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Vu MN, Le HD, Vu TT, Nguyen TN, Chu HH, Bui VN. Integrated RNA Sequencing Analysis Revealed Early Gene Expression Shifts Associated with Cancer Progression in MCF-7 Breast Cancer Cells Cocultured with Adipose-Derived Stem Cells. Curr Issues Mol Biol 2024; 46:11817-11834. [PMID: 39590296 PMCID: PMC11592593 DOI: 10.3390/cimb46110702] [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: 09/17/2024] [Revised: 10/08/2024] [Accepted: 10/10/2024] [Indexed: 11/28/2024] Open
Abstract
Breast cancer remains a prevalent global health challenge, with tumor-removal surgeries being among the most common treatments but often leading to aesthetic defects. Adipose-derived stem cell (ADSC)-enriched fat grafting in breast reconstruction offers promising therapeutic benefits. However, concerns about its oncological safety persist, particularly regarding the potential risks of promoting cancer recurrence. This study investigated the effects of ADSCs on breast cancer progression by coculturing ADSCs with the MCF-7 breast cancer cell line for a short cell cultivation period of 3 days. We performed an RNA-seq analysis to identify significant transcriptomic changes in cocultured MCF-7 cells and carried out functional enrichment analyses to uncover key biological pathways influenced by ADSCs. Our findings revealed that transcriptomic alterations in MCF-7 cells are linked to aggressive cancer traits, including the upregulation of epithelial-mesenchymal transition (EMT) and the HIF-1 signaling pathway, which indicate a shift toward aerobic glycolysis. Some of the observed gene expression changes also correlated with relapse risk and mortality. These findings underscore the need for further research to explore the implications of these genes and pathways in driving aggressive cancer phenotypes and assess the safety of ADSCs in clinical settings.
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Affiliation(s)
- Minh Ngoc Vu
- Institute of Biotechnology (IBT), Vietnam Academy of Science and Technology (VAST), Hanoi 100000, Vietnam (H.H.C.)
- University of Science, Vietnam National University (VNU-HUS), Hanoi 100000, Vietnam
| | - Hoang Duc Le
- Institute of Biotechnology (IBT), Vietnam Academy of Science and Technology (VAST), Hanoi 100000, Vietnam (H.H.C.)
- Faculty of Biotechnology, Graduate University of Science and Technology (GUST), Vietnam Academy of Science and Technology (VAST), Hanoi 100000, Vietnam
| | - Thi Tien Vu
- Institute of Biotechnology (IBT), Vietnam Academy of Science and Technology (VAST), Hanoi 100000, Vietnam (H.H.C.)
| | - Trung Nam Nguyen
- Institute of Biotechnology (IBT), Vietnam Academy of Science and Technology (VAST), Hanoi 100000, Vietnam (H.H.C.)
- Faculty of Biotechnology, Graduate University of Science and Technology (GUST), Vietnam Academy of Science and Technology (VAST), Hanoi 100000, Vietnam
| | - Hoang Ha Chu
- Institute of Biotechnology (IBT), Vietnam Academy of Science and Technology (VAST), Hanoi 100000, Vietnam (H.H.C.)
- Faculty of Biotechnology, Graduate University of Science and Technology (GUST), Vietnam Academy of Science and Technology (VAST), Hanoi 100000, Vietnam
| | - Van Ngoc Bui
- Institute of Biotechnology (IBT), Vietnam Academy of Science and Technology (VAST), Hanoi 100000, Vietnam (H.H.C.)
- Faculty of Biotechnology, Graduate University of Science and Technology (GUST), Vietnam Academy of Science and Technology (VAST), Hanoi 100000, Vietnam
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Valente DS, Ely PB, Kieling L, Konzen AT, Steffen LP, Lazzaretti GS, Zanella RK. Breast fat grafting and cancer: a systematic review of the science behind enhancements and concerns. TRANSLATIONAL BREAST CANCER RESEARCH : A JOURNAL FOCUSING ON TRANSLATIONAL RESEARCH IN BREAST CANCER 2024; 5:14. [PMID: 38751673 PMCID: PMC11093078 DOI: 10.21037/tbcr-23-54] [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: 11/29/2023] [Accepted: 03/28/2024] [Indexed: 05/18/2024]
Abstract
Background Autologous fat transfer (AFT) is gaining popularity in breast surgery, offering a natural-looking and minimally invasive approach for augmentation, reconstruction, and contouring. However, concerns about its impact on breast cancer necessitate an understanding of the interplay between transplanted adipose-derived stem cells (ADSCs) and the breast tissue microenvironment. Renowned for regeneration, ADSCs raise questions about their role in cancer promotion. This systematic review delves into the complex relationship between AFT and breast cancer, exploring how ADSCs may influence development, growth, and metastasis. Methods A systematic search of electronic databases, including PubMed, Embase, and BVS was conducted to identify relevant studies. The search strategy employed a combination of keywords, including "breast augmentation", "fat grafting", "breast enhancement", "mammoplasty", "cancer", "neoplasm" and related terms. Two reviewers independently screened titles and abstracts. Full-text articles were then retrieved for further evaluation based on their potential contribution to the review objectives. Results Two hundred and forty records were identified. Among these, 104 duplicates were removed, resulting in 136 reports available for title and abstract screening. Subsequently, 54 papers were deemed potentially eligible for inclusion, and all reports were retrieved. Conclusions In vitro studies reveal ADSCs dual role in breast cancer, influencing proliferation, migration, and drug resistance through complex signaling pathways. Animal studies highlight distinct ADSC subpopulations impacting tumor growth via direct interactions and extracellular vesicle cargo. In vivo, ADSC-enriched fat grafting is generally safe, showing no increased cancer recurrence risk compared to other methods. Notably, cases of invasive breast carcinoma warrant special attention. ADSC-enriched fat grafts exhibit potential benefits in graft retention and survival rates. Despite promising evidence, further studies are needed to comprehensively understand the intricate relationship between ADSCs and breast cancer for optimized clinical applications and potential therapeutic innovations.
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Affiliation(s)
- Denis Souto Valente
- Division of Surgical Clinics, Federal University of Medical Sciences of Porto Alegre, Porto Alegre, RS, Brazil
| | - Pedro Bins Ely
- Division of Surgical Clinics, Federal University of Medical Sciences of Porto Alegre, Porto Alegre, RS, Brazil
| | - Lucas Kieling
- School of Medicine, Federal University of Medical Sciences of Porto Alegre, Porto Alegre, RS, Brazil
| | - Ana Terezinha Konzen
- School of Medicine, Federal University of Medical Sciences of Porto Alegre, Porto Alegre, RS, Brazil
| | - Lucas Pastori Steffen
- Graduate Program in Health Sciences, Federal University of Medical Sciences of Porto Alegre, Porto Alegre, RS, Brazil
| | - Gloria Sulczinski Lazzaretti
- Graduate Program in Health Sciences, Federal University of Medical Sciences of Porto Alegre, Porto Alegre, RS, Brazil
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Darmasaputra GS, van Rijnberk LM, Galli M. Functional consequences of somatic polyploidy in development. Development 2024; 151:dev202392. [PMID: 38415794 PMCID: PMC10946441 DOI: 10.1242/dev.202392] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/29/2024]
Abstract
Polyploid cells contain multiple genome copies and arise in many animal tissues as a regulated part of development. However, polyploid cells can also arise due to cell division failure, DNA damage or tissue damage. Although polyploidization is crucial for the integrity and function of many tissues, the cellular and tissue-wide consequences of polyploidy can be very diverse. Nonetheless, many polyploid cell types and tissues share a remarkable similarity in function, providing important information about the possible contribution of polyploidy to cell and tissue function. Here, we review studies on polyploid cells in development, underlining parallel functions between different polyploid cell types, as well as differences between developmentally-programmed and stress-induced polyploidy.
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Affiliation(s)
- Gabriella S. Darmasaputra
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, the Netherlands
| | - Lotte M. van Rijnberk
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, the Netherlands
| | - Matilde Galli
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, the Netherlands
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Huang G, Shen H, Xu K, Shen Y, Jiale Jin, Chu G, Xing H, Feng Z, Wang Y. Single-Cell Microgel Encapsulation Improves the Therapeutic Efficacy of Mesenchymal Stem Cells in Treating Intervertebral Disc Degeneration via Inhibiting Pyroptosis. RESEARCH (WASHINGTON, D.C.) 2024; 7:0311. [PMID: 38371273 PMCID: PMC10871001 DOI: 10.34133/research.0311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 01/14/2024] [Indexed: 02/20/2024]
Abstract
While mesenchymal stem cell (MSC) shows great potentials in treating intervertebral disc degeneration, most MSC die soon after intradiscal transplantation, resulting in inferior therapeutic efficacy. Currently, bulk hydrogels are the common solution to improve MSC survival in tissues, although hydrogel encapsulation impairs MSC migration and disrupts extracellular microenvironment. Cell hydrogel encapsulation has been proposed to overcome the limitation of traditional bulk hydrogels, yet this technique has not been used in treating disc degeneration. Using a layer-by-layer self-assembly technique, we fabricated alginate and gelatin microgel to encapsulate individual MSC for treating disc degeneration. The small size of microgel allowed intradiscal injection of coated MSC. We demonstrated that pyroptosis was involved in MSC death under oxidative stress stimulation, and microgel coating suppressed pyroptosis activation by maintaining mitochondria homeostasis. Microgel coating protected MSC in the harsh disc microenvironment, while retaining vital cellular functions such as migration, proliferation, and differentiation. In a rat model of disc degeneration, coated MSC exhibits prolonged retention in the disc and better efficacy of attenuating disc degeneration, as compared with bare MSC treatment alone. Further, microgel-coated MSC exhibited improved therapeutic effects in treating disc degeneration via suppressing the activation of pyroptosis in the disc. For the first time, microgel-encapsulated MSC was used to treat disc degeneration and obtain encouraging outcomes. The developed biocompatible single-cell hydrogel is an effective strategy to protect MSC and maintain cellular functions and may be an efficacious approach to improving the efficacy of MSC therapy in treating disc degeneration. The objective of this study is to improve the efficacy of cell therapy for treating disc degeneration using single-cell hydrogel encapsulation and further to understand related cytoprotective mechanisms.
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Affiliation(s)
- Guanrui Huang
- Department of Orthopedic Surgery, The First Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Haotian Shen
- Department of Orthopedic Surgery, The First Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Kaiwang Xu
- Zhejiang University, Hangzhou 310058, China
| | - Yifan Shen
- Department of Orthopedic Surgery, The First Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jiale Jin
- Department of Orthopedic Surgery, The First Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Guangyu Chu
- Department of Orthopedic Surgery, The First Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hongyuan Xing
- Department of Orthopedic Surgery, The First Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Zhiyun Feng
- Department of Orthopedic Surgery, The First Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yue Wang
- Department of Orthopedic Surgery, The First Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou 310003, China
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Zhu Q, Cao Y, Yuan J, Hu Y. Adipose-derived stem cell exosomes promote tumor characterization and immunosuppressive microenvironment in breast cancer. Cancer Immunol Immunother 2024; 73:39. [PMID: 38294569 PMCID: PMC10830720 DOI: 10.1007/s00262-023-03584-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 11/13/2023] [Indexed: 02/01/2024]
Abstract
Adipose-derived stem cells (ASC) or autologous fat transplantation could be used to ameliorate breast cancer postoperative deformities. This study aims to explore the action of ASC and ASC-exosomes (ASC-exos) in breast cancer characterization and tumor microenvironment immunity, which provided a new method into the application of ASC-exos. ASC were extracted from human adipose tissue for the isolation and verification of ASC-exos. ASC-exos were co-cultured with CD4+T cells, CD14+ monocytes and MCF-7 cells, respectively. The tumor formation of nude mice was also constructed. Cell characterization was determined by CCK8, scratch assay, and Transwell. Hematoxylin-eosin (HE), immunohistochemistry (IHC) and immunofluorescence (IF) staining were used to observe the histopathology and protein expression. CD4+T cell and CD14+ monocytes differentiation was detected by flow cytometry. Western blot, qRT-PCR and RNAseq were used to detect the action of ASC-exos on gene and protein expression. CD4+T cells could take up ASC-exos. ASC-exos inhibited Th1 and Th17 differentiation and promoted Treg differentiation of CD4+T cells. ASC-exos inhibited M1 differentiation and promoted M2 differentiation of CD14+ monocytes. ASC-exos promoted the migration, proliferation, and invasion, while inhibited apoptosis of MCF-7 cells. ASC-exos promoted the tumor formation of breast cancer. The effect of ASC-exos on tumor microenvironment immunity was in accordance with the above in vitro results. TOX, CD4 and LYZ1 genes were upregulated, while Mettl7b and Serpinb2 genes were downregulated in ASC-exos group. Human T-cell leukemia virus 1 infection pathway was significantly enriched in ASC-exos. Thus, ASC-exos promoted breast cancer characterization and tumor microenvironment immunosuppression by regulating macrophage and T cell differentiation.
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Affiliation(s)
- Qin Zhu
- Department of General Surgery, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha, 410008, Hunan, People's Republic of China
| | - Yukun Cao
- Department of General Surgery, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha, 410008, Hunan, People's Republic of China
| | - Jiaqi Yuan
- Department of General Surgery, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha, 410008, Hunan, People's Republic of China
| | - Yu Hu
- Department of General Surgery, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha, 410008, Hunan, People's Republic of China.
