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Kinoshita J, Doden K, Sakimura Y, Hayashi S, Saito H, Tsuji T, Yamamoto D, Moriyama H, Minamoto T, Inaki N. Crosstalk Between Omental Adipose-Derived Stem Cells and Gastric Cancer Cells Regulates Cancer Stemness and Chemotherapy Resistance. Cancers (Basel) 2024; 16:4275. [PMID: 39766174 PMCID: PMC11674675 DOI: 10.3390/cancers16244275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 10/08/2024] [Accepted: 10/10/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Peritoneal metastasis (PM) remains a major challenge in patients with gastric cancer (GC) and occurs preferentially in adipose-rich organs, such as the omentum. Adipose-derived stem cells (ASCs) may influence cancer behavior. This study aimed to investigate whether ASCs isolated from the omentum can act as progenitors of cancer-associated fibroblasts (CAFs) and analyze their effects on the cancer stem cell (CSC) niche and the treatment resistance of GC cells. Methods: ASCs were isolated from the human omentum and their cellular characteristics were analyzed during co-culturing with GC cells. Results: ASCs express CAF markers and promote desmoplasia in cancer stroma in a mouse xenograft model. When co-cultured with GC cells, ASCs enhanced the sphere-forming efficiency of MKN45 and MKN74 cells. ASCs increased IL-6 secretion and enhanced the expression of Nanog and CD44v6 in GC cells; however, these changes were suppressed by the inhibition of IL-6. Xenograft mouse models co-inoculated with MKN45 cells and ASCs showed enhanced CD44v6 and Nanog expression and markedly reduced apoptosis induced by 5-FU treatment. Conclusion: This study improves our understanding of ASCs' role in PM treatment resistance and has demonstrated the potential for new treatment strategies targeting ASCs.
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Affiliation(s)
- Jun Kinoshita
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
| | - Kenta Doden
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
| | - Yusuke Sakimura
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
| | - Saki Hayashi
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
| | - Hiroto Saito
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
| | - Toshikatsu Tsuji
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
| | - Daisuke Yamamoto
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
| | - Hideki Moriyama
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
| | - Toshinari Minamoto
- Japan Community Health Care Organization Kanazawa Hospital, Kanazawa 920-8610, Japan;
- Department of Molecular and Cellular Pathology, Kanazawa University, Kanazawa 920-8640, Japan
| | - Noriyuki Inaki
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
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Ramos C, Gerakopoulos V, Oehler R. Metastasis-associated fibroblasts in peritoneal surface malignancies. Br J Cancer 2024; 131:407-419. [PMID: 38783165 PMCID: PMC11300623 DOI: 10.1038/s41416-024-02717-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 05/06/2024] [Accepted: 05/09/2024] [Indexed: 05/25/2024] Open
Abstract
Over decades, peritoneal surface malignancies (PSMs) have been associated with limited treatment options and poor prognosis. However, advancements in perioperative systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) have significantly improved clinical outcomes. PSMs predominantly result from the spread of intra-abdominal neoplasia, which then form secondary peritoneal metastases. Colorectal, ovarian, and gastric cancers are the most common contributors. Despite diverse primary origins, the uniqueness of the peritoneum microenvironment shapes the common features of PSMs. Peritoneal metastization involves complex interactions between tumour cells and the peritoneal microenvironment. Fibroblasts play a crucial role, contributing to tumour development, progression, and therapy resistance. Peritoneal metastasis-associated fibroblasts (MAFs) in PSMs exhibit high heterogeneity. Single-cell RNA sequencing technology has revealed that immune-regulatory cancer-associated fibroblasts (iCAFs) seem to be the most prevalent subtype in PSMs. In addition, other major subtypes as myofibroblastic CAFs (myCAFs) and matrix CAFs (mCAFs) were frequently observed across PSMs studies. Peritoneal MAFs are suggested to originate from mesothelial cells, submesothelial fibroblasts, pericytes, endothelial cells, and omental-resident cells. This plasticity and heterogeneity of CAFs contribute to the complex microenvironment in PSMs, impacting treatment responses. Understanding these interactions is crucial for developing targeted and local therapies to improve PSMs patient outcomes.
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Affiliation(s)
- Cristiano Ramos
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Vasileios Gerakopoulos
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Rudolf Oehler
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria.
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3
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Saha A, Kolonin MG, DiGiovanni J. Obesity and prostate cancer - microenvironmental roles of adipose tissue. Nat Rev Urol 2023; 20:579-596. [PMID: 37198266 DOI: 10.1038/s41585-023-00764-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2023] [Indexed: 05/19/2023]
Abstract
Obesity is known to have important roles in driving prostate cancer aggressiveness and increased mortality. Multiple mechanisms have been postulated for these clinical observations, including effects of diet and lifestyle, systemic changes in energy balance and hormonal regulation and activation of signalling by growth factors and cytokines and other components of the immune system. Over the past decade, research on obesity has shifted towards investigating the role of peri-prostatic white adipose tissue as an important source of locally produced factors that stimulate prostate cancer progression. Cells that comprise white adipose tissue, the adipocytes and their progenitor adipose stromal cells (ASCs), which proliferate to accommodate white adipose tissue expansion in obesity, have been identified as important drivers of obesity-associated cancer progression. Accumulating evidence suggests that adipocytes are a source of lipids that are used by adjacent prostate cancer cells. However, results of preclinical studies indicate that ASCs promote tumour growth by remodelling extracellular matrix and supporting neovascularization, contributing to the recruitment of immunosuppressive cells, and inducing epithelial-mesenchymal transition through paracrine signalling. Because epithelial-mesenchymal transition is associated with cancer chemotherapy resistance and metastasis, ASCs are considered to be potential targets of therapies that could be developed to suppress cancer aggressiveness in patients with obesity.
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Affiliation(s)
- Achinto Saha
- Division of Pharmacology and Toxicology and Dell Paediatric Research Institute, The University of Texas at Austin, Austin, TX, USA
- Center for Molecular Carcinogenesis and Toxicology, The University of Texas at Austin, Austin, TX, USA
- Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
| | - Mikhail G Kolonin
- The Brown Foundation Institute of Molecular Medicine for the Prevention of Disease, The University of Texas Health Sciences Center at Houston, Houston, Texas, USA.
| | - John DiGiovanni
- Division of Pharmacology and Toxicology and Dell Paediatric Research Institute, The University of Texas at Austin, Austin, TX, USA.
- Center for Molecular Carcinogenesis and Toxicology, The University of Texas at Austin, Austin, TX, USA.
- Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
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4
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Fang Y, Chen L, Imoukhuede PI. Toward Blood-Based Precision Medicine: Identifying Age-Sex-Specific Vascular Biomarker Quantities on Circulating Vascular Cells. Cell Mol Bioeng 2023; 16:189-204. [PMID: 37456786 PMCID: PMC10338416 DOI: 10.1007/s12195-023-00771-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 06/20/2023] [Indexed: 07/18/2023] Open
Abstract
Introduction Abnormal angiogenesis is central to vascular disease and cancer, and noninvasive biomarkers of vascular origin are needed to evaluate patients and therapies. Vascular endothelial growth factor receptors (VEGFRs) are often dysregulated in these diseases, making them promising biomarkers, but the need for an invasive biopsy has limited biomarker research on VEGFRs. Here, we pioneer a blood biopsy approach to quantify VEGFR plasma membrane localization on two circulating vascular proxies: circulating endothelial cells (cECs) and circulating progenitor cells (cPCs). Methods Using quantitative flow cytometry, we examined VEGFR expression on cECs and cPCs in four age-sex groups: peri/premenopausal females (aged < 50 years), menopausal/postmenopausal females (≥ 50 years), and younger and older males with the same age cut-off (50 years). Results cECs in peri/premenopausal females consisted of two VEGFR populations: VEGFR-low (~ 55% of population: population medians ~ 3000 VEGFR1 and 3000 VEGFR2/cell) and VEGFR-high (~ 45%: 138,000 VEGFR1 and 39,000-236,000 VEGFR2/cell), while the menopausal/postmenopausal group only possessed the VEGFR-low cEC population; and 27% of cECs in males exhibited high plasma membrane VEGFR expression (206,000 VEGFR1 and 155,000 VEGFR2/cell). The absence of VEGFR-high cEC subpopulations in menopausal/postmenopausal females suggests that their high-VEGFR cECs are associated with menstruation and could be noninvasive proxies for studying the intersection of age-sex in angiogenesis. VEGFR1 plasma membrane localization in cPCs was detected only in menopausal/postmenopausal females, suggesting a menopause-specific regenerative mechanism. Conclusions Overall, our quantitative, noninvasive approach targeting cECs and cPCs has provided the first insights into how sex and age influence VEGFR plasma membrane localization in vascular cells. Supplementary Information The online version contains supplementary material available at 10.1007/s12195-023-00771-1.
