea
| | - Kye‐Sung Lee
- Center for Scientific InstrumentationDivision of Scientific Instrumentation and ManagementKorea Basic Science Institute (KBSI)Daejeon34133Republic of Korea
| | - Ji Yong Bae
- Center for Scientific InstrumentationDivision of Scientific Instrumentation and ManagementKorea Basic Science Institute (KBSI)Daejeon34133Republic of Korea
| | - Ki Soo Chang
- Center for Scientific InstrumentationDivision of Scientific Instrumentation and ManagementKorea Basic Science Institute (KBSI)Daejeon34133Republic of Korea
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Avşar Abdik E. Differentiated pre-adipocytes promote proliferation, migration and epithelial-mesenchymal transition in breast cancer cells of different p53 status. Mol Biol Rep 2021; 48:5187-5198. [PMID: 34213707 DOI: 10.1007/s11033-021-06521-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 06/25/2021] [Indexed: 12/11/2022]
Abstract
Breast cancer progression and metastasis are associated with stromal cells in the tumor microenvironment. Adipocytes are the most abundant cells surrounding breast stromal tissue, promote tumor progression through the induction of Epithelial-to-Mesenchymal Transition (EMT) which is negatively regulated by tumor suppressor protein p53. In this study aimed to investigate the role of p53 in the progression of breast cancer after mature adipocyte-conditioned medium (CM) application. The proliferative effect of CM obtained from differentiated pre-adipocytes were assessed by MTS assay. 20% CM increased cell proliferation in breast cancer cells, T-47D (mutant p53) and MCF-7 (wild-type p53). The migration and invasion capacity were evaluated by scratch and transwell assays, respectively. CM significantly enhanced migration and invasion capacity in T-47D compared to MCF-7. Gene and protein expressions were detected by qRT-PCR and Western Blot analysis, respectively. CM markedly increased expression levels of Cyclin D1, PI3K, MMP9, Snail and Twist in T-47D compared to MCF-7. However, CM did not change E-Cadherin level in T-47D while downregulated in MCF-7 cells. Also, the protein levels of NFκB p65, p-Akt, Snail, and Vimentin were upregulated in both cells. Overall, the findings highlight how the p53 status affects mature adipocyte-mediated proliferation, migration, and aggressive behavior of breast cancer cell lines. Targeting the tumor microenvironment may represent a promising approach for preventing breast cancer progression and metastasis.
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Affiliation(s)
- Ezgi Avşar Abdik
- Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, 26 Ağustos Campus, Kayisdagi, Istanbul, Turkey.
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González A, Alonso-González C, González-González A, Menéndez-Menéndez J, Cos S, Martínez-Campa C. Melatonin as an Adjuvant to Antiangiogenic Cancer Treatments. Cancers (Basel) 2021; 13:3263. [PMID: 34209857 PMCID: PMC8268559 DOI: 10.3390/cancers13133263] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 02/07/2023] Open
Abstract
Melatonin is a hormone with different functions, antitumor actions being one of the most studied. Among its antitumor mechanisms is its ability to inhibit angiogenesis. Melatonin shows antiangiogenic effects in several types of tumors. Combination of melatonin and chemotherapeutic agents have a synergistic effect inhibiting angiogenesis. One of the undesirable effects of chemotherapy is the induction of pro-angiogenic factors, whilst the addition of melatonin is able to overcome these undesirable effects. This protective effect of the pineal hormone against angiogenesis might be one of the mechanisms underlying its anticancer effect, explaining, at least in part, why melatonin administration increases the sensitivity of tumors to the inhibitory effects exerted by ordinary chemotherapeutic agents. Melatonin has the ability to turn cancer totally resistant to chemotherapeutic agents into a more sensitive chemotherapy state. Definitely, melatonin regulates the expression and/or activity of many factors involved in angiogenesis which levels are affected (either positively or negatively) by chemotherapeutic agents. In addition, the pineal hormone has been proposed as a radiosensitizer, increasing the oncostatic effects of radiation on tumor cells. This review serves as a synopsis of the interaction between melatonin and angiogenesis, and we will outline some antiangiogenic mechanisms through which melatonin sensitizes cancer cells to treatments, such as radiotherapy or chemotherapy.