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Alanteet A, Attia H, Alfayez M, Mahmood A, Alsaleh K, Alsanea S. Liraglutide attenuates obese-associated breast cancer cell proliferation via inhibiting PI3K/Akt/mTOR signaling pathway. Saudi Pharm J 2024; 32:101923. [PMID: 38223522 PMCID: PMC10784703 DOI: 10.1016/j.jsps.2023.101923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 12/13/2023] [Indexed: 01/16/2024] Open
Abstract
This study aims to explore the anti-proliferative, pro-apoptotic, and anti-migration activities of liraglutide (LGT) in MCF-7 breast cancer (BC) cells in subjects with obesity, particularly its effects on the PI3K/Akt/mTOR/AMPK pathway. The role of AMPK/SIRT-1, an essential regulator of adipokine production, in the effect of LGT on the production of adipose-derived adipokine was also assessed. MCF-7 cells were incubated in conditioned medium (CM) generated from adipose-derived stem cells (ADSCs) of obese subjects. MCF-7 cells were then treated with LGT for 72 h. Anti-proliferative, pro-apoptotic, and anti-migration activities were investigated using alamarBlue, annexin V stain, and scratch assay, respectively. Protein levels of phosphorylated PI3K, p-Akt, p-mTOR, and p-AMPK were investigated using immunoblotting. Levels of adipokines in ADSCs were determined using RT-PCR before and after transfection of ADSCs using the specific small interference RNA sequences for AMPK and SIRT-1. LGT evoked anti-proliferative, apoptotic, and potential anti-migratory properties on MCF-7 cells incubated in CM from obese ADSCs and significantly mitigated the activity of the PI3K/Akt/mTOR survival pathway-but not AMPK-in MCF-7 cells. Furthermore, the anti-proliferative effects afforded by LGT were similar to those mediated by LY294002 (PI3K inhibitor) and rapamycin (mTOR inhibitor). Our results reveal that transfection of AMPK/SIRT-1 genes did not affect the beneficial role of LGT in the expression of adipokines in ADSCs. In conclusion, LGT elicits anti-proliferative, apoptotic, and anti-migratory effects on BC cells in obese conditions by suppressing the activity of survival pathways; however, this effect is independent of the AMPK/SIRT1 pathway in ADSCs or AMPK in BC cells.
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Affiliation(s)
- Alaa Alanteet
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Hala Attia
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Musaed Alfayez
- Anatomy Department, Stem Cell Unit, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia
| | - Amer Mahmood
- Anatomy Department, Stem Cell Unit, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia
| | - Khalid Alsaleh
- College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sary Alsanea
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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Liu Q, Guo Z, Li G, Zhang Y, Liu X, Li B, Wang J, Li X. Cancer stem cells and their niche in cancer progression and therapy. Cancer Cell Int 2023; 23:305. [PMID: 38041196 PMCID: PMC10693166 DOI: 10.1186/s12935-023-03130-2] [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: 08/30/2023] [Accepted: 11/09/2023] [Indexed: 12/03/2023] Open
Abstract
High recurrence and metastasis rates and poor prognoses are the major challenges of current cancer therapy. Mounting evidence suggests that cancer stem cells (CSCs) play an important role in cancer development, chemoradiotherapy resistance, recurrence, and metastasis. Therefore, targeted CSC therapy has become a new strategy for solving the problems of cancer metastasis and recurrence. Since the properties of CSCs are regulated by the specific tumour microenvironment, the so-called CSC niche, which targets crosstalk between CSCs and their niches, is vital in our pursuit of new therapeutic opportunities to prevent cancer from recurring. In this review, we aim to highlight the factors within the CSC niche that have important roles in regulating CSC properties, including the extracellular matrix (ECM), stromal cells (e.g., associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and mesenchymal stem cells (MSCs)), and physiological changes (e.g., inflammation, hypoxia, and angiogenesis). We also discuss recent progress regarding therapies targeting CSCs and their niche to elucidate developments of more effective therapeutic strategies to eliminate cancer.
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Affiliation(s)
- Qiuping Liu
- Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466001, Henan, China
| | - Zongliang Guo
- Department of General Surgery, Shanxi Province Cancer Hospital, Affiliated of Shanxi Medical University, Taiyuan, 030013, Shanxi, China
| | - Guoyin Li
- Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466001, Henan, China
| | - Yunxia Zhang
- Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466001, Henan, China
| | - Xiaomeng Liu
- Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466001, Henan, China
| | - Bing Li
- Institute of Translational Medicine, College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, 466001, Henan, China
| | - Jinping Wang
- Department of Ultrasound, Shanxi Province People's Hospital, Taiyuan, 030012, Shanxi, China.
| | - Xiaoyan Li
- Department of blood transfusion, Shanxi Provincial People's Hospital, Taiyuan, 030032, Shanxi, China.
- Department of central laboratory, Shanxi Provincial People's Hospital, Taiyuan, 030032, Shanxi, China.
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Brown MJ, Nickels M, Akam EC, Morris MA. The protective effect of endurance running against the pro-invasive effects of ageing in breast cancer cells and mesenchymal stem cells in vitro. IN VITRO MODELS 2023; 2:263-280. [PMID: 39872498 PMCID: PMC11756502 DOI: 10.1007/s44164-023-00055-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/12/2023] [Accepted: 07/13/2023] [Indexed: 01/30/2025]
Abstract
Purpose Regular exercise is known to reduce cancer risk and may prevent metastases, however, modelling this in vitro is challenging due the heterogeneity of the tumour microenvironment. Exercised serum can be used to capture changes in cellular signalling components in response to different types and durations of exercise. In this study, exercised serum from long-term endurance runners and sprinters of different ages was used to evaluate the impact of exercise on the invasiveness of breast cancer cells and mesenchymal stem cells in vitro. Methods Exercised serum from long-term trained younger and older endurance runners and sprinters was used to supplement cell culture media in the 3D culture of spheroids containing breast cancer cells or mesenchymal stem cells. Spheroids were generated in a 3D semi-solid matrix and cell invasion was measured using ImageJ software. Statistical analyses of invasion were conducted using one-way ANOVAs. Results Invasion was significantly greater in cells cultured with serum from older, inactive participants compared to young, inactive participants (YC vs OC; F (1,3) = 37.135, P = 0.009). No significant difference was found in the invasion of MDA-MB-231 breast cancer cells cultured in serum from older, long-term endurance runners and younger, long-term endurance runners (YE vs OE; F (1,3) = 5.178, P = 0.107), suggesting a protective effect of endurance running against the pro-invasive effects of ageing. Conclusion This is the first study of its kind to demonstrate the protective effects of long-term exercise training type in two populations of different ages against the invasiveness of breast cancer cells in vitro.
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Affiliation(s)
- Marie-Juliet Brown
- School of Sport, Exercise and Health Sciences, Loughborough University, Towers Way, Loughborough, LE11 3TU UK
| | - Matt Nickels
- School of Sport, Exercise and Health Sciences, Loughborough University, Towers Way, Loughborough, LE11 3TU UK
| | - Elizabeth C. Akam
- School of Sport, Exercise and Health Sciences, Loughborough University, Towers Way, Loughborough, LE11 3TU UK
| | - Mhairi A. Morris
- School of Sport, Exercise and Health Sciences, Loughborough University, Towers Way, Loughborough, LE11 3TU UK
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Hamel KM, Liimatta KQ, Belgodere JA, Bunnell BA, Gimble JM, Martin EC. Adipose-Derived Stromal/Stem Cell Response to Tumors and Wounds: Evaluation of Patient Age. Stem Cells Dev 2022; 31:579-592. [PMID: 35262397 PMCID: PMC9836707 DOI: 10.1089/scd.2021.0280] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 03/05/2022] [Indexed: 01/22/2023] Open
Abstract
Tumors were characterized as nonhealing wounds by Virchow in 1858 and Dvorak in 1986. Since then, researchers have analyzed tumors from a new perspective. The parallels between tumorigenesis and physiological wound healing can provide a new framework for developing antitumor therapeutics. One commonality between tumors and wounds is the involvement of the stromal environment, particularly adipose stromal/stem cells (ASCs). ASCs exhibit dual functions, in which they stimulate tumor progression and assist in tissue repair and regeneration. Numerous studies have focused on the role of ASCs in cancer and wound healing, but none to date has linked age, cancer, and wound healing. Furthermore, very few studies have focused on the role of donor-specific characteristics of ASCs, such as age and their role in facilitating ASC behavior in cancer and wound healing. This review article is designed to provide important insights into the impact of donor age on ASC tumor and wound response and their role in facilitating ASC behavior in cancer and wound healing.
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Affiliation(s)
- Katie M. Hamel
- Department of Biological Engineering, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Kara Q. Liimatta
- Department of Biological Engineering, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Jorge A. Belgodere
- Department of Biological Engineering, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Bruce A. Bunnell
- University of North Texas Health Sciences Center, Fort Worth, Texas, USA
| | | | - Elizabeth C. Martin
- Department of Biological Engineering, Louisiana State University, Baton Rouge, Louisiana, USA
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Wang YY, Hung AC, Wu YC, Lo S, Chen HD, Chen YK, Hsieh YC, Hu SCS, Hou MF, Yuan SSF. ADSCs stimulated by resistin promote breast cancer cell malignancy via CXCL5 in a breast cancer coculture model. Sci Rep 2022; 12:15437. [PMID: 36104403 PMCID: PMC9475041 DOI: 10.1038/s41598-022-19290-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/26/2022] [Indexed: 11/25/2022] Open
Abstract
The tumor microenvironment represents one of the main obstacles in breast cancer treatment owing to the presence of heterogeneous stromal cells, such as adipose-derived stem cells (ADSCs), that may interact with breast cancer cells and promote cancer development. Resistin is an adipocytokine associated with adverse breast cancer progression; however, its underlying mechanisms in the context of the breast tumor microenvironment remain largely unidentified. Here, we utilized a transwell co-culture model containing patient-derived ADSCs and breast cancer cell lines to investigate their potential interaction, and observed that breast cancer cells co-cultured with resistin-treated ADSCs (R-ADSCs) showed enhanced cancer cell growth and metastatic ability. Screening by proteome arrays revealed that C-X-C motif chemokine ligand 5 (CXCL5) was released in the conditioned medium of the co-culture system, and phosphorylated ERK was increased in breast cancer cells after co-culture with R-ADSCs. Breast cancer cells treated with the recombinant proteins of CXCL5 showed similarly enhanced cell migration and invasion ability as occurred in the co-culture model, whereas application of neutralizing antibodies against CXCL5 reversed these phenomena. The orthotopic xenograft in mice by breast cancer cells after co-culture with R-ADSCs had a larger tumor growth and more CXCL5 expression than control. In addition, clinical analysis revealed a positive correlation between the expression of resistin and CXCL5 in both tumor tissues and serum specimens of breast cancer patients. The current study suggests that resistin-stimulated ADSCs may interact with breast cancer cells in the tumor microenvironment via CXCL5 secretion, leading to breast cancer cell malignancy.
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Affiliation(s)
- Yen-Yun Wang
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Amos C Hung
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Chia Wu
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Steven Lo
- College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Huan-Da Chen
- Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yuk-Kwan Chen
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Oral Pathology and Maxillofacial Radiology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Oral and Maxillofacial Imaging Center, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ya-Ching Hsieh
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Stephen Chu-Sung Hu
- Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Feng Hou
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shyng-Shiou F Yuan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
- Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
- Department of Biological Science and Technology, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
- Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
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11
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Osteogenic effect of electromagnetic fields on stem cells derived from rat bone marrow cultured in osteogenic medium versus conditioned medium in vitro. Cell Tissue Bank 2022; 24:317-328. [PMID: 36042070 DOI: 10.1007/s10561-022-10034-4] [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: 04/18/2022] [Accepted: 08/03/2022] [Indexed: 11/02/2022]
Abstract
OBJECTIVES This study assessed possible osteogenic differentiation caused by electromagnetic fields (EMF) on rat bone-marrow-derived stem cells (rBMSCs) cultured in osteogenic medium (OM) or in human adipose-stem cell-conditioned medium (hADSC-CM). MATERIALS AND METHODS The rBMSCs were divided into negative and positive control groups, cultured in α-MEM plus 10% FBS or OM respectively. CM and CM + EMF groups, cultured cells in hADSCs-CM or exposed to EMF (50 Hz, 1 mT) for 30 min/day plus hADSCs-CM, respectively. Cells from the OM + EMF were simultaneously cultured in OM and exposed to EMF. Osteogenesis was investigated through alkaline phosphatase activity, alizarin red staining and real-time PCR. RESULTS A meaningfully higher level of ALP activity was observed in the OM + EMF group compared to the other groups. There was a considerable increase in Runx2 expression in the CM + EMF group compared to the positive control and CM groups and a significant increase in Runx2 expression in the OM + EMF in comparison with all other groups after 21 days. Runx2 expression increased significantly in the CM, CM + EMF and positive control groups on day 21 compared to the same groups on day 14. From days 14-21, Ocn expression increased in the CM and CM + EMF groups, but both groups showed a significant decrease compared to the positive controls. CM and EMF had no effect on Ocn expression. On day 21, Ocn expression was significantly higher in the OM + EMF group than in the positive control group. CONCLUSION The synergistic effect of EMF and OM increased the expression of Runx2 and Ocn in rBMSCs.