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Affiliation(s)
- Yingye Fang
- Department of Bioengineering, University of Washington, Seattle, WA USA
| | - Ling Chen
- Division of Biostatistics, Washington University in St. Louis School of Medicine, St. Louis, MO USA
| | - P. I. Imoukhuede
- Department of Bioengineering, University of Washington, Seattle, WA USA
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5
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Blangero F, Robert M, Andraud T, Dumontet C, Vidal H, Eljaafari A. Contribution of Mesenchymal Stem Cells from Obese Adipose Tissue to PD-L1 Over-Expression and Breast Cancer Progression through Pathogenic Th17 Cell Activation. Cancers (Basel) 2023; 15:cancers15112963. [PMID: 37296927 DOI: 10.3390/cancers15112963] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/09/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Obesity is a well-known risk factor for cancer. We have previously reported the role of adipose-tissue-derived mesenchymal stem cells from obese individuals (ob-ASC) in the promotion of pathogenic Th17 cells and immune check point (ICP) upregulation. Thus, we postulated herein that this mechanism could contribute to breast cancer (BC) aggressiveness. METHODS Conditioning medium (CM) from mitogen-activated ob-ASC and immune cell co-cultures were added to two human breast cancer cell line (BCCL) cultures. Expressions of pro-inflammatory cytokines, angiogenesis markers, metalloproteinases, and PD-L1 (a major ICP) were measured at the mRNA and/or protein levels. BCCL migration was explored in wound healing assays. Anti-cytokine neutralizing antibodies (Ab) were added to co-cultures. RESULTS CM from ob-ASC/MNC co-cultures increased IL-1β, IL-8, IL-6, VEGF-A, MMP-9, and PD-L1 expressions in both BCCLs and accelerated their migration. The use of Abs demonstrated differential effects for IL-17A and IFNγ on BCCL pro-inflammatory cytokine over-expression or PD-L1 upregulation, respectively, but potentiating effects on BCCL migration. Finally, co-cultures with ob-ASC, but not lean ASC, enhanced PD-L1 expression. CONCLUSIONS Our results demonstrate increased inflammation and ICP markers and accelerated BCCL migration following the activation of pathogenic Th17 cells by ob-ASC, which could represent a new mechanism linking obesity with BC progression.
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Affiliation(s)
- Ferdinand Blangero
- CarMeN Laboratory, INSERM U1060, INRAE U1397, University Claude Bernard Lyon 1, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, 69310 Pïerre Bénite, France
| | - Maud Robert
- CarMeN Laboratory, INSERM U1060, INRAE U1397, University Claude Bernard Lyon 1, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, 69310 Pïerre Bénite, France
- Bariatric Surgery Department, Edouard Herriot Hospital, 69003 Lyon, France
| | - Thomas Andraud
- CarMeN Laboratory, INSERM U1060, INRAE U1397, University Claude Bernard Lyon 1, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, 69310 Pïerre Bénite, France
| | - Charles Dumontet
- Center of Research in Cancerology of Lyon, INSERM U1052, CNRS 5286, University Claude Bernard Lyon 1, Centre Léon Berard, 69008 Lyon, France
| | - Hubert Vidal
- CarMeN Laboratory, INSERM U1060, INRAE U1397, University Claude Bernard Lyon 1, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, 69310 Pïerre Bénite, France
| | - Assia Eljaafari
- CarMeN Laboratory, INSERM U1060, INRAE U1397, University Claude Bernard Lyon 1, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, 69310 Pïerre Bénite, France
- Research Department, Hospices Civils de Lyon, 69002 Lyon, France
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Trevellin E, Bettini S, Pilatone A, Vettor R, Milan G. Obesity, the Adipose Organ and Cancer in Humans: Association or Causation? Biomedicines 2023; 11:biomedicines11051319. [PMID: 37238992 DOI: 10.3390/biomedicines11051319] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 04/18/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023] Open
Abstract
Epidemiological observations, experimental studies and clinical data show that obesity is associated with a higher risk of developing different types of cancer; however, proof of a cause-effect relationship that meets the causality criteria is still lacking. Several data suggest that the adipose organ could be the protagonist in this crosstalk. In particular, the adipose tissue (AT) alterations occurring in obesity parallel some tumour behaviours, such as their theoretically unlimited expandability, infiltration capacity, angiogenesis regulation, local and systemic inflammation and changes to the immunometabolism and secretome. Moreover, AT and cancer share similar morpho-functional units which regulate tissue expansion: the adiponiche and tumour-niche, respectively. Through direct and indirect interactions involving different cellular types and molecular mechanisms, the obesity-altered adiponiche contributes to cancer development, progression, metastasis and chemoresistance. Moreover, modifications to the gut microbiome and circadian rhythm disruption also play important roles. Clinical studies clearly demonstrate that weight loss is associated with a decreased risk of developing obesity-related cancers, matching the reverse-causality criteria and providing a causality correlation between the two variables. Here, we provide an overview of the methodological, epidemiological and pathophysiological aspects, with a special focus on clinical implications for cancer risk and prognosis and potential therapeutic interventions.
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Affiliation(s)
- Elisabetta Trevellin
- Center for the Study and Integrated Treatment of Obesity (CeSTIO), Internal Medicine 3, Department of Medicine, University Hospital of Padova, 35128 Padova, Italy
| | - Silvia Bettini
- Center for the Study and Integrated Treatment of Obesity (CeSTIO), Internal Medicine 3, Department of Medicine, University Hospital of Padova, 35128 Padova, Italy
| | - Anna Pilatone
- Center for the Study and Integrated Treatment of Obesity (CeSTIO), Internal Medicine 3, Department of Medicine, University Hospital of Padova, 35128 Padova, Italy
| | - Roberto Vettor
- Center for the Study and Integrated Treatment of Obesity (CeSTIO), Internal Medicine 3, Department of Medicine, University Hospital of Padova, 35128 Padova, Italy
| | - Gabriella Milan
- Center for the Study and Integrated Treatment of Obesity (CeSTIO), Internal Medicine 3, Department of Medicine, University Hospital of Padova, 35128 Padova, Italy
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7
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Goodpaster BH, Bergman BC, Brennan AM, Sparks LM. Intermuscular adipose tissue in metabolic disease. Nat Rev Endocrinol 2022; 19:285-298. [PMID: 36564490 DOI: 10.1038/s41574-022-00784-2] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/21/2022] [Indexed: 12/24/2022]
Abstract
Intermuscular adipose tissue (IMAT) is a distinct adipose depot described in early reports as a 'fatty replacement' or 'muscle fat infiltration' that was linked to ageing and neuromuscular disease. Later studies quantifying IMAT with modern in vivo imaging methods (computed tomography and magnetic resonance imaging) revealed that IMAT is proportionately higher in men and women with type 2 diabetes mellitus and the metabolic syndrome than in people without these conditions and is associated with insulin resistance and poor physical function with ageing. In parallel, agricultural research has provided extensive insight into the role of IMAT and other muscle lipids in muscle (that is, meat) quality. In addition, studies using rodent models have shown that IMAT is a bona fide white adipose tissue depot capable of robust triglyceride storage and turnover. Insight into the importance of IMAT in human biology has been limited by the dearth of studies on its biological properties, that is, the quality of IMAT. However, in the past few years, investigations have begun to determine that IMAT has molecular and metabolic features that distinguish it from other adipose tissue depots. These studies will be critical to further decipher the role of IMAT in health and disease and to better understand its potential as a therapeutic target.