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Affiliation(s)
| | | | | | | | - Samuel Cos
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain; (A.G.); (A.G.-G.); (J.M.-M.); (C.M.-C.)
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Maliniak ML, Miller-Kleinhenz J, Cronin-Fenton DP, Lash TL, Gogineni K, Janssen EAM, McCullough LE. Crown-Like Structures in Breast Adipose Tissue: Early Evidence and Current Issues in Breast Cancer. Cancers (Basel) 2021; 13:2222. [PMID: 34066392 PMCID: PMC8124644 DOI: 10.3390/cancers13092222] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/24/2021] [Accepted: 04/26/2021] [Indexed: 12/29/2022] Open
Abstract
Obesity is an established risk factor for postmenopausal breast cancer and has been linked to worse breast cancer prognosis, most clearly for hormone receptor-positive breast cancers. The underlying mechanisms of the obesity-breast cancer association are not fully understood, but growing evidence points to the breast adipose tissue microenvironment playing an important role. Obesity-induced adipose tissue dysfunction can result in a chronic state of low-grade inflammation. Crown-like structures of the breast (CLS-B) were recently identified as a histologic marker of local inflammation. In this review, we evaluate the early evidence of CLS-B in breast cancer. Data from preclinical and clinical studies show that these inflammatory lesions within the breast are associated with local NF-κB activation, increased aromatase activity, and elevation of pro-inflammatory mediators (TNFα, IL-1β, IL-6, and COX-2-derived PGE2)-factors involved in multiple pathways of breast cancer development and progression. There is also substantial evidence from epidemiologic studies that CLS-B are associated with greater adiposity among breast cancer patients. However, there is insufficient evidence that CLS-B impact breast cancer risk or prognosis. Comparisons across studies of prognosis were complicated by differences in CLS-B evaluation and deficiencies in study design, which future studies should take into consideration. Breast adipose tissue inflammation provides a plausible explanation for the obesity-breast cancer association, but further study is needed to establish its role and whether markers such as CLS-B are clinically useful.
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Affiliation(s)
- Maret L. Maliniak
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA; (J.M.-K.); (T.L.L.); (L.E.M.)
| | - Jasmine Miller-Kleinhenz
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA; (J.M.-K.); (T.L.L.); (L.E.M.)
| | | | - Timothy L. Lash
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA; (J.M.-K.); (T.L.L.); (L.E.M.)
- Department of Clinical Epidemiology, Aarhus University Hospital, 8200 Aarhus, Denmark;
- Glenn Family Breast Center, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA;
| | - Keerthi Gogineni
- Glenn Family Breast Center, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA;
- Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Emiel A. M. Janssen
- Department of Pathology, Stavanger University Hospital, 4011 Stavanger, Norway;
| | - Lauren E. McCullough
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA; (J.M.-K.); (T.L.L.); (L.E.M.)
- Glenn Family Breast Center, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA;
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Soni S, Torvund M, Mandal CC. Molecular insights into the interplay between adiposity, breast cancer and bone metastasis. Clin Exp Metastasis 2021; 38:119-138. [PMID: 33591548 DOI: 10.1007/s10585-021-10076-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 02/03/2021] [Indexed: 01/20/2023]
Abstract
Cancer is a complex disease, with various pre-existing health ailments enhancing its pathology. In cancer, the extracellular environment contains various intrinsic physiological factors whose levels are altered with aging and pre-existing conditions. In obesity, the tumor microenvironment and metastases are enriched with factors that are both derived locally, and from other physiological compartments. Similarly, in obesity, the cancer cell environment both at the site of origin and at the secondary site i.e., metastatic niche, contains significantly more phenotypically-altered adipocytes than that of un-obese cancer patients. Indeed, obesity has been linked with cancer progression, metastasis, and therapy resistance. Adipocytes not only interact with tumor cells, but also with adjacent stromal cells at primary and metastatic sites. This review emphasizes the importance of bidirectional interactions between adipocytes and breast tumor cells in breast cancer progression and its bone metastases. This paper not only chronicles the role of various adipocyte-derived factors in tumor growth, but also describes the significance of adipocyte-derived bone metastatic factors in the development of bone metastasis of breast cancer. It provides a molecular view of the interplay between the adipocytes and tumor cells involved in breast cancer bone metastasis. However, more research is needed to determine if targeting cancer-associated adipocytes holds promise as a potential therapeutic approach for breast cancer bone metastasis treatment. Interplay between adipocytes and breast cancer cells at primary cancer site and metastatic bone microenvironment. AMSC Adipose-derived mesenchymal stem cell, CAA Cancer associated adipocytes, CAF Cancer associated fibroblast, BMSC Bone marrow derived mesenchymal stem cell, BMA Bone marrow adipocyte.