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12
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SINGLE-CENTER ONCOLOGIC OUTCOME OF FAT TRANSFER FOR BREAST RECONSTRUCTION FOLLOWING MASTECTOMY IN 1000 CANCER CASES - A MATCHED CASE-CONTROL STUDY. Plast Reconstr Surg 2022; 150:4S-12S. [PMID: 35943964 DOI: 10.1097/prs.0000000000009494] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Autologous fat transfer (AFT) has an important role in breast reconstructive surgery. Nevertheless, Some concerns remain with regards to its oncological safety. We present a single center case-matching study analysing the impact of AFT in cumulative incidence of local recurrences (LR). MATERIALS AND METHODS From a prospectively maintained database, we identified 902 patients who underwent 1025 breast reconstructions from 2005 to 2017. Data regarding demographics, tumor characteristics, surgery details and follow-up were collected. Exclusion criteria were patients with distant metastases at diagnosis, recurrent tumor or incomplete data regarding primary tumor, patients who underwent prophylactic mastectomies and breast-conserving surgeries. Statistical analysis was done to evaluate the impact of the variables on the incidence of LR. A p-value < 0.05 was considered statistically significant. RESULTS After 1:n case-matching, we selected 919 breasts, out of which 425 (46.2%) patients received at least one AFT session vs 494 (53.8%) control cases. LR had an overall rate of 6.8% and we found LR in 14 (3.0%) AFT cases and 54 (9.6%) controls. Statistical analysis showed that AFT did not increase risk of LR: HR 0.337 (CI 0.173-0.658), p=0.00007. Multivariate analysis identified IDC subtype and lymph node metastases to have an increased risk of local recurrences (HR > 1). Conversely, positive hormonal receptor status was associated with a reduced risk of events (HR < 1). CONCLUSIONS AFT was not associated with a higher probability of locoregional recurrence in patients undergoing breast reconstruction therefore it can be safely used for total breast reconstruction or aesthetic refinements.LEVEL OF EVIDENCE: 3.
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13
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Promny T, Kutz CS, Jost T, Distel LV, Kadam S, Schmid R, Arkudas A, Horch RE, Kengelbach-Weigand A. An In Vitro Approach for Investigating the Safety of Lipotransfer after Breast-Conserving Therapy. J Pers Med 2022; 12:1284. [PMID: 36013233 PMCID: PMC9409821 DOI: 10.3390/jpm12081284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/19/2022] [Accepted: 07/30/2022] [Indexed: 11/16/2022] Open
Abstract
The application of lipotransfer after breast-conserving therapy (BCT) and irradiation in breast cancer patients is an already widespread procedure for reconstructing volume deficits of the diseased breast. Nevertheless, the safety of lipotransfer has still not been clarified yet due to contradictory data. The goal of this in vitro study was to further elucidate the potential effects of lipotransfer on the irradiated remaining breast tissue. The mammary epithelial cell line MCF-10A was co-cultured with the fibroblast cell line MRC-5 and irradiated with 2 and 5 Gy. Afterwards, cells were treated with conditioned medium (CM) from adipose-derived stem cells (ADSC), and the effects on the cellular functions of MCF-10A cells and on gene expression at the mRNA level in MCF-10A and MRC-5 cells were analyzed. Treatment with ADSC CM stimulated transmigration and invasion and decreased the surviving fraction of MCF-10A cells. Further, the expression of cytokines, extracellular, and mesenchymal markers was enhanced in mammary epithelial cells. Only an effect of ADSC CM on irradiated fibroblasts could be observed. The present data suggest epithelial-mesenchymal transition-like changes in the epithelial mammary breast cell line. Thus, the benefits of lipotransfer after BCT should be critically weighed against its possible risks for the affected patients.
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Affiliation(s)
- Theresa Promny
- Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Chiara-Sophia Kutz
- Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Tina Jost
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Luitpold V. Distel
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Sheetal Kadam
- Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Rafael Schmid
- Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Andreas Arkudas
- Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Raymund E. Horch
- Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Annika Kengelbach-Weigand
- Department of Plastic and Hand Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
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14
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Papadopoulou A, Kalodimou VE, Mavrogonatou E, Karamanou K, Yiacoumettis AM, Panagiotou PN, Pratsinis H, Kletsas D. Decreased differentiation capacity and altered expression of extracellular matrix components in irradiation-mediated senescent human breast adipose-derived stem cells. IUBMB Life 2022; 74:969-981. [PMID: 35833571 DOI: 10.1002/iub.2659] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 06/06/2022] [Indexed: 11/10/2022]
Abstract
Radiotherapy is widely used for the treatment of breast cancer. However, we have shown that ionizing radiation can provoke premature senescence in breast stromal cells. In particular, breast stromal fibroblasts can become senescent after irradiation both in vitro and in vivo and they express an inflammatory phenotype and an altered profile of extracellular matrix components, thus facilitating tumor progression. Adipose-derived stem cells (ASCs) represent another major component of the breast tissue stroma. They are multipotent cells and due to their ability to differentiate in multiple cell lineages they play an important role in tissue maintenance and repair in normal and pathologic conditions. Here, we investigated the characteristics of human breast ASCs that became senescent prematurely after their exposure to ionizing radiation. We found decreased expression levels of the specific mesenchymal cell surface markers CD105, CD73, CD44, and CD90. In parallel, we demonstrated a significantly reduced expression of transcription factors regulating osteogenic (i.e., RUNX2), adipogenic (i.e., PPARγ), and chondrogenic (i.e., SOX9) differentiation; this was followed by an analogous reduction in their differentiation capacity. Furthermore, they overexpress inflammatory markers, that is, IL-6, IL-8, and ICAM-1, and a catabolic phenotype, marked by the reduction of collagen type I and the increase of MMP-1 and MMP-13 expression. Finally, we detected changes in proteoglycan expression, for example, the upregulation of syndecan 1 and syndecan 4 and the downregulation of decorin. Notably, all these alterations, when observed in the breast stroma, represent poor prognostic factors for tumor development. In conclusion, we showed that ionizing radiation-mediated prematurely senescent human breast ASCs have a decreased differentiation potential and express specific changes adding to the formation of a permissive environment for tumor growth.
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Affiliation(s)
- Adamantia Papadopoulou
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece
| | - Vasiliki E Kalodimou
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece
| | - Eleni Mavrogonatou
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece
| | - Konstantina Karamanou
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece
| | - Andreas M Yiacoumettis
- Plastic and Reconstructive Surgery Department, Metropolitan General Hospital, Athens, Greece
| | - Petros N Panagiotou
- Department of Plastic Surgery and Burns Unit, KAT General Hospital of Athens, Athens, Greece
| | - Harris Pratsinis
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece
| | - Dimitris Kletsas
- Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece
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15
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Seitz AJ, Asaad M, Hanson SE, Butler CE, Largo RD. Autologous Fat Grafting for Oncologic Patients: A Literature Review. Aesthet Surg J 2021; 41:S61-S68. [PMID: 34002764 DOI: 10.1093/asj/sjab126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Autologous fat grafting (AFG) serves as an effective method to address volume defects, contour irregularities, and asymmetry in both aesthetic and reconstructive procedures. In recent years, there has been growing concern about the potential of cancer recurrence and interference with cancer surveillance in oncologic patients receiving AFG. The adipose tissue contains adipose-derived stem cells (ASCs), a specific type of mesenchymal stem cells, that facilitate secretion of numerous growth factors which in turn stimulate tissue regeneration and angiogenesis. As such, it has been theorized that ASCs may also have the potential to stimulate cancer cell proliferation and growth when used in oncologic patients. Multiple research studies have demonstrated the ability of ACSs to facilitate tumor proliferation in animal models. However, clinical research in oncologic patients has yielded contradictory findings. Although the literature pertaining to oncologic safety in head and neck, as well as sarcoma, cancer patients remains limited, studies demonstrate no increased risk of tumor recurrence in these patient populations receiving AFG. Similarly, both the efficacy and safety of AFG have been well established in breast cancer patients through numerous clinical studies. More recently, preclinical research in animal models has shown that AFG has the potential to facilitate tissue regeneration and improve joint contracture following irradiation. Ultimately, further research is needed to elucidate the safety of AFG in a variety of oncologic patients, as well as explore its use in tissue regeneration, particularly in the setting of radiotherapy. Level of Evidence: 4.
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Affiliation(s)
- Allison J Seitz
- Department of Plastic & Reconstructive Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Malke Asaad
- Department of Plastic & Reconstructive Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Summer E Hanson
- Department of Surgery, University of Chicago Medicine and Biological Sciences, Chicago, IL, USA
| | - Charles E Butler
- Department of Plastic & Reconstructive Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rene D Largo
- Department of Plastic & Reconstructive Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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16
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Effect of 3D printed polycaprolactone scaffold with a bionic structure on the early stage of fat grafting. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 123:111973. [PMID: 33812601 DOI: 10.1016/j.msec.2021.111973] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/30/2021] [Accepted: 02/10/2021] [Indexed: 11/24/2022]
Abstract
Mature adipocytes are sensitive to stress and hypoxia, which are the two major obstacles in large-volume fat grafting. Bionic scaffolds are considered beneficial for fat grafting; however, their mechanism is still unclear. In this study, polycaprolactone scaffolds were fabricated by a 3D-printing technique and compounded with liposuction fat. They were implanted subcutaneously into nude mice. At different times, gross and histological observations were performed to evaluate the retention rates and histological morphologies. Adipocyte viability, apoptosis, and vascularization were analyzed by special immunostaining. Quantitative polymerase chain reaction was used to detect the variations in hypoxia and inflammation. The results showed that the volume and weight retentions in the scaffold group were higher than those in the fat group with the former exhibiting fewer vacuoles and less fibrosis. In immunostaining, elevated CD31+ capillaries, more perilipin+ adipocytes, and fewer TUNEL+ apoptotic cells were observed in the scaffold group by week 4. The lower expression of HIF-1α indicated the alleviation of hypoxia. In conclusion, the scaffold provided mechanical support to resist skin tension, thereby decreasing the interstitial pressure, and improving substance exchange and vascular ingrowth. In this regard, the scaffold attenuated hypoxia and promoted vascularization, making it a feasible method to increase long-term retention in fat grafting using scaffolds with suitable degradation rates and additional vascular maturation stimulation.
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17
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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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18
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Mohd Ali N, Yeap SK, Ho WY, Boo L, Ky H, Satharasinghe DA, Tan SW, Cheong SK, Huang HD, Lan KC, Chiew MY, Ong HK. Adipose MSCs Suppress MCF7 and MDA-MB-231 Breast Cancer Metastasis and EMT Pathways Leading to Dormancy via Exosomal-miRNAs Following Co-Culture Interaction. Pharmaceuticals (Basel) 2020; 14:ph14010008. [PMID: 33374139 PMCID: PMC7824212 DOI: 10.3390/ph14010008] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/27/2020] [Accepted: 11/30/2020] [Indexed: 02/07/2023] Open
Abstract
Globally, breast cancer is the most frequently diagnosed cancer in women, and it remains a substantial clinical challenge due to cancer relapse. The presence of a subpopulation of dormant breast cancer cells that survived chemotherapy and metastasized to distant organs may contribute to relapse. Tumor microenvironment (TME) plays a significant role as a niche in inducing cancer cells into dormancy as well as involves in the reversible epithelial-to-mesenchymal transition (EMT) into aggressive phenotype responsible for cancer-related mortality in patients. Mesenchymal stem cells (MSCs) are known to migrate to TME and interact with cancer cells via secretion of exosome- containing biomolecules, microRNA. Understanding of interaction between MSCs and cancer cells via exosomal miRNAs is important in determining the therapeutic role of MSC in treating breast cancer cells and relapse. In this study, exosomes were harvested from a medium of indirect co-culture of MCF7-luminal and MDA-MB-231-basal breast cancer cells (BCCs) subtypes with adipose MSCs. The interaction resulted in different exosomal miRNAs profiles that modulate essential signaling pathways and cell cycle arrest into dormancy via inhibition of metastasis and epithelial-to-mesenchymal transition (EMT). Overall, breast cancer cells displayed a change towards a more dormant-epithelial phenotype associated with lower rates of metastasis and higher chemoresistance. The study highlights the crucial roles of adipose MSCs in inducing dormancy and identifying miRNAs-dormancy related markers that could be used to identify the metastatic pattern, predict relapses in cancer patients and to be potential candidate targets for new targeted therapy.
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Affiliation(s)
- Norlaily Mohd Ali
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras 43000, Malaysia; (N.M.A.); (L.B.); (S.K.C.)
| | - Swee Keong Yeap
- Marine Biotechnology, China-ASEAN College of Marine Sciences, Xiamen University Malaysia Campus, Jalan Sunsuria, Bandar Sunsuria, Sepang, Selangor 43900, Malaysia;
| | - Wan Yong Ho
- Faculty of Medicine and Health Sciences, University of Nottingham (Malaysia Campus), Semenyih 43500, Malaysia;
| | - Lily Boo
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras 43000, Malaysia; (N.M.A.); (L.B.); (S.K.C.)
| | - Huynh Ky
- Department of Agriculture Genetics and Breeding, College of Agriculture and Applied Biology, Cantho University, Can Tho 900100, Vietnam;
| | - Dilan Amila Satharasinghe
- Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine and Animal Science, University of Peradeniya, Peradeniya 20400, Sri Lanka;
| | - Sheau Wei Tan
- Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400, Malaysia;
| | - Soon Keng Cheong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras 43000, Malaysia; (N.M.A.); (L.B.); (S.K.C.)