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Affiliation(s)
| | - Bryan C Bergman
- Division of Endocrinology, Diabetes, and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Andrea M Brennan
- Translational Research Institute, AdventHealth, Orlando, FL, USA
| | - Lauren M Sparks
- Translational Research Institute, AdventHealth, Orlando, FL, USA
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CXCR4 and CXCR7 signaling promotes tumor progression and obesity-associated epithelial-mesenchymal transition in prostate cancer cells. Oncogene 2022; 41:4633-4644. [DOI: 10.1038/s41388-022-02466-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 08/25/2022] [Accepted: 08/30/2022] [Indexed: 12/13/2022]
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Saha A, Hamilton-Reeves J, DiGiovanni J. White adipose tissue-derived factors and prostate cancer progression: mechanisms and targets for interventions. Cancer Metastasis Rev 2022; 41:649-671. [PMID: 35927363 PMCID: PMC9474694 DOI: 10.1007/s10555-022-10056-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 07/27/2022] [Indexed: 12/01/2022]
Abstract
Obesity represents an important risk factor for prostate cancer, driving more aggressive disease, chemoresistance, and increased mortality. White adipose tissue (WAT) overgrowth in obesity is central to the mechanisms that lead to these clinical observations. Adipose stromal cells (ASCs), the progenitors to mature adipocytes and other cell types in WAT, play a vital role in driving PCa aggressiveness. ASCs produce numerous factors, especially chemokines, including the chemokine CXCL12, which is involved in driving EMT and chemoresistance in PCa. A greater understanding of the impact of WAT in obesity-induced progression of PCa and the underlying mechanisms has begun to provide opportunities for developing interventional strategies for preventing or offsetting these critical events. These include weight loss regimens, therapeutic targeting of ASCs, use of calorie restriction mimetic compounds, and combinations of compounds as well as specific receptor targeting strategies.
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Affiliation(s)
- Achinto Saha
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78723, USA
- Center for Molecular Carcinogenesis and Toxicology, The University of Texas at Austin, Austin, TX, 78723, USA
- Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX, 78723, USA
| | - Jill Hamilton-Reeves
- Departments of Urology and Dietetics & Nutrition, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - John DiGiovanni
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78723, USA.
- Center for Molecular Carcinogenesis and Toxicology, The University of Texas at Austin, Austin, TX, 78723, USA.
- Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX, 78723, USA.
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd, Austin, TX, 78723, USA.
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10
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Bunnell BA, Martin EC, Matossian MD, Brock CK, Nguyen K, Collins-Burow B, Burow ME. The effect of obesity on adipose-derived stromal cells and adipose tissue and their impact on cancer. Cancer Metastasis Rev 2022; 41:549-573. [PMID: 35999486 DOI: 10.1007/s10555-022-10063-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 08/16/2022] [Indexed: 11/24/2022]
Abstract
The significant increase in the incidence of obesity represents the next global health crisis. As a result, scientific research has focused on gaining deeper insights into obesity and adipose tissue biology. As a result of the excessive accumulation of adipose tissue, obesity results from hyperplasia and hypertrophy within the adipose tissue. The functional alterations in the adipose tissue are a confounding contributing factor to many diseases, including cancer. The increased incidence and aggressiveness of several cancers, including colorectal, postmenopausal breast, endometrial, prostate, esophageal, hematological, malignant melanoma, and renal carcinomas, result from obesity as a contributing factor. The increased morbidity and mortality of obesity-associated cancers are attributable to increased hormones, adipokines, and cytokines produced by the adipose tissue. The increased adipose tissue levels observed in obese patients result in more adipose stromal/stem cells (ASCs) distributed throughout the body. ASCs have been shown to impact cancer progression in vitro and in preclinical animal models. ASCs influence tumor biology via multiple mechanisms, including the increased recruitment of ASCs to the tumor site and increased production of cytokines and growth factors by ASCs and other cells within the tumor stroma. Emerging evidence indicates that obesity induces alterations in the biological properties of ASCs, subsequently leading to enhanced tumorigenesis and metastasis of cancer cells. As the focus of this review is the interaction and impact of ASCs on cancer, the presentation is limited to preclinical data generated on cancers in which there is a demonstrated role for ASCs, such as postmenopausal breast, colorectal, prostate, ovarian, multiple myeloma, osteosarcoma, cervical, bladder, and gastrointestinal cancers. Our group has investigated the interactions between obesity and breast cancer and the mechanisms that regulate ASCs and adipocytes in these different contexts through interactions between cancer cells, immune cells, and other cell types present in the tumor microenvironment (TME) are discussed. The reciprocal and circular feedback loop between obesity and ASCs and the mechanisms by which ASCs from obese patients alter the biology of cancer cells and enhance tumorigenesis will be discussed. At present, the evidence for ASCs directly influencing human tumor growth is somewhat limited, though recent clinical studies suggest there may be some link.
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Affiliation(s)
- Bruce A Bunnell
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA.
| | - Elizabeth C Martin
- Department of Biological and Agricultural Engineering, Louisiana State University, Baton Rouge, LA, USA
| | - Margarite D Matossian
- Department of Microbiology, Immunology and Genetics, University of Chicago, IL, Chicago, USA
| | - Courtney K Brock
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Khoa Nguyen
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Bridgette Collins-Burow
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Matthew E Burow
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
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11
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Guillaume VGJ, Ruhl T, Boos AM, Beier JP. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:394-406. [PMID: 35274703 PMCID: PMC9052412 DOI: 10.1093/stcltm/szac002] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 11/22/2021] [Indexed: 11/14/2022] Open
Abstract
Adipose-derived stem or stromal cells (ASCs) possess promising potential in the fields of tissue engineering and regenerative medicine due to their secretory activity, their multilineage differentiation potential, their easy harvest, and their rich yield compared to other stem cell sources. After the first identification of ASCs in humans in 2001, the knowledge of their cell biology and cell characteristics have advanced, and respective therapeutic options were determined. Nowadays, ASC-based therapies are on the verge of translation into clinical practice. However, conflicting evidence emerged in recent years about the safety profile of ASC applications as they may induce tumor progression and invasion. Numerous in-vitro and in-vivo studies demonstrate a potential pro-oncogenic effect of ASCs on various cancer entities. This raises questions about the safety profile of ASCs and their broad handling and administration. However, these findings spark controversy as in clinical studies ASC application did not elevate tumor incidence rates, and other experimental studies reported an inhibitory effect of ASCs on different cancer cell types. This comprehensive review aims at providing up-to-date information about ASCs and cancer cell interactions, and their potential carcinogenesis and tumor tropism. The extracellular signaling activity of ASCs, the interaction of ASCs with the tumor microenvironment, and 3 major organ systems (the breast, the skin, and genitourinary system) will be presented with regard to cancer formation and progression.
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Affiliation(s)
- Vincent G J Guillaume
- Corresponding author: Vincent G. J. Guillaume, Resident Physician and Research Assistant, Department of Plastic Surgery, Hand Surgery, Burn Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany. Tel: 0049-241-80-89700; Fax: 0241-80-82448;
| | - Tim Ruhl
- Department of Plastic Surgery, Hand Surgery, Burn Center, University Hospital RWTH Aachen, Aachen, Germany
| | - Anja M Boos
- Department of Plastic Surgery, Hand Surgery, Burn Center, University Hospital RWTH Aachen, Aachen, Germany
| | - Justus P Beier
- Department of Plastic Surgery, Hand Surgery, Burn Center, University Hospital RWTH Aachen, Aachen, Germany
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12
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Gao Z, Lu A, Daquinag AC, Yu Y, Huard M, Tseng C, Gao X, Huard J, Kolonin MG. Partial Ablation of Non-Myogenic Progenitor Cells as a Therapeutic Approach to Duchenne Muscular Dystrophy. Biomolecules 2021; 11:biom11101519. [PMID: 34680151 PMCID: PMC8534118 DOI: 10.3390/biom11101519] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/27/2021] [Accepted: 10/12/2021] [Indexed: 01/04/2023] Open
Abstract
Duchenne muscular dystrophy (DMD), caused by the loss of dystrophin, remains incurable. Reduction in muscle regeneration with DMD is associated with the accumulation of fibroadipogenic progenitors (FAPs) differentiating into myofibroblasts and leading to a buildup of the collagenous tissue aggravating DMD pathogenesis. Mesenchymal stromal cells (MSCs) expressing platelet-derived growth factor receptors (PDGFRs) are activated in muscle during DMD progression and give rise to FAPs promoting DMD progression. Here, we hypothesized that muscle dysfunction in DMD could be delayed via genetic or pharmacologic depletion of MSC-derived FAPs. In this paper, we test this hypothesis in dystrophin-deficient mdx mice. To reduce fibro/adipose infiltration and potentiate muscle progenitor cells (MPCs), we used a model for inducible genetic ablation of proliferating MSCs via a suicide transgene, viral thymidine kinase (TK), expressed under the Pdgfrb promoter. We also tested if MSCs from fat tissue, the adipose stromal cells (ASCs), contribute to FAPs and could be targeted in DMD. Pharmacological ablation was performed with a hunter-killer peptide D-CAN targeting ASCs. MSC depletion with these approaches resulted in increased endurance, measured based on treadmill running, as well as grip strength, without significantly affecting fibrosis. Although more research is needed, our results suggest that depletion of pathogenic MSCs mitigates muscle damage and delays the loss of muscle function in mouse models of DMD.