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Affiliation(s)
- Sneha Soni
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh, Ajmer, Rajasthan, 305817, India
| | - Meaghan Torvund
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA
| | - Chandi C Mandal
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh, Ajmer, Rajasthan, 305817, India.
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Li FW, Zeng L, Luo SK. Microenvironmental Changes in the Surviving Fat 1 Year After Autologous Fat Transplantation for Breast Augmentation. Aesthet Surg J 2021; 41:NP127-NP133. [PMID: 32504528 DOI: 10.1093/asj/sjaa156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Autologous fat is currently one of the most commonly used soft tissue materials in plastic surgery, but the changes that occur in fat after transplantation are unclear. Existing studies on the changes in surviving fat mostly involve animal experiments. OBJECTIVES The aim of this study was to obtain surviving fat 1 year after clinical autologous fat transplantation for breast augmentation, to explain the microenvironmental changes after fat transplantation from a clinical perspective, and to verify previous research conclusions, thus providing new insight into fat survival. METHODS Samples of surviving fat were obtained from 5 patients 1 year after they had undergone autologous fat transplantation for breast augmentation, and normal fat samples were obtained from 5 patients who had not undergone this procedure. The differences between CD68 and CD31 were analyzed immunohistochemically, and between CD34 and Ki67 by immunofluorescence. We also tested whether UCP-1 is expressed in surviving fat. RESULTS The relative CD68, CD34, and Ki67 expression levels in the surviving fat tissue were significantly higher than those in the normal fat tissue (PCD68 = 0.04, PCD34 = 0.03, PKi67 = 0.02). The relative CD31 expression was not significantly different between the two groups (P = 0.52). No UCP-1 expression was observed in any surviving fat tissue. CONCLUSIONS Chronic inflammatory reactions mediated by macrophages were detectable 1 year after autologous fat transplantation for breast augmentation. The mesenchymal stem cell content in surviving fat was higher than that in normal fat, but the number of blood vessels was close to that in normal breast fat tissue. No genesis of brown fat was found. LEVEL OF EVIDENCE: 5
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Affiliation(s)
- Fang-Wei Li
- Department of Plastic and Reconstructive Surgery, Guangdong Second Provincial General Hospital, Guangzhou City, China
| | - Li Zeng
- Department of Plastic and Reconstructive Surgery, Guangdong Second Provincial General Hospital, Guangzhou City, China
| | - Sheng-Kang Luo
- Department of Plastic and Reconstructive Surgery, Guangdong Second Provincial General Hospital, Guangzhou City, China
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Chung JH, Kim KJ, Jung SP, Park SH, Yoon ES. Analysis of oncological safety of autologous fat grafting after immediate breast reconstruction. Gland Surg 2021; 10:584-594. [PMID: 33708542 DOI: 10.21037/gs-20-645] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background Fat grafting is now a common procedure for breast reconstruction. Many clinical studies have reported its aesthetic efficacy and oncological safety, but some experimental studies raise about the recurrence risk because of its regenerating property. This study aims to investigate the possibility of cancer recurrence associated with fat grafting. Methods In this retrospective cohort study, we analyzed a total of 339 patients who had undergone immediate reconstructive surgery after nipple-sparing mastectomy (NSM) or skin-sparing mastectomy (SSM) in our institution between February 28, 2009 and March 23, 2019. Patients who had undergone breast conserving surgery, radical mastectomy, or delayed reconstruction were excluded. We used univariate and multivariate Cox proportional hazards regression models to evaluate the association between fat grafting and cancer recurrence. Results Among the 339 patients during a median follow-up of 52 months, 27 patients (8.0%) were confirmed to have recurrent cancer. Of 67 patients who had undergone fat grafting, 10 patients were confirmed to have cancer recurrence. In multivariate analyses, fat grafting [hazard ratio (HR), 2.52; 95% CI, 1.005-6.317; P=0.0488] was independently associated with cancer recurrence. Conclusions In population of breast cancer patient who underwent immediate reconstruction in our institution, fat grafting showed significant higher risk of cancer recurrence. Although these results are at odds with many existing studies, it suggests that more careful follow-up may be necessary for patients who had undergone fat grafting after reconstructive surgery.