- Cryocord Sdn Bhd, Persiaran Cyberpoint Selatan, Cyberjaya 63000, Malaysia
| | - Hsien Da Huang
- School of Life and Health Sciences, Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen 518172, China;
| | - Kuan Chun Lan
- Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu 30010, Taiwan;
| | - Men Yee Chiew
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30010, Taiwan;
| | - Han Kiat Ong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras 43000, Malaysia; (N.M.A.); (L.B.); (S.K.C.)
- Correspondence:
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19
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Khanh VC, Fukushige M, Moriguchi K, Yamashita T, Osaka M, Hiramatsu Y, Ohneda O. Type 2 Diabetes Mellitus Induced Paracrine Effects on Breast Cancer Metastasis Through Extracellular Vesicles Derived from Human Mesenchymal Stem Cells. Stem Cells Dev 2020; 29:1382-1394. [PMID: 32900278 DOI: 10.1089/scd.2020.0126] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cancer metastasis is the leading cause of mortality among breast cancer patients. Type 2 diabetes mellitus (T2DM) has been suggested as a risk factor of breast cancer; however, whether or not T2DM is associated with breast tumor metastasis remains unclear. In this study, we examined the involvement of T2DM with breast cancer metastasis by a combined approach of a meta-analysis and experimental research. The results of a systematic review and meta-analysis suggested that diabetes significantly increases the risk of lymph node metastasis by 1.10-fold (P < 0.01). Consistently, our data from experimental research showed that T2DM induced paracrine effects of mesenchymal stem cells (MSCs), a key contributor to cancer progression, to stimulate metastasis of breast cancer cells (BCCs) by two independent mechanisms. First, T2DM induced the excess secretion of interleukin 6 (IL6) from MSCs, which activated the JAK/STAT3 pathway in BCCs, thus promoting the metastasis of BCCs. Second, beside the EGR-1-/IL6-dependent mechanism, T2DM altered the functions of MSC-derived extracellular vesicles (EVs), which are highly associated with the metastasis of BCCs. Our present study showed that T2DM is a risk factor for breast cancer metastasis, and MSC-derived EVs might be useful for developing a novel anti-breast cancer therapy strategy.
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Affiliation(s)
- Vuong Cat Khanh
- Laboratory of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan
| | - Mizuho Fukushige
- Laboratory of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan
| | - Kana Moriguchi
- Laboratory of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan
| | - Toshiharu Yamashita
- Laboratory of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan
| | - Motoo Osaka
- Department of Cardiovascular Surgery, University of Tsukuba, Tsukuba, Japan
| | - Yuji Hiramatsu
- Department of Cardiovascular Surgery, University of Tsukuba, Tsukuba, Japan
| | - Osamu Ohneda
- Laboratory of Regenerative Medicine and Stem Cell Biology, Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan
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20
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Effect of Breast Cancer and Adjuvant Therapy on Adipose-Derived Stromal Cells: Implications for the Role of ADSCs in Regenerative Strategies for Breast Reconstruction. Stem Cell Rev Rep 2020; 17:523-538. [PMID: 32929604 DOI: 10.1007/s12015-020-10038-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/04/2020] [Indexed: 12/14/2022]
Abstract
Tissue engineering using Adipose Derived Stromal Cells (ADSCs) has emerged as a novel regenerative medicine approach to replace and reconstruct soft tissue damaged or lost as a result of disease process or therapeutic surgical resection. ADSCs are an attractive cell source for soft tissue regeneration due to the fact that they are easily accessible, multipotent, non-immunogenic and pro-angiogenic. ADSC based regenerative strategies have been successfully translated to the clinical setting for the treatment of Crohn's fistulae, musculoskeletal pathologies, wound healing, and cosmetic breast augmentation (fat grafting). ADSCs are particularly attractive as a source for adipose tissue engineering as they exhibit preferential differentiation to adipocytes and support maintenance of mature adipose graft volume. The potential for reconstruction with an autologous tissue sources and a natural appearance and texture is particularly appealing in the setting of breast cancer; up to 40% of patients require mastectomy for locoregional control and current approaches to post-mastectomy breast reconstruction (PMBR) are limited by the potential for complications at the donor and reconstruction sites. Despite their potential, the use of ADSCs in breast cancer patients is controversial due to concerns regarding oncological safety. These concerns relate to the regeneration of tissue at a site where a malignancy has been treated and the impact this may have on stimulating local disease recurrence or dissemination. Pre-clinical data suggest that ADSCs exhibit pro-oncogenic characteristics and are involved in stimulating progression, and growth of tumour cells. However, there have been conflicting reports on the oncologic outcome, in terms of locoregional recurrence, for breast cancer patients in whom ADSC enhanced fat grafting was utilised as an alternative to reconstruction for small volume defects. A further consideration which may impact the successful translation of ADSC based regenerative strategies for post cancer reconstruction is the potential effects of cancer therapy. This review aims to address the effect of malignant cells, adjuvant therapies and patient-specific factors that may influence the success of regenerative strategies using ADSCs for post cancer tissue regeneration.
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21
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Uribe J, Liu HY, Mohamed Z, Chiou AE, Fischbach C, Daniel S. Supported Membrane Platform to Assess Surface Interactions between Extracellular Vesicles and Stromal Cells. ACS Biomater Sci Eng 2020; 6:3945-3956. [PMID: 33463350 DOI: 10.1021/acsbiomaterials.0c00133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Extracellular vesicles (EVs) are membrane-encapsulated particles secreted by eukaryotic cells that stimulate cell communication and horizontal cargo exchange. EV interactions with stromal cells can result in molecular changes in the recipient cell and, in some cases, lead to disease progression. However, mechanisms leading to these changes are poorly understood. A few model systems are available for studying the outcomes of surface interactions between EV membranes with stromal cells. Here, we created a hybrid supported bilayer incorporating EVs membrane material, called an extracellular vesicle supported bilayer, EVSB. Using EVSBs, we investigated the surface interactions between breast cancer EVs and adipose-derived stem cells (ADSCs) by culturing ADSCs on EVSBs and analyzing cell adhesion, spreading, viability, vascular endothelial growth factor (VEGF) secretion, and myofibroblast differentiation. Results show that cell viability, adhesion, spreading, and proangiogenic activity were enhanced, conditions that promote oncogenic activity, but cell differentiation was not. This model system could be used to develop therapeutic strategies to limit EV-ADSC interactions and proangiogenic conditions. Finally, this model system is not limited to the study of cancer but can be used to study surface interactions between EVs from any origin and any target cell to investigate EV mechanisms leading to cellular changes in other diseases.
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Affiliation(s)
- Johana Uribe
- Meinig School of Biomedical Engineering, Cornell University, 101 Weill Hall, 273 Tower Road, Ithaca, New York 14853, United States
| | - Han-Yuan Liu
- School of Chemical and Biomolecular Engineering, Cornell University, 120 Olin Hall, 6-44 Ho Plaza, Ithaca, New York 14853, United States
| | - Zeinab Mohamed
- Meinig School of Biomedical Engineering, Cornell University, 101 Weill Hall, 273 Tower Road, Ithaca, New York 14853, United States
| | - Aaron E Chiou
- Meinig School of Biomedical Engineering, Cornell University, 101 Weill Hall, 273 Tower Road, Ithaca, New York 14853, United States
| | - Claudia Fischbach
- Meinig School of Biomedical Engineering, Cornell University, 101 Weill Hall, 273 Tower Road, Ithaca, New York 14853, United States.,School of Chemical and Biomolecular Engineering, Cornell University, 120 Olin Hall, 6-44 Ho Plaza, Ithaca, New York 14853, United States
| | - Susan Daniel
- Meinig School of Biomedical Engineering, Cornell University, 101 Weill Hall, 273 Tower Road, Ithaca, New York 14853, United States.,School of Chemical and Biomolecular Engineering, Cornell University, 120 Olin Hall, 6-44 Ho Plaza, Ithaca, New York 14853, United States
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22
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Fajka-Boja R, Szebeni GJ, Hunyadi-Gulyás É, Puskás LG, Katona RL. Polyploid Adipose Stem Cells Shift the Balance of IGF1/IGFBP2 to Promote the Growth of Breast Cancer. Front Oncol 2020; 10:157. [PMID: 32133294 PMCID: PMC7040181 DOI: 10.3389/fonc.2020.00157] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 01/29/2020] [Indexed: 12/17/2022] Open
Abstract
Background: The close proximity of adipose tissue and mammary epithelium predispose involvement of adipose cells in breast cancer development. Adipose-tissue stem cells (ASCs) contribute to tumor stroma and promote growth of cancer cells. In our previous study, we have shown that murine ASCs, which undergo polyploidization during their prolonged in vitro culturing, enhanced the proliferation of 4T1 murine breast cancer cells in IGF1 dependent manner. Aims: In the present study, our aim was to clarify the regulation of ASC-derived IGF1. Methods: 4T1 murine breast carcinoma cells were co-transplanted with visceral fat-derived ASCs (vASC) or with the polyploid ASC.B6 cell line into female BALB/c mice and tumor growth and lung metastasis were monitored. The conditioned media of vASCs and ASC.B6 cells were subjected to LC-MS/MS analysis and the production of IGFBP2 was verified by Western blotting. The regulatory effect was examined by adding recombinant IGFBP2 to the co-culture of ASC.B6 and 4T1. Akt/protein kinase B (PKB) activation was detected by Western blotting. Results: Polyploid ASCs promoted the tumor growth and metastasis more potently than vASCs with normal karyotype. vASCs produced the IGF1 regulator IGFBP2, which inhibited proliferation of 4T1 cells. Downregulation of IGFBP2 by polyploidization of ASCs and enhanced secretion of IGF1 allowed survival signaling in 4T1 cells, leading to Akt phosphorylation. Conclusions: Our results implicate that ASCs in the tumor microenvironment actively regulate the growth of breast cancer cells through the IGF/IGFBP system.
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Affiliation(s)
- Roberta Fajka-Boja
- Artificial Chromosome and Stem Cell Research Laboratory, Biological Research Centre, Institute of Genetics, Szeged, Hungary
| | - Gábor J Szebeni
- Laboratory of Functional Genomics, Biological Research Centre, Institute of Genetics, Szeged, Hungary.,Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary
| | - Éva Hunyadi-Gulyás
- Laboratory of Proteomics Research, Biological Research Centre, Institute of Biochemistry, Szeged, Hungary
| | - László G Puskás
- Laboratory of Functional Genomics, Biological Research Centre, Institute of Genetics, Szeged, Hungary.,Avidin Ltd., Szeged, Hungary
| | - Róbert L Katona
- Artificial Chromosome and Stem Cell Research Laboratory, Biological Research Centre, Institute of Genetics, Szeged, Hungary
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23
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Conci C, Bennati L, Bregoli C, Buccino F, Danielli F, Gallan M, Gjini E, Raimondi MT. Tissue engineering and regenerative medicine strategies for the female breast. J Tissue Eng Regen Med 2019; 14:369-387. [PMID: 31825164 PMCID: PMC7065113 DOI: 10.1002/term.2999] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 11/06/2019] [Accepted: 11/11/2019] [Indexed: 12/16/2022]
Abstract
The complexity of mammary tissue and the variety of cells involved make tissue regeneration an ambitious goal. This review, supported by both detailed macro and micro anatomy, illustrates the potential of regenerative medicine in terms of mammary gland reconstruction to restore breast physiology and morphology, damaged by mastectomy. Despite the widespread use of conventional therapies, many critical issues have been solved using the potential of stem cells resident in adipose tissue, leading to commercial products. in vitro research has reported that adipose stem cells are the principal cellular source for reconstructing adipose tissue, ductal epithelium, and nipple structures. In addition to simple cell injection, construct made by cells seeded on a suitable biodegradable scaffold is a viable alternative from a long‐term perspective. Preclinical studies on mice and clinical studies, most of which have reached Phase II, are essential in the commercialization of cellular therapy products. Recent studies have revealed that the enrichment of fat grafting with stromal vascular fraction cells is a viable alternative to breast reconstruction. Although in the future, organ‐on‐a‐chip can be envisioned, for the moment researchers are still focusing on therapies that are a long way from regenerating the whole organ, but which nevertheless prevent complications, such as relapse and loss in terms of morphology.