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MESH Headings
- Animals
- Cell Differentiation/genetics
- Cell Proliferation/genetics
- Disease Models, Animal
- Dystrophin/genetics
- Humans
- Mesenchymal Stem Cells/metabolism
- Mice
- Mice, Inbred mdx
- Muscle, Skeletal/growth & development
- Muscle, Skeletal/metabolism
- Muscle, Skeletal/pathology
- Muscular Dystrophy, Duchenne/genetics
- Muscular Dystrophy, Duchenne/pathology
- Muscular Dystrophy, Duchenne/therapy
- Myofibroblasts/cytology
- Myofibroblasts/metabolism
- Promoter Regions, Genetic/genetics
- Receptors, Platelet-Derived Growth Factor/genetics
- Stem Cells/cytology
- Stem Cells/metabolism
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Affiliation(s)
- Zhanguo Gao
- Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX 77030, USA; (Z.G.); (A.C.D.); (Y.Y.)
| | - Aiping Lu
- Center for Regenerative Sports Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA; (A.L.); (M.H.); (X.G.)
| | - Alexes C. Daquinag
- Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX 77030, USA; (Z.G.); (A.C.D.); (Y.Y.)
| | - Yongmei Yu
- Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX 77030, USA; (Z.G.); (A.C.D.); (Y.Y.)
| | - Matthieu Huard
- Center for Regenerative Sports Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA; (A.L.); (M.H.); (X.G.)
| | - Chieh Tseng
- M.D. Anderson Cancer Center, The University of Texas Health Science Center, Houston, TX 77030, USA;
| | - Xueqin Gao
- Center for Regenerative Sports Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA; (A.L.); (M.H.); (X.G.)
| | - Johnny Huard
- Center for Regenerative Sports Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA; (A.L.); (M.H.); (X.G.)
- Correspondence: (J.H.); (M.G.K.); Tel.: +970-479-1595 (J.H.); +713-500-3146 (M.G.K.)
| | - Mikhail G. Kolonin
- Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX 77030, USA; (Z.G.); (A.C.D.); (Y.Y.)
- Correspondence: (J.H.); (M.G.K.); Tel.: +970-479-1595 (J.H.); +713-500-3146 (M.G.K.)
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13
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Scully T, Ettela A, LeRoith D, Gallagher EJ. Obesity, Type 2 Diabetes, and Cancer Risk. Front Oncol 2021; 10:615375. [PMID: 33604295 PMCID: PMC7884814 DOI: 10.3389/fonc.2020.615375] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/09/2020] [Indexed: 12/12/2022] Open
Abstract
Obesity and type 2 diabetes have both been associated with increased cancer risk and are becoming increasingly prevalent. Metabolic abnormalities such as insulin resistance and dyslipidemia are associated with both obesity and type 2 diabetes and have been implicated in the obesity-cancer relationship. Multiple mechanisms have been proposed to link obesity and diabetes with cancer progression, including an increase in insulin/IGF-1 signaling, lipid and glucose uptake and metabolism, alterations in the profile of cytokines, chemokines, and adipokines, as well as changes in the adipose tissue directly adjacent to the cancer sites. This review aims to summarize and provide an update on the epidemiological and mechanistic evidence linking obesity and type 2 diabetes with cancer, focusing on the roles of insulin, lipids, and adipose tissue.
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Affiliation(s)
- Tiffany Scully
- Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
| | - Abora Ettela
- Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
| | - Derek LeRoith
- Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
- Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
| | - Emily Jane Gallagher
- Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
- Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
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14
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Ruffolo C, Ferrara F, Trevellin E, Cataldo I, Fornasier C, Pozza A, Campo Dell'Orto M, Angriman I, Dei Tos AP, Bardini R, Massani M, Kotsafti A, Scarpa M. Can Vascular Endothelial Growth Factors and CD34 Expression Implement NICE (Narrow-Band Imaging International Colorectal Endoscopic) Classification in Colorectal Polypoid Lesion Diagnosis? Eur Surg Res 2020; 61:72-82. [PMID: 33080605 DOI: 10.1159/000510266] [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: 02/09/2020] [Accepted: 07/13/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF) is a subfamily of growth factors involved in angiogenesis; CD34+ cells are normally found in endothelial progenitor cells and endothelial cells of blood vessels. Colonic adenomatous polyps may not always be completely removable endoscopically, and a preoperative diagnosis might still be necessary. The aim of the study was to evaluate whether VEGF-A, VEGF-C and CD34 mRNA expression along colorectal carcinogenesis steps can implement NICE (Narrow-Band Imaging International Colorectal Endoscopic) classification in the diagnosis of malignancy in colorectal polypoid lesions. METHODS Seventy-one subjects with colonic adenoma or cancer who underwent screening narrow-band imaging (NBI) colonoscopy were prospectively enrolled in the MICCE1 project (Treviso center). Polyps were classified according to the NICE classification. Real-time RT-PCR for VEGF-A, VEGF-C and CD34 mRNA expression was performed. Nonparametric statistics, receiver-operating characteristic curve analysis and logistic multiple regression analysis were used. RESULTS VEGF-A and CD34 mRNA expression was significantly higher in sessile adenomas than in polypoid ones (p < 0.001 and p = 0.01, respectively). VEGF-A, VEGF-C and CD34 mRNA expression was significantly higher in adenocarcinoma than in adenoma (p = 0.01, p = 0.01 and p = 0.01, respectively). The accuracy of VEGF-A, VEGF-C and CD34 mRNA expression for prediction of malignancy was 0.79 (95% CI 0.65-0.90), 0.81 (95% CI 0.66-0.91) and 0.80 (95% CI 0.65-0.90), respectively, while the accuracy of the NICE classification was 0.85 (95% CI 0.72-0.94). The determination coefficient R2, which indicates the amount of the variability explained by a regression model, for NICE classification alone was 0.24 (p < 0.001). A regression model that included NICE classification and VEGF-C mRNA expression showed an R2 = 0.39 as well as a model including NICE classification and CD34 mRNA levels. CONCLUSIONS This study demonstrated that VEGF-C and CD34 mRNA levels might be useful to stratify colorectal polyps in different risk of progression classes by implementing the accuracy of the NICE classification. Studies on in vivo detection of these markers are warranted.
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Affiliation(s)
- Cesare Ruffolo
- General Surgery Unit, Padova University Hospital, Padova, Italy,
| | - Francesco Ferrara
- Gastroenterology Unit, Cà Foncello Regional Hospital, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | | | - Ivana Cataldo
- Pathology Unit, Cà Foncello Regional Hospital, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Caterina Fornasier
- Department of Surgery, Cà Foncello Regional Hospital, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Anna Pozza
- Department of Surgery, Cà Foncello Regional Hospital, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Marta Campo Dell'Orto
- Pathology Unit, Cà Foncello Regional Hospital, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Imerio Angriman
- General Surgery Unit, Padova University Hospital, Padova, Italy
| | - Angelo Paolo Dei Tos
- Pathology Unit, Cà Foncello Regional Hospital, Azienda ULSS2 Marca Trevigiana, Treviso, Italy.,Pathology Unit, University of Padova, Padova, Italy
| | - Romeo Bardini
- General Surgery Unit, Padova University Hospital, Padova, Italy
| | - Marco Massani
- Department of Surgery, Cà Foncello Regional Hospital, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Andromachi Kotsafti
- Laboratory of Advanced Translational Research, Veneto Institute of Oncology (IOV-IRCCS), Padova, Italy
| | - Marco Scarpa
- General Surgery Unit, Padova University Hospital, Padova, Italy
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15
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Castro-Oropeza R, Vazquez-Santillan K, Díaz-Gastelum C, Melendez-Zajgla J, Zampedri C, Ferat-Osorio E, Rodríguez-González A, Arriaga-Pizano L, Maldonado V. Adipose-derived mesenchymal stem cells promote the malignant phenotype of cervical cancer. Sci Rep 2020; 10:14205. [PMID: 32848147 PMCID: PMC7450089 DOI: 10.1038/s41598-020-69907-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 05/27/2020] [Indexed: 12/24/2022] Open
Abstract
Epidemiological studies indicate that obesity negatively affects the progression and treatment of cervical-uterine cancer. Recent evidence shows that a subpopulation of adipose-derived stem cells can alter cancer properties. In the present project, we described for the first time the impact of adipose-derived stem cells over the malignant behavior of cervical cancer cells. The transcriptome of cancer cells cultured in the presence of stem cells was analyzed using RNA-seq. Changes in gene expression were validated using digital-PCR. Bioinformatics tools were used to identify the main transduction pathways disrupted in cancer cells due to the presence of stem cells. In vitro and in vivo assays were conducted to validate cellular and molecular processes altered in cervical cancer cells owing to stem cells. Our results show that the expression of 95 RNAs was altered in cancer cells as a result of adipose-derived stem cells. Experimental assays indicate that stem cells provoke an increment in migration, invasion, angiogenesis, and tumorigenesis of cancer cells; however, no alterations were found in proliferation. Bioinformatics and experimental analyses demonstrated that the NF-kappa B signaling pathway is enriched in cancer cells due to the influence of adipose-derived stem cells. Interestingly, the tumor cells shift their epithelial to a mesenchymal morphology, which was reflected by the increased expression of specific mesenchymal markers. In addition, stem cells also promote a stemness phenotype in the cervical cancer cells. In conclusion, our results suggest that adipose-derived stem cells induce cervical cancer cells to acquire malignant features where NF-kappa B plays a key role.