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Affiliation(s)
- Jae-Ho Chung
- Department of Plastic and Reconstructive Surgery, Korea University Hospital, Seoul, Republic of Korea
| | - Ki-Jae Kim
- Department of Plastic and Reconstructive Surgery, Korea University Hospital, Seoul, Republic of Korea
| | - Seung Pil Jung
- Division of Breast and Endocrine Surgery, Korea University Hospital, Seoul, Republic of Korea
| | - Seung-Ha Park
- Department of Plastic and Reconstructive Surgery, Korea University Hospital, Seoul, Republic of Korea
| | - Eul-Sik Yoon
- Department of Plastic and Reconstructive Surgery, Korea University Hospital, Seoul, Republic of Korea
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Fang J, Chen F, Liu D, Gu F, Wang Y. Adipose tissue-derived stem cells in breast reconstruction: a brief review on biology and translation. Stem Cell Res Ther 2021; 12:8. [PMID: 33407902 PMCID: PMC7789635 DOI: 10.1186/s13287-020-01955-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 09/27/2020] [Indexed: 02/07/2023] Open
Abstract
Recent developments in adipose-derived stromal/stem cell (ADSC) biology provide new hopes for tissue engineering and regeneration medicine. Due to their pluripotent activity, paracrine activity, and immunomodulatory function, ADSCs have been widely administrated and exhibited significant therapeutic effects in the treatment for autoimmune disorders, neurodegenerative diseases, and ischemic conditions both in animals and human clinical trials. Cell-assisted lipotransfer (CAL) based on ADSCs has emerged as a promising cell therapy technology and significantly improved the fat graft retention. Initially applied for cosmetic breast and facial enhancement, CAL has found a potential use for breast reconstruction in breast cancer patients. However, more challenges emerge related to CAL including lack of a standardized surgical procedure, the controversy in the effectiveness of CAL, and the potential oncogenic risk of ADSCs in cancer patients. In this review, we summarized the latest research and intended to give an outline involving the biological characteristics of ADSCs as well as the preclinical and clinical application of ADSCs.
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Affiliation(s)
- Jun Fang
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China.,Department of Radiation Therapy, Zhejiang Cancer Hospital, Hangzhou, China.,Radiotherapy, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Feng Chen
- Department of Breast Tumor Surgery, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Dong Liu
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China.,Department of Radiation Therapy, Zhejiang Cancer Hospital, Hangzhou, China.,Radiotherapy, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Feiying Gu
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China.,Department of Radiation Therapy, Zhejiang Cancer Hospital, Hangzhou, China.,Radiotherapy, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Yuezhen Wang
- Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, China. .,Department of Radiation Therapy, Zhejiang Cancer Hospital, Hangzhou, China. .,Radiotherapy, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China.
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Acheva A, Kärki T, Schaible N, Krishnan R, Tojkander S. Adipokine Leptin Co-operates With Mechanosensitive Ca 2 +-Channels and Triggers Actomyosin-Mediated Motility of Breast Epithelial Cells. Front Cell Dev Biol 2021; 8:607038. [PMID: 33490070 PMCID: PMC7815691 DOI: 10.3389/fcell.2020.607038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 12/07/2020] [Indexed: 12/24/2022] Open
Abstract
In postmenopausal women, a major risk factor for the development of breast cancer is obesity. In particular, the adipose tissue-derived adipokine leptin has been strongly linked to tumor cell proliferation, migration, and metastasis, but the underlying mechanisms remain unclear. Here we show that treatment of normal mammary epithelial cells with leptin induces EMT-like features characterized by higher cellular migration speeds, loss of structural ordering of 3D-mammo spheres, and enhancement of epithelial traction forces. Mechanistically, leptin triggers the phosphorylation of myosin light chain kinase-2 (MLC-2) through the interdependent activity of leptin receptor and Ca2+ channels. These data provide evidence that leptin-activated leptin receptors, in co-operation with mechanosensitive Ca2+ channels, play a role in the development of breast carcinomas through the regulation of actomyosin dynamics.