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Affiliation(s)
- Claudio Conci
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milan, Italy
| | - Lorenzo Bennati
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milan, Italy
| | - Chiara Bregoli
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milan, Italy
| | - Federica Buccino
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milan, Italy
| | - Francesca Danielli
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milan, Italy
| | - Michela Gallan
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milan, Italy
| | - Ereza Gjini
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milan, Italy
| | - Manuela T Raimondi
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Milan, Italy
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24
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Gentile P, Calabrese C, De Angelis B, Pizzicannella J, Kothari A, Garcovich S. Impact of the Different Preparation Methods to Obtain Human Adipose-Derived Stromal Vascular Fraction Cells (AD-SVFs) and Human Adipose-Derived Mesenchymal Stem Cells (AD-MSCs): Enzymatic Digestion Versus Mechanical Centrifugation. Int J Mol Sci 2019; 20:5471. [PMID: 31684107 PMCID: PMC6862236 DOI: 10.3390/ijms20215471] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 10/27/2019] [Accepted: 11/01/2019] [Indexed: 12/16/2022] Open
Abstract
Autologous therapies using adipose-derived stromal vascular fraction (AD-SVFs) and adult adipose-derived mesenchymal stem cells (AD-MSCs) warrant careful preparation of the harvested adipose tissue. Currently, no standardized technique for this preparation exists. Processing quantitative standards (PQSs) define manufacturing quantitative variables (such as time, volume, and pressure). Processing qualitative standards (PQLSs) define the quality of the materials and methods in manufacturing. The purpose of the review was to use PQSs and PQLSs to report the in vivo and in vitro results obtained by different processing kits that use different procedures (enzymatic vs. non-enzymatic) to isolate human AD-SVFs/AD-MSCs. PQSs included the volume of fat tissue harvested and reagents used, the time/gravity of centrifugation, and the time, temperature, and tilt level/speed of incubation and/or centrifugation. PQLSs included the use of a collagenase, a processing time of 30 min, kit weight, transparency of the kit components, the maintenance of a closed sterile processing environment, and the use of a small centrifuge and incubating rocker. Using a kit with the PQSs and PQLSs described in this study enables the isolation of AD-MSCs that meet the consensus quality criteria. As the discovery of new critical quality attributes (CQAs) of AD-MSCs evolve with respect to purity and potency, adjustments to these benchmark PQSs and PQLs will hopefully isolate AD-MSCs of various CQAs with greater reproducibility, quality, and safety. Confirmatory studies will no doubt need to be completed.
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Affiliation(s)
- Pietro Gentile
- Surgical Science Department, Plastic and Reconstructive Surgery, University of Rome "Tor Vergata", 00179 Rome, Italy.
| | | | - Barbara De Angelis
- Surgical Science Department, Plastic and Reconstructive Surgery, University of Rome "Tor Vergata", 00179 Rome, Italy.
| | | | - Ashutosh Kothari
- Chief of Breast Surgery Unit, Guy's Hospital, Guy's and St. Thomas' NHS Foundation Trust, London SE1 9RT, UK.
| | - Simone Garcovich
- Institute of Dermatology, F. Policlinico Gemelli IRCSS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
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25
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Subcutaneous and Visceral Adipose-Derived Mesenchymal Stem Cells: Commonality and Diversity. Cells 2019; 8:cells8101288. [PMID: 31640218 PMCID: PMC6830091 DOI: 10.3390/cells8101288] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/16/2019] [Accepted: 10/17/2019] [Indexed: 12/18/2022] Open
Abstract
Adipose-derived mesenchymal stem cells (ASCs) are considered to be a useful tool for regenerative medicine, owing to their capabilities in differentiation, self-renewal, and immunomodulation. These cells have become a focus in the clinical setting due to their abundance and easy isolation. However, ASCs from different depots are not well characterized. Here, we analyzed the functional similarities and differences of subcutaneous and visceral ASCs. Subcutaneous ASCs have an extraordinarily directed mode of motility and a highly dynamic focal adhesion turnover, even though they share similar surface markers, whereas visceral ASCs move in an undirected random pattern with more stable focal adhesions. Visceral ASCs have a higher potential to differentiate into adipogenic and osteogenic cells when compared to subcutaneous ASCs. In line with these observations, visceral ASCs demonstrate a more active sonic hedgehog pathway that is linked to a high expression of cilia/differentiation related genes. Moreover, visceral ASCs secrete higher levels of inflammatory cytokines interleukin-6, interleukin-8, and tumor necrosis factor α relative to subcutaneous ASCs. These findings highlight, that both ASC subpopulations share multiple cellular features, but significantly differ in their functions. The functional diversity of ASCs depends on their origin, cellular context and surrounding microenvironment within adipose tissues. The data provide important insight into the biology of ASCs, which might be useful in choosing the adequate ASC subpopulation for regenerative therapies.
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26
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Rocha A, Leite Y, Silva A, Conde Júnior A, Costa C, Silva G, Bezerra D, Cavalcante M, Feitosa M, Argôlo Neto N, Serakides R, Carvalho M. Immunophenotyping, plasticity tests and nanotagging of stem cells derived from adipose tissue of wild rodent agouti (Dasyprocta prymnolopha). ARQ BRAS MED VET ZOO 2019. [DOI: 10.1590/1678-4162-10677] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
ABSTRACT There is a growing interest in the study of unspecialized mesenchymal stem cells, for there are still some discussions about their in vitro behavior. Regenerative medicine is a science undergoing improvement which develops treatments as cell therapy using somatic stem cells. In several studies, adipose tissue is presented as a source of multipotent adult cells that has several advantages over other tissue sources. This study aimed to characterize and evaluate the tagging of mesenchymal stem cells from the agoutis adipose tissue (Dasyprocta prymonolopha), with fluorescent intracytoplasmic nanocrystals. Fibroblast cells were observed, plastic adherent, with extended self-renewal, ability to form colonies, multipotency by differentiation into three lineages, population CD90 + and CD45 - expression, which issued high red fluorescence after the tagging with fluorescent nanocrystals by different paths and cryopreserved for future use. It is possible to conclude that mesenchymal stem cells from agouti adipose tissue have biological characteristics and in vitro behavior that demonstrate its potential for use in clinical tests.
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27
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O'Halloran N, Khan S, Gilligan K, Dwyer R, Kerin M, Lowery A. Oncological Risk in Autologous Stem Cell Donation for Novel Tissue-Engineering Approaches to Postmastectomy Breast Regeneration. BREAST CANCER-BASIC AND CLINICAL RESEARCH 2019; 13:1178223419864896. [PMID: 31555047 PMCID: PMC6753512 DOI: 10.1177/1178223419864896] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 01/30/2023]
Abstract
Adipose tissue engineering using adipose-derived stem cells (ADSCs) has emerged
as an opportunity to develop novel approaches to postmastectomy breast
reconstruction with the potential for an autologous tissue source with a natural
appearance and texture. As of yet, the role of ADSCs in breast cancer
development and metastasis is not completely understood; therefore, we must
consider the oncological safety of employing an autologous source of ADSCs for
use in breast regeneration. This study investigated the regenerative properties
of ADSCs isolated from breast cancer patients, including those who had received
neoadjuvant chemotherapy, and noncancer controls. The ADSCs were characterised
for several parameters central to tissue regeneration, including cell viability,
proliferation, differentiation potential, and cytokine secretion. A stem cell
population was isolated and confirmed by flow cytometry and multilineage
differentiation. There was no difference in cell phenotype or surface antigen
expression between ADSCs from different sources. Adipose-derived stem cells
isolated from the breast of cancer patients exhibited reduced adipogenic
differentiation potential compared with ADSCs from other sources. The greatest
degree of adipogenic differentiation was observed in ADSCs isolated from the
subcutaneous abdominal fat of noncancer controls. The proliferation rate of
ADSCs isolated from the breast of cancer patients was increased compared with
other sources; however, it was decreased in ADSCs isolated from breast cancer
patients who had recently been treated with neoadjuvant chemotherapy. A number
of cytokines were detected in the cell conditioned media of ADSCs from different
sources, including matrix metalloproteinase-2 (MMP-2), which was detected at
higher levels in the secretome of ADSCs from breast cancer patients compared
with noncancer controls. This study provides important information relating to
the suitability of ADSCs as an autologous cell source for adipose tissue
engineering in postcancer reconstruction. Results indicate that while the
surface phenotype does not differ, the differentiation capacity, proliferative
rate, and secreted cytokine profile are affected by the presence or treatment of
breast cancer. These findings support further investigation into the
regenerative potential of these ADSCs, if they are to be considered in clinical
reconstructive strategies.
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Affiliation(s)
- Niamh O'Halloran
- Discipline of Surgery, The Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland
| | - Sonja Khan
- Discipline of Surgery, The Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland
| | - Katie Gilligan
- Discipline of Surgery, The Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland
| | - Roisin Dwyer
- Discipline of Surgery, The Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland
| | - Michael Kerin
- Discipline of Surgery, The Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland
| | - Aoife Lowery
- Discipline of Surgery, The Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland
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28
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Khoo D, Ung O, Blomberger D, Hutmacher DW. Nipple Reconstruction: A Regenerative Medicine Approach Using 3D-Printed Tissue Scaffolds. TISSUE ENGINEERING PART B-REVIEWS 2019; 25:126-134. [PMID: 30379123 DOI: 10.1089/ten.teb.2018.0253] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
IMPACT STATEMENT This work provides a comprehensive overview and critique of nipple reconstruction techniques to date. It then explores different tissue engineering concepts and how these may improve clinical outcomes for patients undergoing nipple reconstruction. A novel technique is proposed, whereby a three-dimensional-printed tissue-engineered construct is used as an autologous graft to assist nipple reconstruction.
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Affiliation(s)
- Denver Khoo
- 1 Faculty of Medicine, University of Queensland, Brisbane, Australia
| | - Owen Ung
- 1 Faculty of Medicine, University of Queensland, Brisbane, Australia.,2 Centre for Breast Health, Unit 1 Surgery-Breast Endocrine Unit, Royal Brisbane and Women's Hospital, Brisbane, Australia
| | - Daniela Blomberger
- 3 Centre in Regenerative Medicine, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
| | - Dietmar W Hutmacher
- 3 Centre in Regenerative Medicine, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.,4 ARC Centre in Additive Biomanufacturing, Queensland University of Technology, Brisbane, Australia
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29
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Cleversey C, Robinson M, Willerth SM. 3D Printing Breast Tissue Models: A Review of Past Work and Directions for Future Work. MICROMACHINES 2019; 10:E501. [PMID: 31357657 PMCID: PMC6723606 DOI: 10.3390/mi10080501] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Revised: 07/22/2019] [Accepted: 07/25/2019] [Indexed: 12/24/2022]
Abstract
Breast cancer often results in the removal of the breast, creating a need for replacement tissue. Tissue engineering offers the promise of generating such replacements by combining cells with biomaterial scaffolds and serves as an attractive potential alternative to current surgical repair methods. Such engineered tissues can also serve as important tools for drug screening and provide in vitro models for analysis. 3D bioprinting serves as an exciting technology with significant implications and applications in the field of tissue engineering. Here we review the work that has been undertaken in hopes of generating the recognized in-demand replacement breast tissue using different types of bioprinting. We then offer suggestions for future work needed to advance this field for both in vitro and in vivo applications.
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Affiliation(s)
- Chantell Cleversey
- Doctor of Medicine (MD), Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Meghan Robinson
- Department of Urological Sciences, Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada
- Department of Mechanical Engineering and Division of Medical Science, University of Victoria, Victoria, BC V8W 2Y2, Canada
| | - Stephanie M Willerth
- Department of Urological Sciences, Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
- Department of Mechanical Engineering and Division of Medical Science, University of Victoria, Victoria, BC V8W 2Y2, Canada.
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30
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Scioli MG, Storti G, D'Amico F, Gentile P, Kim BS, Cervelli V, Orlandi A. Adipose-Derived Stem Cells in Cancer Progression: New Perspectives and Opportunities. Int J Mol Sci 2019; 20:3296. [PMID: 31277510 PMCID: PMC6651808 DOI: 10.3390/ijms20133296] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 07/01/2019] [Accepted: 07/02/2019] [Indexed: 12/12/2022] Open
Abstract
Growing importance has been attributed to interactions between tumors, the stromal microenvironment and adult mesenchymal stem cells. Adipose-derived stem cells (ASCs) are routinely employed in regenerative medicine and in autologous fat transfer procedures. To date, clinical trials have failed to demonstrate the potential pro-oncogenic role of ASC enrichment. Nevertheless, some pre-clinical studies from in vitro and in vivo models have suggested that ASCs act as a potential tumor promoter for different cancer cell types, and support tumor progression and invasiveness through the activation of several intracellular signals. Interaction with the tumor microenvironment and extracellular matrix remodeling, the exosomal release of pro-oncogenic factors as well as the induction of epithelial-mesenchymal transitions are the most investigated mechanisms. Moreover, ASCs have also demonstrated an elective tumor homing capacity and this tumor-targeting capacity makes them a suitable carrier for anti-cancer drug delivery. New genetic and applied nanotechnologies may help to design promising anti-cancer cell-based approaches through the release of loaded intracellular nanoparticles. These new anti-cancer therapies can more effectively target tumor cells, reaching higher local concentrations even in pharmacological sanctuaries, and thus minimizing systemic adverse drug effects. The potential interplay between ASCs and tumors and potential ASCs-based therapeutic approaches are discussed.
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Affiliation(s)
- Maria Giovanna Scioli
- Anatomic Pathology Institute, Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy
| | - Gabriele Storti
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, Tor Vergata University of Rome, 00133 Rome, Italy
| | - Federico D'Amico
- Anatomic Pathology Institute, Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy
| | - Pietro Gentile
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, Tor Vergata University of Rome, 00133 Rome, Italy
| | - Bong-Sung Kim
- Division of Plastic Surgery and Hand Surgery, University Hospital Zurich, 8091 Zurich, Switzerland
| | - Valerio Cervelli
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, Tor Vergata University of Rome, 00133 Rome, Italy
| | - Augusto Orlandi
- Anatomic Pathology Institute, Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy.