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Affiliation(s)
- Rosario Castro-Oropeza
- Epigenetics Laboratories, National Institute of Genomic Medicine (INMEGEN), 14610, Mexico City, Mexico
| | - Karla Vazquez-Santillan
- Epigenetics Laboratories, National Institute of Genomic Medicine (INMEGEN), 14610, Mexico City, Mexico
| | - Claudia Díaz-Gastelum
- Epigenetics Laboratories, National Institute of Genomic Medicine (INMEGEN), 14610, Mexico City, Mexico
| | - Jorge Melendez-Zajgla
- Functional Genomics Laboratories, National Institute of Genomic Medicine (INMEGEN), 14610, Mexico City, Mexico
| | - Cecilia Zampedri
- Functional Genomics Laboratories, National Institute of Genomic Medicine (INMEGEN), 14610, Mexico City, Mexico
| | - Eduardo Ferat-Osorio
- Gastrosurgery Service, UMAE, National Medical Center "Siglo XXI", Mexican Institute of Social Security (IMSS), Mexico City, Mexico
| | - Arturo Rodríguez-González
- Gastrosurgery Service, UMAE, National Medical Center "Siglo XXI", Mexican Institute of Social Security (IMSS), Mexico City, Mexico
| | - Lourdes Arriaga-Pizano
- Medical Research Unit on Immunochemistry, National Medical Center "Siglo XXI", Mexican Institute of Social Security (IMSS), Mexico City, Mexico
| | - Vilma Maldonado
- Epigenetics Laboratories, National Institute of Genomic Medicine (INMEGEN), 14610, Mexico City, Mexico.
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16
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Cantini G, Di Franco A, Mannelli M, Scimè A, Maggi M, Luconi M. The Role of Metabolic Changes in Shaping the Fate of Cancer-Associated Adipose Stem Cells. Front Cell Dev Biol 2020; 8:332. [PMID: 32478073 PMCID: PMC7242628 DOI: 10.3389/fcell.2020.00332] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 04/16/2020] [Indexed: 12/18/2022] Open
Abstract
Adipose tissue in physiological and in metabolically altered conditions (obesity, diabetes, metabolic syndrome) strictly interacts with the developing tumors both systemically and locally. In addition to the cancer-associated fibroblasts, adipose cells have also recently been described among the pivotal actors of the tumor microenvironment responsible for sustaining tumor development and progression. In particular, emerging evidence suggests that not only the mature adipocytes but also the adipose stem cells (ASCs) are able to establish a strict crosstalk with the tumour cells, thus resulting in a reciprocal reprogramming of both the tumor and adipose components. This review will focus on the metabolic changes induced by this interaction as a driver of fate determination occurring in cancer-associated ASCs (CA-ASCs) to support the tumor metabolic requirements. We will showcase the major role played by the metabolic changes occurring in the adipose tumor microenvironment that regulates ASC fate and consequently cancer progression. Our new results will also highlight the CA-ASC response in vitro by using a coculture system of primary ASCs grown with cancer cells originating from two different types of adrenal cancers [adrenocortical carcinoma (ACC) and pheochromocytoma]. In conclusion, the different factors involved in this crosstalk process will be analyzed and their effects on the adipocyte differentiation potential and functions of CA-ASCs will be discussed.
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Affiliation(s)
- Giulia Cantini
- Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy
| | - Alessandra Di Franco
- Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy
| | - Massimo Mannelli
- Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy
| | - Anthony Scimè
- Molecular, Cellular and Integrative Physiology, Faculty of Health, York University, Toronto, ON, Canada
| | - Mario Maggi
- Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy.,Istituto Nazionale Biostrutture e Biosistemi, Rome, Italy.,Azienda Ospedaliero Universitaria Careggi, Florence, Italy
| | - Michaela Luconi
- Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy.,Istituto Nazionale Biostrutture e Biosistemi, Rome, Italy.,Azienda Ospedaliero Universitaria Careggi, Florence, Italy
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17
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Eckel-Mahan K, Ribas Latre A, Kolonin MG. Adipose Stromal Cell Expansion and Exhaustion: Mechanisms and Consequences. Cells 2020; 9:cells9040863. [PMID: 32252348 PMCID: PMC7226766 DOI: 10.3390/cells9040863] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 03/12/2020] [Accepted: 03/17/2020] [Indexed: 12/13/2022] Open
Abstract
Adipose tissue (AT) is comprised of a diverse number of cell types, including adipocytes, stromal cells, endothelial cells, and infiltrating leukocytes. Adipose stromal cells (ASCs) are a mixed population containing adipose progenitor cells (APCs) as well as fibro-inflammatory precursors and cells supporting the vasculature. There is growing evidence that the ability of ASCs to renew and undergo adipogenesis into new, healthy adipocytes is a hallmark of healthy fat, preventing disease-inducing adipocyte hypertrophy and the spillover of lipids into other organs, such as the liver and muscles. However, there is building evidence indicating that the ability for ASCs to self-renew is not infinite. With rates of ASC proliferation and adipogenesis tightly controlled by diet and the circadian clock, the capacity to maintain healthy AT via the generation of new, healthy adipocytes appears to be tightly regulated. Here, we review the contributions of ASCs to the maintenance of distinct adipocyte pools as well as pathogenic fibroblasts in cancer and fibrosis. We also discuss aging and diet-induced obesity as factors that might lead to ASC senescence, and the consequences for metabolic health.
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Affiliation(s)
- Kristin Eckel-Mahan
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA;
| | - Aleix Ribas Latre
- Helmholtz Institute for Metabolic, Obesity and Vascular Research Center, D-04103 Leipzig, Germany;
| | - Mikhail G. Kolonin
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX 77030, USA;
- Correspondence:
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18
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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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19
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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: 109] [Impact Index Per Article: 18.2] [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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20
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Otto W, Macrae F, Sierdziński J, Smaga J, Król M, Wilińska E, Zieniewicz K. Microsatellite instability and manifestations of angiogenesis in stage IV of sporadic colorectal carcinoma. Medicine (Baltimore) 2019; 98:e13956. [PMID: 30608431 PMCID: PMC6344194 DOI: 10.1097/md.0000000000013956] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 11/05/2018] [Accepted: 12/11/2018] [Indexed: 12/20/2022] Open
Abstract
Angiogenesis represents one of the critical mechanisms that facilitates carcinoma development. The study objective was to evaluate whether the microsatellite instability of colorectal carcinoma has impact on the angiogenesis activity in liver metastases.In a cohort of 80 randomly selected patients with stage IV colorectal carcinoma, 30% were recognized as microsatellite unstable (Microsatellite instability high-frequency (MSI-H)). The endothelial progenitor cell fraction (CD309+) was counted within the subpopulation of CD34+CD45+ cell and CD34+CD45- cells by flow cytometer. vascular endothelial growth factor (VEGF) factor levels were quantified in serum samples by enzyme-linked immunosorbent assay (ELISA). A control group consisted of 36 healthy volunteers. The relationship of genomic instability to angiogenesis activity was evaluated by multivariate analysis in comparison to the controls, adopting a P < .05 value as statistically significant.The expression of endothelial progenitor cells (EPCs) and VEGF was significantly higher in MSI-H compared to both microsatellite stability (MSS) patients and healthy controls (P < .008). Multi-parametric analysis showed microsatellite instability (OR=9.12, P < .01), metastases in both lobes (OR = 32.83, P < .001) and simultaneous metastases outside liver (OR = 8.32, P < .01), as independent factors associated with increased angiogenesis as assessed by measures of EPC and VEGF. A higher percentage of EPCs within the white blood cell fraction (total % EPCs / white blood cells (WBC)) and higher serum concentrations of VEGF were present in patients with MSI-H colorectal cancer, and not with MSS cancers (P < .001).MSI-H patients with colorectal cancer metastases are associated with the overexpression of circulating EPCs and VEGF, potentially driving angiogenesis. This should be considered in therapeutic decision-making.