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Affiliation(s)
- Anna Acheva
- Section of Pathology, Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland
| | - Tytti Kärki
- Department of Applied Physics, School of Science, Aalto University, Espoo, Finland
| | - Niccole Schaible
- Beth Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Ramaswamy Krishnan
- Beth Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Sari Tojkander
- Section of Pathology, Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland
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Modulating the Crosstalk between the Tumor and the Microenvironment Using SiRNA: A Flexible Strategy for Breast Cancer Treatment. Cancers (Basel) 2020; 12:cancers12123744. [PMID: 33322132 PMCID: PMC7763441 DOI: 10.3390/cancers12123744] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/27/2020] [Accepted: 12/04/2020] [Indexed: 02/06/2023] Open
Abstract
Simple Summary With this review we aimed to collect the most relevant scientific findings regarding siRNA therapeutic tools against breast cancer microenvironment. Remarkably, breast cancer treatments have been redirected towards the tumor microenvironment components, mainly involved in patients’ relapse and pharmacological resistance. Therefore, siRNAs represent a promising strategy to jeopardize the tumor microenvironment interplay thanks to their non-toxic and specific effects. Abstract Tumorigenesis is a complex and multistep process in which sequential mutations in oncogenes and tumor-suppressor genes result in enhanced proliferation and apoptosis escape. Over the past decades, several studies have provided evidence that tumors are more than merely a mass of malignant cancer cells, with the tumor microenvironment (TME) also contributing to cancer progression. For this reason, the focus of cancer research in recent years has shifted from the malignant cancer cell itself to the TME and its interactions. Since the TME actively participates in tumor progression, therapeutic strategies targeting it have created great interest. In this context, much attention has been paid to the potential application of small interfering RNA (siRNA), a class of non-coding RNA that has the ability to downregulate the expression of target genes in a sequence-specific way. This is paving the way for a novel therapeutic approach for the treatment of several diseases, including cancer. In this review, we describe recent efforts in developing siRNA therapeutics for the treatment of breast cancer, with particular emphasis on TME regulation. We focus on studies that adapt siRNA design to reprogram/re-educate the TME and eradicate the interplay between cancer cells and TME.
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50
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Saleh K, Carton M, Dieras V, Heudel PE, Brain E, D'Hondt V, Mailliez A, Patsouris A, Mouret-Reynier MA, Goncalves A, Ferrero JM, Petit T, Emile G, Uwer L, Debled M, Dalenc F, Jouannaud C, Ladoire S, Leheurteur M, Cottu P, Veron L, Savignoni A, Courtinard C, Robain M, Delaloge S, Deluche E. Impact of body mass index on overall survival in patients with metastatic breast cancer. Breast 2020; 55:16-24. [PMID: 33307392 PMCID: PMC7725947 DOI: 10.1016/j.breast.2020.11.014] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 11/21/2020] [Accepted: 11/23/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND High Body mass index (BMI) is a risk factor for breast cancer among postmenopausal women and an adverse prognostic factor in early-stage. Little is known about its impact on clinical outcomes in patients with metastatic breast cancer (MBC). METHODS The National ESME-MBC observational cohort includes all consecutive patients newly diagnosed with MBC between Jan 2008 and Dec 2016 in the 18 French comprehensive cancer centers. RESULTS Of 22 463 patients in ESME-MBC, 12 999 women had BMI data available at MBC diagnosis. Median BMI was 24.9 kg/m2 (range 12.1-66.5); 20% of women were obese and 5% underweight. Obesity was associated with more de novo MBC, while underweight patients had more aggressive cancer features. Median overall survival (OS) of the BMI cohort was 47.4 months (95% CI [46.2-48.5]) (median follow-up: 48.6 months). Underweight was independently associated with a worse OS (median OS 33 months; HR 1.14, 95%CI, 1.02-1.27) and first line progression-free survival (HR, 1.11; 95%CI, 1.01; 1.22), while overweight or obesity had no effect. CONCLUSION Overweight and obesity are not associated with poorer outcomes in women with metastatic disease, while underweight appears as an independent adverse prognostic factor.