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31
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Gentile P, Garcovich S. Concise Review: Adipose-Derived Stem Cells (ASCs) and Adipocyte-Secreted Exosomal microRNA (A-SE-miR) Modulate Cancer Growth and proMote Wound Repair. J Clin Med 2019; 8:855. [PMID: 31208047 PMCID: PMC6616456 DOI: 10.3390/jcm8060855] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 06/05/2019] [Accepted: 06/12/2019] [Indexed: 12/13/2022] Open
Abstract
Adipose-derived stem cells (ASCs) have been routinely used from several years in regenerative surgery without any definitive statement about their potential pro-oncogenic or anti-oncogenic role. ASCs has proven to favor tumor progression in several experimental cancer models, playing a central role in regulating tumor invasiveness and metastatic potential through several mechanisms, such as the paracrine release of exosomes containing pro-oncogenic molecules and the induction of epithelial-mesenchymal transition. However, the high secretory activity and the preferential tumor-targeting make also ASCs a potentially suitable vehicle for delivery of new anti-cancer molecules in tumor microenvironment. Nanotechnologies, viral vectors, drug-loaded exosomes, and micro-RNAs (MiR) represent additional new tools that can be applied for cell-mediated drug delivery in a tumor microenvironment. Recent studies revealed that the MiR play important roles in paracrine actions on adipose-resident macrophages, and their dysregulation has been implicated in the pathogenesis of obesity, diabetes, and diabetic complications as wounds. Numerous MiR are present in adipose tissues, actively participating in the regulation of adipogenesis, adipokine secretion, inflammation, and inter-cellular communications in the local tissues. These results provide important insights into Adipocyte-secreted exosomal microRNA (A-SE-MiR) function and they suggest evaluating the potential role of A-SE-MiR in tumor progression, the mechanisms underlying ASCs-cancer cell interplay and clinical safety of ASCs-based therapies.
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Affiliation(s)
- Pietro Gentile
- Surgical Science Department, Plastic and Reconstructive Surgery Unit, University of "Tor Vergata", 00133 Rome, Italy.
| | - Simone Garcovich
- Institute of Dermatology, F. Policlinico Gemelli IRCSS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
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32
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Claro F, Morari J, Moreira LR, Sarian LOZ, Velloso LA. Breast Lipofilling Does Not Pose Evidence of Chronic Inflammation in Rats. Aesthet Surg J 2019; 39:NP202-NP212. [PMID: 30265289 DOI: 10.1093/asj/sjy257] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Laboratory reports on adipose tissue suggest that fat grafting to the breast may pose an oncologic risk. One possible reason for this is the theoretic chronic inflammation due to adipokynes released by grafted white adipose tissue (WAT). OBJECTIVES The aim of this study was to analyze inflammatory activity in lipofilled breast through the use of proinflammatory markers. METHODS Fifty-four paired-breasts of female rats were divided into 4 groups: control, sham, and breasts grafted with either autologous subcutaneous (SC) WAT or autologous omentum (OM). The WAT was prepared through centrifugation, and the grafting was performed with the use of 0.9-mm blunt-tip cannula. The rats were killed 8 weeks postoperatively, and their breasts were harvested for immunohistochemical staining for CD68-expressing macrophages, gene expression (real-time PCR) for monocyte chemoattractant protein 1 (MCP-1), F4/80, Cox-2, and IL-6. RESULTS The weights of the rats that underwent a procedure differed from those of the unmanipulated control group (P < 0.01). The macrophage counts of CD68 differed only between breasts lipofilled with OM and control (P < 0.01). MCP-1, F4/80, and Cox-2 were similarly expressed among the groups (P = 0.422, P = 0.143, and P = 0.209, respectively). The expression of IL-6 differed between breast samples grafted with SC and OM WAT (P = 0.015), but not between samples of control and OM (P = 0.752), and control and SC (P = 0.056). CONCLUSIONS No inflammation activity was identified in the microenvironment of lipofilled breasts, indicating that chronic inflammation does not seem to be triggered by the breast lipofilling procedure.
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Affiliation(s)
- Francisco Claro
- Department of Gynecology and Obstetrics, Laboratory of Specialized Pathology and Laboratory of Cell Signaling, Obesity and Comorbidities, School of Medical Sciences, State University of Campinas, Campinas-SP, Brazil
| | - Joseane Morari
- Department of Gynecology and Obstetrics, Laboratory of Specialized Pathology and Laboratory of Cell Signaling, Obesity and Comorbidities, School of Medical Sciences, State University of Campinas, Campinas-SP, Brazil
| | - Luciana R Moreira
- Department of Gynecology and Obstetrics, Laboratory of Specialized Pathology and Laboratory of Cell Signaling, Obesity and Comorbidities, School of Medical Sciences, State University of Campinas, Campinas-SP, Brazil
| | - Luis O Z Sarian
- Department of Gynecology and Obstetrics, Laboratory of Specialized Pathology and Laboratory of Cell Signaling, Obesity and Comorbidities, School of Medical Sciences, State University of Campinas, Campinas-SP, Brazil
| | - Licio A Velloso
- Department of Gynecology and Obstetrics, Laboratory of Specialized Pathology and Laboratory of Cell Signaling, Obesity and Comorbidities, School of Medical Sciences, State University of Campinas, Campinas-SP, Brazil
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33
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Lee JS, Eo P, Kim MC, Kim JB, Jin HK, Bae JS, Jeong JH, Park HY, Yang JD. Effects of Stromal Vascular Fraction on Breast Cancer Growth and Fat Engraftment in NOD/SCID Mice. Aesthetic Plast Surg 2019; 43:498-513. [PMID: 30635686 DOI: 10.1007/s00266-018-01304-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 12/23/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND To overcome unpredictable fat graft resorption, cell-assisted lipotransfer using stromal vascular fraction (SVF) has been introduced. However, its effect on cancer growth stimulation and its oncological safety are debatable. We investigated the effect of SVF on adjacent breast cancer and transplanted fat in a mouse model. METHODS A breast cancer xenograft model was constructed by injecting 2 × 106 MDA-MB-231-luc breast cancer cells into the right lower back of 40 NOD/SCID mice. Two weeks later, cancer size was sorted according to signal density using an in vivo optical imaging system, and 36 mice were included. Human fat was extracted from the abdomen, and SVFs were isolated using a component isolator. The mice were divided into four groups: A, controls; B, injected with 30 μl SVF; C, injected with 0.5 ml fat and 30 μl saline; group D, injected with 0.5 ml fat and 30 μl SVF. Magnetic resonance imaging and three-dimensional micro-computed tomography volumetric analysis were performed at 4 and 8 weeks. RESULTS Tumor volume was 43.6, 42.3, 48.7, and 42.4 mm3 at the initial time point and 6780, 5940, 6080, and 5570 mm3 at 8 weeks in groups A, B, C, and D, respectively. Fat graft survival volume after 8 weeks was 49.32% and 62.03% in groups C and D, respectively. At 2-month follow-up after fat grafting in the xenograft model, SVF injection showed an increased fat survival rate and did not increase the adjacent tumor growth significantly. CONCLUSION Fat grafting with SVF yields satisfactory outcome in patients who undergo breast reconstruction surgery. NO LEVEL ASSIGNED This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.
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Affiliation(s)
- Joon Seok Lee
- Department of Plastic and Reconstructive Surgery, School of Medicine, Kyungpook National University, 130 Dongdeokro, Jung-gu, Daegu, 41944, South Korea
| | - PilSeon Eo
- Department of Plastic and Reconstructive Surgery, School of Medicine, Kyungpook National University, 130 Dongdeokro, Jung-gu, Daegu, 41944, South Korea
| | | | - Jae Bong Kim
- Department of Plastic and Reconstructive Surgery, School of Medicine, Kyungpook National University, 130 Dongdeokro, Jung-gu, Daegu, 41944, South Korea
| | - Hee Kyung Jin
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu, 41944, South Korea
| | - Jae-Sung Bae
- Department of Physiology, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea
| | - Jae-Hwan Jeong
- Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea
| | - Ho Yong Park
- Department of Surgery, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea
| | - Jung Dug Yang
- Department of Plastic and Reconstructive Surgery, School of Medicine, Kyungpook National University, 130 Dongdeokro, Jung-gu, Daegu, 41944, South Korea.
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Oncologic Safety of Fat Grafting for Autologous Breast Reconstruction in an Animal Model of Residual Breast Cancer. Plast Reconstr Surg 2019; 143:103-112. [PMID: 30589782 DOI: 10.1097/prs.0000000000005085] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Clinical outcomes suggest that postoncologic reconstruction with fat grafting yields cumulative incidence curves of recurrence comparable to those of other breast reconstruction procedures; however, results from experimental research studies suggest that adipose stem cells can stimulate cancer growth. In this study, a novel animal model of residual cancer was developed in mouse mammary pads to test whether lipofilling impacts the probability of locoregional recurrence of breast cancer after breast conserving surgery. METHODS Mammary fat pads of female NOD-SCID gamma mice were each injected with MCF-7 cells in Matrigel. Tumors were allowed to engraft for 2 weeks, after which time either sterile saline (n = 20) or human fat graft (n = 20) was injected adjacent to tumor sites. After 8 weeks, tumors were assessed for volume measurement, histologic grade, Ki67 positivity, and metastatic spread. RESULTS Animals receiving lipofilling after tumor cell engraftment had lower tumor volume and mass (p = 0.046 and p = 0.038, respectively). Macroscopic invasion was higher in the saline group. Histologic grade was not significantly different in the two groups (p = 0.17). Ki67 proliferation index was lower in tumors surrounded by fat graft (p = 0.01). No metastatic lesion was identified in any animal. CONCLUSIONS Adipose transfer for breast reconstruction performed in the setting of residual breast tumor in a clinically relevant animal model did not increase tumor size, proliferation, histologic grade, or metastatic spread. This study supports the oncologic safety of lipofilling as part of the surgical platform for breast reconstruction after cancer therapy.
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Fat Graft Safety after Oncologic Surgery: Addressing the Contradiction between In Vitro and Clinical Studies. Plast Reconstr Surg 2019; 142:1489-1499. [PMID: 30489524 DOI: 10.1097/prs.0000000000004992] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND The authors investigate the in vitro and in vivo interaction of human breast cancer cells and human adipose-derived stem cells to address the controversy on the safety of postmastectomy fat grafting. METHODS The authors co-cultured human adipose-derived stem cells and MDA-MB-231 breast cancer cells in an in vitro cell migration assay to examine the migration of breast cancer cells. In the in vivo arm, the authors injected breast cancer cells (group I), human breast cancer cells plus human adipose-derived stem cells (group II), human breast cancer cells plus human fat graft (group III), and human breast cancer cells plus human fat graft plus human adipose-derived stem cells (group IV) to the mammary fat pads of female nude mice (n = 20). The authors examined the tumors, livers, and lungs histologically after 2 weeks. RESULTS Migration of breast cancer cells increased significantly when co-cultured with adipose-derived stem cells (p < 0.05). The tumor growth rate in group IV was significantly higher than in groups I and II (p < 0.05). The tumor growth rate in group III was also higher than in groups I and II, but this difference was not statistically significant (p > 0.05). Histologically, there was no liver/lung metastasis at the end of 2 weeks. The vascular density in the tumors from group IV was significantly higher than in other groups (p < 0.01). CONCLUSION The injection of breast cancer cells, fat graft, and adipose-derived stem cells together increases breast cancer xenograft growth rates significantly.
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Moskalenko RA, Korneva YS. [Role of adipose tissue in the development and progression of colorectal cancer]. Arkh Patol 2019; 81:52-56. [PMID: 30830106 DOI: 10.17116/patol20198101152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The paper gives the current data available in the literature on the relationship and pathogenetic mechanisms of influence of adipose tissue on colorectal carcinogenesis. It considers the aspects of changes in adipose tissue and microenvironment of the tumor itself, including those under the influence of biologically active substances secreted by adipocytes; differences in subcutaneous and visceral fat and their importance in the development and progression of colorectal cancer (CRC), as well as the role of adipose tissue-derived stem cells. Understanding these mechanisms for adipose tissue influence on CRC will assist not only in preventing this disease, but also in searching for new therapeutic targets.
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Affiliation(s)
- R A Moskalenko
- Medical Institute, Sumy State University, Ministry of Education and Science of Ukraine, Sumy, Ukraine
| | - Yu S Korneva
- Smolensk State Medical University, Ministry of Health of Russia, Smolensk, Russia; Smolensk Regional Institute of Pathology, Smolensk, Russia
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Ishihara M, Kishimoto S, Nakamura S, Fukuda K, Sato Y, Hattori H. Biomaterials as cell carriers for augmentation of adipose tissue-derived stromal cell transplantation. Biomed Mater Eng 2019; 29:567-585. [PMID: 30400072 DOI: 10.3233/bme-181009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Adipose tissue-derived stromal cells (ADSCs) contain lineage-committed progenitor cells that have the ability to differentiate into various cell types that may be useful for autologous cell transplantation to correct defects of skin, adipose, cartilage, bone, tendon, and blood vessels. The multipotent characteristics of ADSCs, as well as their abundance in the human body, make them an attractive potential resource for wound repair and applications to tissue engineering. ADSC transplantation has been used in combination with biomaterials, including cell sheets, hydrogel, and three-dimensional (3D) scaffolds based on chitosan, fibrin, atelocollagen, and decellularized porcine dermis, etc. Furthermore, low molecular weight heparin/protamine nanoparticles (LH/P NPs) have been used as an inducer of ADSC aggregation. The tissue engineering potential of these biomaterials as cell carriers is increased by the synergistic relationship between ADSCs and the biomaterials, resulting in the release of angiogenic cytokines and growth factors. In this review article, we describe the advantages of ADSC transplantation for tissue engineering, focusing on biomaterials as cell carriers which we have studied.