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Affiliation(s)
| | - Finlay Macrae
- Department of Colorectal Medicine and Genetics, The Royal Melbourne Hospital, and Department of Medicine, The University of Melbourne, Australia
| | | | | | - Maria Król
- Department of Oncology, Hematology & Internal Medicine
| | - Ewa Wilińska
- Department of Pathology Central Teaching Hospital, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland
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21
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Obesity and gastrointestinal cancer: the interrelationship of adipose and tumour microenvironments. Nat Rev Gastroenterol Hepatol 2018; 15:699-714. [PMID: 30323319 DOI: 10.1038/s41575-018-0069-7] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Increasing recognition of an association between obesity and many cancer types exists, but how the myriad of local and systemic effects of obesity affect key cellular and non-cellular processes within the tumour microenvironment (TME) relevant to carcinogenesis, tumour progression and response to therapies remains poorly understood. The TME is a complex cellular environment in which the tumour exists along with blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, signalling molecules and the extracellular matrix. Obesity, in particular visceral obesity, might fuel the dysregulation of key pathways relevant to both the adipose microenvironment and the TME, which interact to promote carcinogenesis in at-risk epithelium. The tumour-promoting effects of obesity can occur at the local level as well as systemically via circulating inflammatory, growth factor and metabolic mediators associated with adipose tissue inflammation, as well as paracrine and autocrine effects. This Review explores key pathways linking visceral obesity and gastrointestinal cancer, including inflammation, hypoxia, altered stromal and immune cell function, energy metabolism and angiogenesis.
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22
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Louwen F, Ritter A, Kreis NN, Yuan J. Insight into the development of obesity: functional alterations of adipose-derived mesenchymal stem cells. Obes Rev 2018. [PMID: 29521029 DOI: 10.1111/obr.12679] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Obesity is associated with a variety of disorders including cardiovascular diseases, diabetes mellitus and cancer. Obesity changes the composition and structure of adipose tissue, linked to pro-inflammatory environment, endocrine/metabolic dysfunction, insulin resistance and oxidative stress. Adipose-derived mesenchymal stem cells (ASCs) have multiple functions like cell renewal, spontaneous repair and homeostasis in adipose tissue. In this review article, we have summarized the recent data highlighting that ASCs in obesity are defective in various functionalities and properties including differentiation, angiogenesis, motility, multipotent state, metabolism and immunomodulation. Inflammatory milieu, hypoxia and abnormal metabolites in obese tissue are crucial for impairing the functions of ASCs. Further work is required to explore the precise molecular mechanisms underlying its alterations and impairments. Based on these data, we suggest that deregulated ASCs, possibly also other mesenchymal stem cells, are important in promoting the development of obesity. Restoration of ASCs/mesenchymal stem cells might be an additional strategy to combat obesity and its associated diseases.
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Affiliation(s)
- F Louwen
- Department of Gynecology and Obstetrics, J. W. Goethe-University, Frankfurt, Germany
| | - A Ritter
- Department of Gynecology and Obstetrics, J. W. Goethe-University, Frankfurt, Germany
| | - N N Kreis
- Department of Gynecology and Obstetrics, J. W. Goethe-University, Frankfurt, Germany
| | - J Yuan
- Department of Gynecology and Obstetrics, J. W. Goethe-University, Frankfurt, Germany
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23
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Himbert C, Delphan M, Scherer D, Bowers LW, Hursting S, Ulrich CM. Signals from the Adipose Microenvironment and the Obesity-Cancer Link-A Systematic Review. Cancer Prev Res (Phila) 2018; 10:494-506. [PMID: 28864539 DOI: 10.1158/1940-6207.capr-16-0322] [Citation(s) in RCA: 128] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 06/06/2017] [Accepted: 07/11/2017] [Indexed: 12/13/2022]
Abstract
Obesity and its associated metabolic dysregulation are established risk factors for many cancers. However, the biologic mechanisms underlying this relationship remain incompletely understood. Given the rising rates of both obesity and cancer worldwide, and the challenges for many people to lose excess adipose tissue, a systematic approach to identify potential molecular and metabolic targets is needed to develop effective mechanism-based strategies for the prevention and control of obesity-driven cancer. Epidemiologic, clinical, and preclinical data suggest that within the growth-promoting, proinflammatory microenvironment accompanying obesity, crosstalk between adipose tissue (comprised of adipocytes, macrophages and other cells) and cancer-prone cells may occur via obesity-associated hormones, cytokines, and other mediators that have been linked to increased cancer risk and/or progression. We report here a systematic review on the direct "crosstalk" between adipose tissue and carcinomas in humans. We identified 4,641 articles with n = 20 human clinical studies, which are summarized as: (i) breast (n = 7); (ii) colorectal (n = 4); (iii) esophageal (n = 2); (iv) esophageal/colorectal (n = 1); (v) endometrial (n = 1); (vi) prostate (n = 4); and (vii) ear-nose-throat (ENT) cancer (n = 1). Findings from these clinical studies reinforce preclinical data and suggest organ-dependent crosstalk between adipose tissue and carcinomas via VEGF, IL6, TNFα, and other mechanisms. Moreover, visceral white adipose tissue plays a more central role, as it is more bioenergetically active and is associated with a more procancer secretome than subcutaneous adipose tissue. Efforts to eavesdrop and ultimately interfere with this cancer-enhancing crosstalk may lead to new targets and strategies for decreasing the burden of obesity-related cancers. Cancer Prev Res; 10(9); 494-506. ©2017 AACR.
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Affiliation(s)
- Caroline Himbert
- Huntsman Cancer Institute, Population Sciences, Salt Lake City, Utah.,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
| | - Mahmoud Delphan
- Huntsman Cancer Institute, Population Sciences, Salt Lake City, Utah.,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.,Exercise Immunology, Physical Education and Sport Sciences Department, Tarbiat Modares University, Tehran, Iran
| | - Dominique Scherer
- Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
| | - Laura W Bowers
- Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina
| | - Stephen Hursting
- Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina
| | - Cornelia M Ulrich
- Huntsman Cancer Institute, Population Sciences, Salt Lake City, Utah. .,Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
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24
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Lengyel E, Makowski L, DiGiovanni J, Kolonin MG. Cancer as a Matter of Fat: The Crosstalk between Adipose Tissue and Tumors. Trends Cancer 2018; 4:374-384. [PMID: 29709261 PMCID: PMC5932630 DOI: 10.1016/j.trecan.2018.03.004] [Citation(s) in RCA: 299] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 03/05/2018] [Accepted: 03/06/2018] [Indexed: 02/09/2023]
Abstract
Obesity has been linked to the increased risk and aggressiveness of many types of carcinoma. A state of chronic inflammation in adipose tissue (AT), resulting in genotoxic stress, may contribute to carcinogenesis and cancer initiation. Evidence that AT plays a role in cancer aggressiveness is solid and mounting. During cancer progression, tumor cells engage in a metabolic symbiosis with adjacent AT. Mature adipocytes provide adipokines and lipids to cancer cells, while stromal and immune cells from AT infiltrate carcinomas and locally secrete paracrine factors within the tumor microenvironment. This review focuses on the crosstalk between AT and tumor cells that promotes tumor growth and increases cellular lipid metabolism, metastasis, and chemoresistance.