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Affiliation(s)
- Khalil Saleh
- Department of Cancer Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94800, Villejuif, France
| | - Matthieu Carton
- Department of Biostatistics, Institut Curie, 26 Rue D'Ulm, 75005, Paris & Saint-Cloud, France
| | - Véronique Dieras
- Medical Oncology Department, Centre Eugéne Marquis, Avenue de La Bataille Flandres-Dunkerque, 35000, Rennes, France
| | - Pierre-Etienne Heudel
- Department of Medical Oncology, Centre Léon Bérard, 28 Prom. Léa et Napoléon Bullukian, 69008, Lyon, France
| | - Etienne Brain
- Department of Medical Oncology, Institut Curie, Saint-Cloud, France
| | - Véronique D'Hondt
- Department of Medical Oncology, Institut Du Cancer de Montpellier, 208 Rue des Apothicaires, 34298, Montpellier, INSERM U1194, University of Montpellier, France
| | - Audrey Mailliez
- Medical Oncology Department, Centre Oscar Lambret, 3 Rue Frédéric Combemale, 59000, Lille, France
| | - Anne Patsouris
- Department of Medical Oncology, Institut de Cancérologie de L'Ouest Nantes & Angers, 15 Rue André Boquel, 49055, Angers, France
| | - Marie-Ange Mouret-Reynier
- Department of Medical Oncology, Centre Jean Perrin, 58 Rue Montalembert, 63011, Clermont Ferrand, France
| | - Anthony Goncalves
- Department of Medical Oncology, Institut Paoli-Calmettes, 232 Boulevard de Sainte-Marguerite, 13009, Marseille, France
| | - Jean Marc Ferrero
- Department of Medical Oncology, Centre Antoine Lacassagne, 33 Avenue de Valambrose, 06189, Nice, France
| | - Thierry Petit
- Department of Medical Oncology, Centre Paul Strauss, 3 Rue de La Porte de L'Hôpital, 67000, Strasbourg, France
| | - George Emile
- Department of Medical Oncology, Centre François Baclesse, 3 Avenue Du Général Harris, 14000, Caen, France
| | - Lionel Uwer
- Department of Medical Oncology, Institut de Cancérologie de Lorraine, Vandoeuvre-lès-Nancy, 6 Avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy, France
| | - Marc Debled
- Department of Medical Oncology, Institut Bergonie, 229 Cours de L'Argonne, F-33000, Bordeaux, France
| | - Florence Dalenc
- Department of Medical Oncology, Institut Claudius Regaud - IUCT Oncopole, 1 Avenue Irène-Joliot-Curie, 31059, Toulouse, France
| | - Christelle Jouannaud
- Department of Medical Oncology, Institut de Cancérologie Jean-Godinot, 1 Rue Du Général Koenig, 51100, Reims, France
| | - Sylvain Ladoire
- Department of Medical Oncology, Centre Georges François Leclerc, 1 Rue Professeur Marion, 21079, Dijon, France
| | - Marianne Leheurteur
- Department of Medical Oncology, Centre Henri Becquerel, Rue D'Amiens, 76000, Rouen, France
| | - Paul Cottu
- Department of Medical Oncology, Institut Curie, 26 Rue D'Ulm, 75005, Paris & Saint-Cloud, France
| | - Lucie Veron
- Department of Cancer Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94800, Villejuif, France
| | - Alexia Savignoni
- Department of Biostatistics, Institut Curie, 26 Rue D'Ulm, 75005, Paris & Saint-Cloud, France
| | - Coralie Courtinard
- Department of Research and Development, R&D Unicancer, 101 Rue de Tolbiac, 75654, Paris, France
| | - Mathieu Robain
- Department of Research and Development, R&D Unicancer, 101 Rue de Tolbiac, 75654, Paris, France
| | - Suzette Delaloge
- Department of Cancer Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94800, Villejuif, France.
| | - Elise Deluche
- Department of Cancer Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94800, Villejuif, France; Department of Medical Oncology, CHU de Limoges, 2 Avenue Martin Luther King, Limoges, France
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