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Affiliation(s)
- Masayuki Ishihara
- Division of Biomedical Engineering Research Institute, National Defense Medical College, Saitama 359-8513, Japan
| | - Satoko Kishimoto
- Research Support Center, Dokkyo Medical University, Tochigi 321-0293, Japan
| | - Shingo Nakamura
- Division of Biomedical Engineering Research Institute, National Defense Medical College, Saitama 359-8513, Japan
| | - Koichi Fukuda
- Division of Biomedical Engineering Research Institute, National Defense Medical College, Saitama 359-8513, Japan
| | - Yoko Sato
- Division of Biomedical Engineering Research Institute, National Defense Medical College, Saitama 359-8513, Japan
| | - Hidemi Hattori
- Department of Biochemistry and Applied Sciences, University of Miyazaki, Miyazaki 889-2162, Japan
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Chiu CH. Does Stromal Vascular Fraction Ensure a Higher Survival in Autologous Fat Grafting for Breast Augmentation? A Volumetric Study Using 3-Dimensional Laser Scanning. Aesthet Surg J 2019; 39:41-52. [PMID: 29438465 DOI: 10.1093/asj/sjy030] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background Cell-assisted lipotransfer (CAL) has been considered a promising technique for promoting adipogenesis and angiogenesis in fat grafts. Objectives The author sought to objectively analyze the change of breast volume in patients who underwent stromal vascular fraction (SVF)-enriched fat grafting for breast augmentation and compared the clinical results with those who underwent conventional fat grafting without SVF by using 3-dimensional laser scanning. Methods From April 2015 to March 2016, 105 patients who underwent traditional fat grafting without SVF enrichment for breast augmentation were assigned to group A and served as the control. The other 101 patients who underwent SVF-enriched fat grafting for breast augmentation were assigned to group B. The charts of these patients were retrospectively reviewed. Results The survival rate of the transplanted fat was 67.9% in group A and 68.7% in group B at 12 months after the operation. Postoperative complication rate was 3.8% in group A and 5.9% in group B. The differences were statistically insignificant. Conclusions SVF does not ensure a higher survival rate in autologous fat grafting for breast augmentation. Considering the potential drawbacks of adipose-derived stem cells (ADSC) and the extra cost of the consumables, in particular the need for harvesting larger amount of fat which could be reserved for additional fat grafting at a later time to achieve even better improvement, the results of this study do not support the use of SVF in autologous fat grafting for breast augmentation in terms of graft survival and postoperative complications. Level of Evidence 3
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Wu YC, Wang WT, Huang LJ, Cheng RY, Kuo YR, Hou MF, Lai CS, Yu J. Differential Response of Non-cancerous and Malignant Breast Cancer Cells to Conditioned Medium of Adipose tissue-derived Stromal Cells (ASCs). Int J Med Sci 2019; 16:893-901. [PMID: 31337963 PMCID: PMC6643111 DOI: 10.7150/ijms.27125] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 04/03/2019] [Indexed: 01/22/2023] Open
Abstract
Background: The application of adipose tissue-derived stromal cells (ASCs) in regenerative medicine has become a growing trend due to its abundance and differentiation potentials. However, several breast cancer studies indicated that ASCs promote tumor progression, therefore, the use of ASCs for reconstruction after oncological surgery poses potential risks. In this study, we aimed to examine whether cancerous or non-cancerous breast cells will exhibit different responses to ASC-derived CM. Methods: ASCs were isolated from residuals of subcutaneous adipose tissue obtained from patients undergoing surgery. Cancerous MCF-7, MDA-MB231, and MDA-MB468 cell lines and one non-cancerous M10/H184B5F5 cell line were cultured with variant concentrations of ASC-derived conditioned medium (CM) for analysis. Results: ASC-derived CM significantly reduced cell viability by triggering apoptosis in MCF-7, MDA-MB231, and MDA-MB468 cell lines. ATM-Chk2-dependent DNA damage response was activated early in cancer cells when exposed to ASC-derived CM. By contrast, prompted cell proliferation instead of cell death was detected in M10/H184B5F5 cells under the treatment of lower CM concentration. Even when exposed to the highest concentration of CM, only cell cycle arrest accompanied by a weak DNA damage response were detected in M10/H184B5F5 cells, no cell deaths were observed. Conclusions: Overall, this study demonstrated that cancerous and non-cancerous breast cells respond differently to ASC-derived CM. ASC-derived CM triggered significant cell death in breast cancer cell lines, however non-cancerous breast cells exhibited dissimilar response to ASC-derived CM.
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Affiliation(s)
- Yi-Chia Wu
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Department of Plastic Surgery, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.,Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,PhD. Programme in Translational Medicine, Kaohsiung Medical University, Kaohsiung, and Academia Sinica, Taipei, Taiwan
| | - Wei-Ting Wang
- Center of Teaching and Research, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Li-Ju Huang
- Center of Teaching and Research, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Ruo-You Cheng
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yur-Ren Kuo
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Feng Hou
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Sheng Lai
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - John Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linko, Taoyuan, Taiwan.,Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
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Discussion: Oncologic Safety of Fat Graft for Autologous Breast Reconstruction in an Animal Model of Residual Breast Cancer. Plast Reconstr Surg 2018; 143:113. [PMID: 30589783 DOI: 10.1097/prs.0000000000005086] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Mehdipour F, Razmkhah M, Rezaeifard S, Bagheri M, Talei A, Khalatbari B, Ghaderi A. Mesenchymal stem cells induced anti‐inflammatory features in B cells from breast tumor draining lymph nodes. Cell Biol Int 2018; 42:1658-1669. [DOI: 10.1002/cbin.11062] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 09/30/2018] [Indexed: 08/30/2023]
Abstract
AbstractThe immune‐modulatory effect of adipose‐derived stem cells (ASCs) on B cells in cancer has not been well elucidated. Herein, the interaction between B cells and ASCs isolated from the breast fat of either normal (nASCs) or breast cancer women (cASCs) was investigated. B cells derived from breast tumor draining lymph nodes were co‐cultured with nASCs or cASCs and B cells proliferation was assessed in direct and transwell assays. Moreover, B cells were co‐cultured with cASCs, nASCs or mesenchymal stromal cells of the tumor tissue (TSCs) and B cell cytokine production was assessed using flow cytometery. cASCs or TSCs were co‐cultured with either intact or B cell depleted lymphocytes and frequencies of CD25+FoxP3+ Tregs, IL‐10+ or IFN‐γ+CD4+ T cells were assessed. Results showed that co‐culture of B cells with ASCs in transwell chambers did not affect B cell proliferation. nASCs, however, was able to significantly reduce B cell proliferation in direct co‐culture experiments (P = 0.004). The frequencies of IL‐10+, TNF‐α+, IL‐2+, and IFN‐γ+ B cells were not significantly different in the co‐cultures of B cells with ASCs or TSCs. But the TNF‐α+/ IL‐10+ B cells ratio decreased in all co‐cultures, a reduction merely significant in B cell‐cASCs co‐culture (P = 0.01). The frequencies of CD4+ T cells subsets in either intact or B cell depleted lymphocytes did not undergo significant changes following co‐culture with ASCs or TSCs. Therefore, ASCs is capable of inhibiting B cell proliferation in a contact dependent manner and shifting the cytokine profile of B cells toward an anti‐inflammatory profile.
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Affiliation(s)
- Fereshteh Mehdipour
- Shiraz Institute for Cancer Research School of Medicine, Shiraz University of Medical Sciences P.O. Box: 71345‐3119 Shiraz Iran
| | - Mahboobeh Razmkhah
- Shiraz Institute for Cancer Research School of Medicine, Shiraz University of Medical Sciences P.O. Box: 71345‐3119 Shiraz Iran
| | - Somayeh Rezaeifard
- Shiraz Institute for Cancer Research School of Medicine, Shiraz University of Medical Sciences P.O. Box: 71345‐3119 Shiraz Iran
| | | | - Abdol‐Rasoul Talei
- Breast Diseases Research Center Shiraz University of Medical Sciences Shiraz Iran
| | - Behzad Khalatbari
- Department of Plastic Surgery Shiraz University of Medical Sciences Shiraz Iran
| | - Abbas Ghaderi
- Shiraz Institute for Cancer Research School of Medicine, Shiraz University of Medical Sciences P.O. Box: 71345‐3119 Shiraz Iran
- Department of Immunology, School of Medicine Shiraz University of Medical Sciences Shiraz Iran
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Wu S, Wang Y, Yuan Z, Wang S, Du H, Liu X, Wang Q, Zhu X. Human adipose‑derived mesenchymal stem cells promote breast cancer MCF7 cell epithelial‑mesenchymal transition by cross interacting with the TGF‑β/Smad and PI3K/AKT signaling pathways. Mol Med Rep 2018; 19:177-186. [PMID: 30483746 PMCID: PMC6297785 DOI: 10.3892/mmr.2018.9664] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 10/19/2018] [Indexed: 01/14/2023] Open
Abstract
The influence and underlying mechanisms of human adipose-derived stem cells (Hu-ADSCs) on breast cancer cells in the tumor microenvironment remain unclear. Understanding the association between Hu-ADSCs and cancer cells may provide targets for breast cancer treatment and reference for the clinical application of stem cells. Therefore, a Hu-ADSC and breast cancer MCF7 cell coculture system was established to investigate the paracrine effects of Hu-ADSCs on MCF7 cell migration and invasion, in addition to the potential mechanism of action by reverse transcription-quantitative polymerase chain reaction and western blotting. Hu-ADSCs enhanced MCF7 cell migration and invasion by decreasing the expression of epithelial marker E-cadherin, and increasing the expression of interstitial marker N-cadherin and epithelial-mesenchymal transition (EMT) transcription factors in vitro. The EMT effect of cocultured MCF7 cells was inhibited with the addition of anti-transforming growth factor (TGF)-β1 or phosphoinositide 3-kinase (PI3K) inhibitor LY294002, accompanied by a significant decrease in phosphorylated (p)-mothers against decapentaplegic homolog (Smad) and p-protein kinase B (AKT) expression. The data suggested that the paracrine effect of Hu-ADSCs in the tumor microenvironment promoted the EMT of MCF7 cells by cross interacting with the TGF-β/Smad and PI3K/AKT pathways.
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Affiliation(s)
- Simeng Wu
- Research Center, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Yajun Wang
- Research Center, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Zhe Yuan
- Cord Blood Bank, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Siliang Wang
- Department of Medical Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Hongmei Du
- Department of Medical Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Xue Liu
- Research Center, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Qiushi Wang
- Department of Blood Transfusion, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Xike Zhu
- Research Center, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
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Wang Y, Shi W, Kuss M, Mirza S, Qi D, Krasnoslobodtsev A, Zeng J, Band H, Band V, Duan B. 3D Bioprinting of Breast Cancer Models for Drug Resistance Study. ACS Biomater Sci Eng 2018; 4:4401-4411. [PMID: 33418833 DOI: 10.1021/acsbiomaterials.8b01277] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Ying Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, People’s Republic of China
| | | | | | | | - Dianjun Qi
- Department of General Practice, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Shenyang, Liaoning, People’s Republic of China
| | - Alexey Krasnoslobodtsev
- Department of Physics, University of Nebraska at Omaha, 6001 Dodge Street, Omaha 68182, Nebraska, United States
| | - Jiping Zeng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, People’s Republic of China
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Fajka-Boja R, Marton A, Tóth A, Blazsó P, Tubak V, Bálint B, Nagy I, Hegedűs Z, Vizler C, Katona RL. Increased insulin-like growth factor 1 production by polyploid adipose stem cells promotes growth of breast cancer cells. BMC Cancer 2018; 18:872. [PMID: 30185144 PMCID: PMC6126028 DOI: 10.1186/s12885-018-4781-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 08/29/2018] [Indexed: 02/08/2023] Open
Abstract
Background Adipose-tissue stem cells (ASCs) are subject of intensive research since their successful use in regenerative therapy. The drawback of ASCs is that they may serve as stroma for cancer cells and assist tumor progression. It is disquieting that ASCs frequently undergo genetic and epigenetic changes during their in vitro propagation. In this study, we describe the polyploidization of murine ASCs and the accompanying phenotypical, gene expressional and functional changes under long term culturing. Methods ASCs were isolated from visceral fat of C57BL/6 J mice, and cultured in vitro for prolonged time. The phenotypical changes were followed by microscopy and flow cytometry. Gene expressional changes were determined by differential transcriptome analysis and changes in protein expression were shown by Western blotting. The tumor growth promoting effect of ASCs was examined by co-culturing them with 4 T1 murine breast cancer cells. Results After five passages, the proliferation of ASCs decreases and cells enter a senescence-like state, from which a proportion of cells escape by polyploidization. The resulting ASC line is susceptible to adipogenic, osteogenic and chondrogenic differentiation, and expresses the stem cell markers CD29 and Sca-1 on an upregulated level. Differential transcriptome analysis of ASCs with normal and polyploid karyotype shows altered expression of genes that are involved in regulation of cancer, cellular growth and proliferation. We verified the increased expression of Klf4 and loss of Nestin on protein level. We found that elevated production of insulin-like growth factor 1 by polyploid ASCs rendered them more potent in tumor growth promotion in vitro. Conclusions Our model indicates how ASCs with altered genetic background may support tumor progression. Electronic supplementary material The online version of this article (10.1186/s12885-018-4781-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Roberta Fajka-Boja
- Biological Research Centre of the Hungarian Academy of Sciences, Institute of Genetics, H-6726 Temesvári krt. 62, Szeged, Hungary
| | - Annamária Marton
- Biological Research Centre of the Hungarian Academy of Sciences, Institute of Biochemistry, H-6726 Temesvári krt. 62, Szeged, Hungary
| | - Anna Tóth
- Biological Research Centre of the Hungarian Academy of Sciences, Institute of Genetics, H-6726 Temesvári krt. 62, Szeged, Hungary
| | - Péter Blazsó
- Biological Research Centre of the Hungarian Academy of Sciences, Institute of Genetics, H-6726 Temesvári krt. 62, Szeged, Hungary
| | - Vilmos Tubak
- Creative Laboratory Ltd, H-6726 Temesvári krt. 62, Szeged, Hungary
| | - Balázs Bálint
- Biological Research Centre of the Hungarian Academy of Sciences, Institute of Biochemistry, H-6726 Temesvári krt. 62, Szeged, Hungary
| | - István Nagy
- Biological Research Centre of the Hungarian Academy of Sciences, Institute of Biochemistry, H-6726 Temesvári krt. 62, Szeged, Hungary
| | - Zoltán Hegedűs
- Biological Research Centre of the Hungarian Academy of Sciences, Institute of Biophysics, H-6726 Temesvári krt. 62, Szeged, Hungary
| | - Csaba Vizler
- Biological Research Centre of the Hungarian Academy of Sciences, Institute of Biochemistry, H-6726 Temesvári krt. 62, Szeged, Hungary
| | - Robert L Katona
- Biological Research Centre of the Hungarian Academy of Sciences, Institute of Genetics, H-6726 Temesvári krt. 62, Szeged, Hungary.