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Affiliation(s)
- Ernst Lengyel
- Departments of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, IL, USA
| | - Liza Makowski
- Department of Medicine - Division of Hematology and Oncology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - John DiGiovanni
- Division of Pharmacology and Toxicology, College of Pharmacy, Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX, USA
| | - Mikhail G Kolonin
- The Brown Foundation, Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, USA.
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25
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Ramirez AG, Parma DL, Muñoz E, Mendoza KD, Harb C, Holden AEC, Wargovich M. An anti-inflammatory dietary intervention to reduce breast cancer recurrence risk: Study design and baseline data. Contemp Clin Trials 2017; 57:1-7. [PMID: 28342988 PMCID: PMC6110085 DOI: 10.1016/j.cct.2017.03.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 03/10/2017] [Accepted: 03/13/2017] [Indexed: 11/30/2022]
Abstract
U.S. breast cancer survivors (BCSs) are expected to increase to 4 million in the next 5-10years. Cancer recurrence risk is highest among obese survivors. Inflammatory (Pro-I) biomarkers including C-reactive protein (CRP), Interleukins -3, -6, and -8 (IL-3, IL-6, IL-8), and Tumor Necrosis Factor (TNF)-α have been associated with cancer recurrence risk. Nutritional interventions aimed at reducing inflammation (INF) may contribute to reduced cancer recurrence risk, but studies have been limited to animal models. The goals of this one-year, culinary-based, pilot intervention were to: 1) decrease Pro-I biomarkers and increase anti-inflammatory (AI) cytokine, IL-10, by promoting AI food incorporation into BCS diets; and 2) examine intervention effects on cancer risk factors including body mass index (BMI) and circulating adipose stromal cells (ASCs). A total of 153 BCSs were recruited. Overweight and obese women aged 18 or older were randomized into Intervention (IG; n=76) and Control (CG; n=77) groups. CG received monthly nutritional brochures from the American Institute for Cancer Research. IG attended 6 monthly workshops (lectures on AI topics and chef-prepared food demonstrations), and received monthly newsletters and telephone calls incorporating Motivational Interviewing. At baseline, 6- and 12-month assessments, fasting serum was assayed for Pro-I/AI marker and ASC levels. Using R and Stata version 14 (Stata Corp, 2015), no significant differences were found between groups on baseline demographic variables. Correlations between serum cytokine levels, BMI, % body fat, ASCs, and self-reported variables are discussed.
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Affiliation(s)
- Amelie G Ramirez
- Department of Epidemiology and Biostatistics, The University of Texas Health Science Center at San Antonio, USA.
| | - Dorothy Long Parma
- Department of Epidemiology and Biostatistics, The University of Texas Health Science Center at San Antonio, USA
| | - Edgar Muñoz
- Department of Epidemiology and Biostatistics, The University of Texas Health Science Center at San Antonio, USA
| | - Kristin D Mendoza
- Department of Epidemiology and Biostatistics, The University of Texas Health Science Center at San Antonio, USA
| | - Crystel Harb
- Department of Epidemiology and Biostatistics, The University of Texas Health Science Center at San Antonio, USA
| | - Alan E C Holden
- Department of Epidemiology and Biostatistics, The University of Texas Health Science Center at San Antonio, USA
| | - Michael Wargovich
- Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, USA
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26
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Daquinag AC, Dadbin A, Snyder B, Wang X, Sahin AA, Ueno NT, Kolonin MG. Non-glycanated Decorin Is a Drug Target on Human Adipose Stromal Cells. MOLECULAR THERAPY-ONCOLYTICS 2017; 6:1-9. [PMID: 28607949 PMCID: PMC5458115 DOI: 10.1016/j.omto.2017.05.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 05/10/2017] [Indexed: 12/28/2022]
Abstract
Adipose stromal cells (ASCs) have been identified as a mesenchymal cell population recruited from white adipose tissue (WAT) by tumors and supporting cancer progression. We have previously reported the existence of a non-glycanated decorin isoform (ngDCN) marking mouse ASCs. We identified a peptide CSWKYWFGEC that binds to ngDCN and hence can serve as a vehicle for ASC-directed therapy delivery. We used hunter-killer peptides composed of CSWKYWFGEC and a pro-apoptotic moiety to deplete ASCs and suppress growth of mouse tumors. Here, we report the discovery of the human non-glycanated decorin isoform. We show that CSWKYWFGEC can be used as a probe to identify ASCs in human WAT and tumors. We demonstrate that human ngDCN is expressed on ASC surface. Finally, we validate ngDCN as a molecular target for pharmacological depletion of human ASCs with hunter-killer peptides. We propose that ngDCN-targeting agents could be developed for obesity and cancer treatment.
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Affiliation(s)
- Alexes C Daquinag
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Ali Dadbin
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Brad Snyder
- Department of Surgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Xiaoping Wang
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Aysegul A Sahin
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Naoto T Ueno
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Mikhail G Kolonin
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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27
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Pieper IL, Smith R, Bishop JC, Aldalati O, Chase AJ, Morgan G, Thornton CA. Isolation of Mesenchymal Stromal Cells From Peripheral Blood of ST Elevation Myocardial Infarction Patients. Artif Organs 2017; 41:654-666. [DOI: 10.1111/aor.12829] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Revised: 06/16/2016] [Accepted: 06/30/2016] [Indexed: 12/18/2022]
Affiliation(s)
| | - Rachel Smith
- Swansea University Medical School, Institute of Life Science
| | | | - Omar Aldalati
- Regional Cardiac Centre, Morriston Hospital; Swansea Wales UK
| | - Alex J. Chase
- Regional Cardiac Centre, Morriston Hospital; Swansea Wales UK
| | - Gareth Morgan
- Swansea University Medical School, Institute of Life Science
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28
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Zhang Y, Kolonin MG. Cytokine signaling regulating adipose stromal cell trafficking. Adipocyte 2016; 5:369-374. [PMID: 27994950 DOI: 10.1080/21623945.2016.1220452] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 07/27/2016] [Accepted: 07/28/2016] [Indexed: 01/31/2023] Open
Abstract
Adipocyte progenitors, known as adipose stromal cells (ASC), can become mobilized, recruited by tumors, and contribute to cancer progression. Mechanisms underlying ASC trafficking have remained obscure. We recently reported that CXCL1 expressed by cancer cells chemoattracts ASC expressing CXCR1 in obesity. As a candidate mechanism of CXCL1 activation, we identified interleukin (IL)-22, systemic circulation of which is increased in obesity. It has been reported that IL-22 signaling through IL-22R is upstream of CXCL1. Here, we provide evidence that IL-22 expression by leukocytes infiltrating WAT and IL-22R expression by tumors is obesity-dependent. We propose that obesity-associated adipocyte death and the resulting recruitment of leukocytes triggers the IL-22 signaling cascade that induces CXCL1 secretion by cancer cells responsible for ASC trafficking to tumors.
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29
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Zhang T, Tseng C, Zhang Y, Sirin O, Corn PG, Li-Ning-Tapia EM, Troncoso P, Davis J, Pettaway C, Ward J, Frazier ML, Logothetis C, Kolonin MG. CXCL1 mediates obesity-associated adipose stromal cell trafficking and function in the tumour microenvironment. Nat Commun 2016; 7:11674. [PMID: 27241286 PMCID: PMC4895055 DOI: 10.1038/ncomms11674] [Citation(s) in RCA: 115] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 04/19/2016] [Indexed: 12/25/2022] Open
Abstract
White adipose tissue (WAT) overgrowth in obesity is linked with increased aggressiveness of certain cancers. Adipose stromal cells (ASCs) can become mobilized from WAT, recruited by tumours and promote cancer progression. Mechanisms underlying ASC trafficking are unclear. Here we demonstrate that chemokines CXCL1 and CXCL8 chemoattract ASC by signalling through their receptors, CXCR1 and CXCR2, in cell culture models. We further show that obese patients with prostate cancer have increased epithelial CXCL1 expression. Concomitantly, we observe that cells with ASC phenotype are mobilized and infiltrate tumours in obese patients. Using mouse models, we show that the CXCL1 chemokine gradient is required for the obesity-dependent tumour ASC recruitment, vascularization and tumour growth promotion. We demonstrate that αSMA expression in ASCs is induced by chemokine signalling and mediates the stimulatory effects of ASCs on endothelial cells. Our data suggest that ASC recruitment to tumours, driven by CXCL1 and CXCL8, promotes prostate cancer progression. Adipose stromal cells (ASC) have been shown to migrate to tumours and promote tumour growth. Using animal models and human tissue samples, the authors show here that ASC recruitment to prostate cancers is mediated by the chemokine CXCL1, which is secreted from tumour cells, and acts on CXCR1 on ASCs.