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Goto H, Shimono Y, Funakoshi Y, Imamura Y, Toyoda M, Kiyota N, Kono S, Takao S, Mukohara T, Minami H. Adipose-derived stem cells enhance human breast cancer growth and cancer stem cell-like properties through adipsin. Oncogene 2018; 38:767-779. [DOI: 10.1038/s41388-018-0477-8] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 07/28/2018] [Accepted: 08/02/2018] [Indexed: 12/19/2022]
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Mamchur A, Leman E, Salah S, Avivi A, Shams I, Manov I. Adipose-Derived Stem Cells of Blind Mole Rat Spalax Exhibit Reduced Homing Ability: Molecular Mechanisms and Potential Role in Cancer Suppression. Stem Cells 2018; 36:1630-1642. [PMID: 30004601 DOI: 10.1002/stem.2884] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Revised: 06/17/2018] [Accepted: 06/05/2018] [Indexed: 12/18/2022]
Abstract
Adipose-derived stem cells (ADSCs) are recruited by cancer cells from the adjacent tissue, and they become an integral part of the tumor microenvironment. Here, we report that ADSCs from the long-living, tumor-resistant blind mole rat, Spalax, have a low ability to migrate toward cancer cells compared with cells from its Rattus counterpart. Tracking 5-ethynyl-2'-deoxyuridine (EdU)-labeled ADSCs, introduced to tumor-bearing nude mice, toward the xenografts, we found that rat ADSCs intensively migrated and penetrated the tumors, whereas only a few Spalax ADSCs reached the tumors. Moreover, rat ADSCs, but not Spalax ADSCs, acquired endothelial-like phenotype and incorporated in the intratumoral reticular structure resembling a vasculature. Likewise, endothelial-like cells differentiated from Spalax and rat ADSCs could form capillary-like structures; however, the tube densities were higher in rat-derived cells. Using time-lapse microscopy, in vitro wound-healing, and transwell migration assays, we demonstrated the impaired motility and low polarization ability of Spalax ADSCs. To assess whether the phosphorylated status of myosin light chain (MLC) is involved in the decreased motility of Spalax ADSCs, we inhibited MLC phosphorylation by blocking of Rho-kinase (ROCK). Inhibition of ROCK resulted in the suppression of MLC phosphorylation, acquisition of actin polarization, and activation of motility and migration of Spalax ADSCs. We propose that reduced ADSCs migration to cancer and poor intratumoral angiogenesis play a role in Spalax's cancer resistance. Learning more about the molecular strategy of noncancerous cells in Spalax to resist oncogenic stimuli and maintain a nonpermissive tumor milieu may lead us to developing new cancer-preventive strategy in humans. Stem Cells 2018;36:1630-1642.
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Affiliation(s)
| | - Eva Leman
- Faculty of Natural Sciences, Department of Evolutionary and Environmental Biology, University of Haifa, Haifa, Israel
| | - Safaa Salah
- Faculty of Natural Sciences, Department of Evolutionary and Environmental Biology, University of Haifa, Haifa, Israel
| | - Aaron Avivi
- Institute of Evolution, University of Haifa, Haifa, Israel
| | - Imad Shams
- Institute of Evolution, University of Haifa, Haifa, Israel.,Faculty of Natural Sciences, Department of Evolutionary and Environmental Biology, University of Haifa, Haifa, Israel
| | - Irena Manov
- Institute of Evolution, University of Haifa, Haifa, Israel
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Autologous and not allogeneic adipose-derived stem cells improve acute burn wound healing. PLoS One 2018; 13:e0197744. [PMID: 29787581 PMCID: PMC5963767 DOI: 10.1371/journal.pone.0197744] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 05/08/2018] [Indexed: 01/08/2023] Open
Abstract
Adipose-derived stem cells (ADSCs) transplant has been reported to be a potential treatment for burn wounds. However, the effects of autogenicity and allogenicity of ADSCs on burn wound healing have not been investigated and the method for using ADSCs still needs to be established. This study compared the healing effects of autologous and allogenic ADSCs and determined an optimal method of using ADSCs to treat acute burn wounds. Experiments were performed in 20 male Wistar rats (weight, 176-250 g; age, 6-7 weeks). Two identical full-thickness burn wounds (radius, 4 mm) were created in each rat. ADSCs harvested from inguinal area and characterized by their high multipotency were injected into burn wounds in the original donor rats (autologous ADSCs group) or in other rats (allogenic ADSCs group). The injection site was either the wound center or the four corners 0.5 cm from the wound edge. The reduction of burn surface areas in the two experimental groups and in control group were evaluated with Image J software for 15 days post-wounding to determine the wound healing rates. Wound healing was significantly faster in the autologous ADSCs group compared to both the allogenic ADSCs group (p<0.05) and control group (p<0.05). Wound healing in the allogenic ADSC group did not significantly differ from that in control group. Notably, ADSC injections 0.5cm from the wound edge showed significantly improved healing compared to ADSCs injections in the wound center (p<0.05). This study demonstrated the therapeutic efficacy of ADSCs in treating acute burn wounds in rats. However, only autologous ADSCs improved healing in acute burn wounds; allogenic ADSCs did not. This study further determined a superior location of using ADSCs injections to treat burn wounds including the injection site. Future studies will replicate the experiment in a larger and long-term scale burn wounds in higher mammalian models to facilitate ADSCs therapy in burn wound clinical practice.
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Razmkhah M, Mansourabadi Z, Mohtasebi MS, Talei AR, Ghaderi A. Cancer and normal adipose-derived mesenchymal stem cells (ASCs): Do they have differential effects on tumor and immune cells? Cell Biol Int 2018; 42:334-343. [PMID: 29076586 DOI: 10.1002/cbin.10905] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 10/25/2017] [Indexed: 12/24/2022]
Abstract
Adipose-derived mesenchymal stem cells (ASCs) are known to have immunomodulatory properties through soluble factors or by direct cell-to-cell contact. This study aimed to assess the expression of HLA-G and IDO activity in breast cancer and normal ASCs and to see whether ASC is capable of modulating both tumor cells and immune system cells in vitro. ASCs were enzymatically isolated from 15 breast cancer patients and 10 normal individuals. Then they were cultured, and the impact of their conditioned media on the movement of the MDA-MB-231 breast cancer cell line was studied in wound healing scratch assay. Next, PBLs from the peripheral blood of normal individuals were separated and co-cultured with breast cancer and normal ASCs. PBLs proliferation and apoptosis were assessed using CFSE labeling dye and annexin V/7AAD staining, respectively. IDO activity and HLA-G protein expression in ASCs were examined using kynurenine assay and Western blotting, respectively. Tumor-derived ASCs, especially those from higher stages of breast cancer, have stronger effects on the proliferation and movement of MDA-MB-231 cells than normal ASCs (P-value < 0.05). Apoptosis in PBLs increased in the presence of ASCs compared to PBLs cultured alone (P-value < 0.05). In contrast, necrosis of PBLs decreased in the presence of ASCs compared to apoptosis in these cells (P-value < 0.001). Collectively, ASCs may have strategic effects on both tumor cells and cells of the immune system in the tumor microenvironment, resulting in tumor development, growth, and metastasis.
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Affiliation(s)
- Mahboobeh Razmkhah
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Mansourabadi
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Sadat Mohtasebi
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abdol-Rasoul Talei
- Breast Diseases Research Center (BDRC), Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abbas Ghaderi
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Xiong BJ, Tan QW, Chen YJ, Zhang Y, Zhang D, Tang SL, Zhang S, Lv Q. The Effects of Platelet-Rich Plasma and Adipose-Derived Stem Cells on Neovascularization and Fat Graft Survival. Aesthetic Plast Surg 2018; 42:1-8. [PMID: 29302732 DOI: 10.1007/s00266-017-1062-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Accepted: 12/13/2017] [Indexed: 02/05/2023]
Abstract
BACKGROUND Adipose-derived stem cell (ADSCs)-assisted and platelet-rich plasma (PRP)-assisted lipofilling aim to enhance angiogenesis and cell proliferation and are promising techniques for lipofilling. This study aimed to compare the outcomes of ADSCs-assisted and PRP-assisted lipofilling. METHODS Adipose tissue and human venous blood were obtained from women with early breast cancer. Human ADSCs were isolated and amplified in vitro. PRP was extracted through double centrifugation. The effect of PRP on ADSCs proliferation was evaluated. In the in vivo study, 1 ml of adipose tissue with saline (control group), PRP (PRP group), or ADSCs (ADSCs group) was injected subcutaneously into the dorsum of nude mice. At 2, 4, 8, and 12 weeks after injection, tissues were assessed for volume retention and ultrasound abnormality. For histological assessment, hematoxylin and eosin staining were performed. RESULTS Cytokines in PRP and blood were comparable. Regarding the in vitro assay, PRP significantly improved ADSCs proliferation, and the effect was dose-dependent. Concerning the in vivo study, for each time point, ADSCs-assisted lipofilling showed superior volume maintenance. Similarly, the PRP group showed improved angiogenesis and fat survival, as compared with the control group. The angiogenic effect of PRP was inferior to that of ADSCs at most time points. No significant difference was observed at 12 weeks after lipofilling. Complication rates were comparable between the PRP group and ADSCs group. CONCLUSIONS PRP-assisted and ADSCs-assisted lipofilling can significantly improve the cosmetic results of grafted fat. PRP-assisted lipofilling, which is considered convenient and clinically available, is a promising technique to improve neovascularization and fat survival. NO LEVEL ASSIGNED This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Soluble factors from adipose tissue-derived mesenchymal stem cells promote canine hepatocellular carcinoma cell proliferation and invasion. PLoS One 2018; 13:e0191539. [PMID: 29346427 PMCID: PMC5773216 DOI: 10.1371/journal.pone.0191539] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 01/05/2018] [Indexed: 12/21/2022] Open
Abstract
The potential effects of adipose tissue-derived mesenchymal stem cells (AT-MSCs) on the growth and invasion of canine tumours including hepatocellular carcinoma (HCC) are not yet understood. Moreover in humans, the functional contribution of AT-MSCs to malignancies remains controversial. The purpose of this study was to investigate the effects of AT-MSCs on the proliferation and invasion of canine HCC cells in vitro. The effect of AT-MSCs on mRNA levels of factors related to HCC progression were also evaluated. Conditioned medium from AT-MSCs (AT-MSC-CM) significantly enhanced canine HCC cell proliferation and invasion. Moreover, mRNA expression levels of transforming growth factor-beta 1, epidermal growth factor A, hepatocyte growth factor, platelet-derived growth factor-beta, vascular endothelial growth factor, and insulin-like growth factor 2 were 2.3 ± 0.4, 2.0 ± 0.5, 5.7 ± 1.9, 1.7 ± 0.2, 2.1 ± 0.4, and 1.4 ± 0.3 times higher, respectively (P < 0.05). The mRNA expression level of MMP-2 also increased (to 4.0 ± 1.2 times control levels) in canine HCC cells co-cultured with AT-MSCs, but MMP-9 mRNA significantly decreased (to 0.5 ± 0.1 times control levels). These findings suggest that soluble factors from AT-MSCs promote the proliferation and invasion of canine HCC cells.
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