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Affiliation(s)
- Tao Zhang
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA
| | - Chieh Tseng
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA
| | - Yan Zhang
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA
| | - Olga Sirin
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA
| | - Paul G Corn
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Elsa M Li-Ning-Tapia
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Patricia Troncoso
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - John Davis
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Curtis Pettaway
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - John Ward
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Marsha L Frazier
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Christopher Logothetis
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Mikhail G Kolonin
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA
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30
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Tseng C, Kolonin MG. Proteolytic Isoforms of SPARC Induce Adipose Stromal Cell Mobilization in Obesity. Stem Cells 2015; 34:174-90. [PMID: 26381424 DOI: 10.1002/stem.2192] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 08/14/2015] [Indexed: 12/30/2022]
Abstract
Adipose stromal cells (ASC) are mesenchymal adipocyte progenitors that reside in the peri-endothelium of fat tissue. ASC mobilization and migration accompany white adipose tissue (WAT) remodeling and pathological conditions. Mechanisms regulating ASC trafficking are largely unknown. We previously reported that binding of the matricellular protein secreted protein acidic and rich in cysteine (SPARC) to β1 integrin on ASC surface induces their motility. Here, we show that SPARC is required for ASC mobilization. We report two SPARC proteolytic isoforms, C-SPARC (lacking the N terminus) and N-SPARC (lacking the C terminus), generated in mesenteric WAT of obese mice. C-SPARC, but not N-SPARC, binds to β1 integrin on ASC, while N-SPARC preferentially binds to the extracellular matrix (ECM) and blocks ECM/integrin interaction. Interestingly, both C-SPARC and N-SPARC induce ASC deadhesion from the ECM, which is associated with modulation of integrin-dependent FAK-ERK signaling and integrin-independent ILK-Akt signaling. We show that these SPARC isoforms, acting on ASC through distinct mechanisms, have an additive effect in inducing ASC migration.
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Affiliation(s)
- Chieh Tseng
- Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, 77030, USA
| | - Mikhail G Kolonin
- Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, 77030, USA
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31
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Strong AL, Burow ME, Gimble JM, Bunnell BA. Concise review: The obesity cancer paradigm: exploration of the interactions and crosstalk with adipose stem cells. Stem Cells 2015; 33:318-26. [PMID: 25267443 DOI: 10.1002/stem.1857] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 07/28/2014] [Accepted: 08/06/2014] [Indexed: 01/04/2023]
Abstract
With the recognition of obesity as a global health crisis, researchers have devoted greater effort to defining and understanding the pathophysiological molecular pathways regulating the biology of adipose tissue and obesity. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, has been linked to an increased incidence and aggressiveness of colon, hematological, prostate, and postmenopausal breast cancers. The increased morbidity and mortality of obesity-associated cancers have been attributed to higher levels of hormones, adipokines, and cytokines secreted by the adipose tissue. The increased amount of adipose tissue also results in higher numbers of adipose stromal/stem cells (ASCs). These ASCs have been shown to impact cancer progression directly through several mechanisms, including the increased recruitment of ASCs to the tumor site and increased production of cytokines and growth factors by ASCs and other cells within the tumor stroma. Emerging evidence indicates that obesity induces alterations in the biologic properties of ASCs, subsequently leading to enhanced tumorigenesis and metastasis of cancer cells. This review will discuss the links between obesity and cancer tumor progression, including obesity-associated changes in adipose tissue, inflammation, adipokines, and chemokines. Novel topics will include a discussion of the contribution of ASCs to this complex system with an emphasis on their role in the tumor stroma. The reciprocal and circular feedback loop between obesity and ASCs as well as the mechanisms by which ASCs from obese patients alter the biology of cancer cells and enhance tumorigenesis will be discussed.
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Affiliation(s)
- Amy L Strong
- Center for Stem Cell Research and Regenerative Medicine
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Abstract
PURPOSE OF REVIEW There is emerging evidence that obesity is associated with an increase in the incidence, severity, and mortality from different types of cancer, including postmenopausal breast cancer. Here, we discuss the role of white adipose tissue (WAT) cells and of related soluble factors in the local and metastatic growth of this neoplastic disease. Moreover, we discuss the recent increase in the use of WAT-derived progenitor cells in breast cancer patients to enhance the quality of breast reconstruction and the related risks. RECENT FINDINGS In several murine models, WAT cells and progenitors were found to have cooperative roles in promoting local breast cancer. Moreover, they were found to contribute to adipocytes and pericytes supporting the cancer vasculature, and stimulated the metastatic progression of breast cancer. There are some clinically retrospective data showing a significant increase in the frequency of intraepithelial neoplasia in patients who received a lipofilling procedure for breast reconstruction compared with controls. SUMMARY Preclinical models and clinical studies are urgently needed to investigate how to inhibit the tumor-promoting activity of WAT cells and progenitors. The risks associated with the use of WAT cells for breast reconstructions should be better investigated retrospectively and prospectively.
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Petit JY, Maisonneuve P, Rotmensz N, Bertolini F, Clough KB, Sarfati I, Gale KL, Macmillan RD, Rey P, Benyahi D, Rietjens M. Safety of Lipofilling in Patients with Breast Cancer. Clin Plast Surg 2015; 42:339-44, viii. [DOI: 10.1016/j.cps.2015.03.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Increased pre-surgical numbers of endothelial progenitor cells and circulating endothelial cells in colorectal cancer fail to predict outcome. Int J Colorectal Dis 2015; 30:315-21. [PMID: 25598043 DOI: 10.1007/s00384-014-2116-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/23/2014] [Indexed: 02/04/2023]
Abstract
INTRODUCTION The endothelium and angiogenesis are therapeutic targets in cancer. Response to treatment may be assessed by laboratory plasma markers such as circulating endothelial cells (CECs), endothelial progenitor cells (EPCs), von Willebrand factor (vWf), soluble E selectin, vascular endothelial growth factor (VEGF) and angiogenin. We hypothesised that these markers, obtained before surgery, would predict 2-year outcome after surgery with or without anti-angiogenic therapy for colorectal cancer (CRC). METHODS We recruited 154 patients with CRC, of whom 51 were treated with surgery alone, 74 were treated with standard chemotherapy (5-fluorouracil) and 29 were treated with standard chemotherapy plus anti-VEGF therapy (Avastin). Peripheral blood was taken before surgery. CD34(+)/CD45(-)/CD146(+) CECs and CD34(+)/CD45(-)/CD309 [KDR](+) EPCs were measured by flow cytometry and plasma markers by ELISA. RESULTS After a mean of 2.1 years follow-up (range 1.9-2.3 years), 52 of the patients (33.7 %) experienced a poor outcome (radiological and/or histological evidence of tumour spread or recurrence, or death [n = 26]). In univariate analysis, poor outcome was linked to Dukes' stage (p < 0.001), American Joint Committee on Cancer (AJCC) stage (p < 0.001), type of treatment (surgery alone, standard chemotherapy with or without anti-antigenic therapy) (p = 0.047), CECs (p < 0.02) and EPCs (p < 0.01). In subsequent binary logistic regression analysis, only Dukes' stage (hazard ratio 2.3, 95 % confidence interval 1.0-5.3, p = 0.047) and modified AJCC stage (4.62, 1.88-11.33, p < 0.001) predicted a poor outcome. CONCLUSION Endothelial cell markers (CECs, EPCs, vWf, soluble E selectin) and growth factors (VEGF and angiogenin), measured before surgery, have nothing extra to offer in predicting 2-year outcome in colorectal cancer when compared to Dukes' or AJCC stage.
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35
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Abd Elmageed ZY, Yang Y, Thomas R, Ranjan M, Mondal D, Moroz K, Fang Z, Rezk BM, Moparty K, Sikka SC, Sartor O, Abdel-Mageed AB. Neoplastic reprogramming of patient-derived adipose stem cells by prostate cancer cell-associated exosomes. Stem Cells 2015; 32:983-97. [PMID: 24715691 DOI: 10.1002/stem.1619] [Citation(s) in RCA: 234] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2013] [Revised: 11/19/2013] [Accepted: 11/21/2013] [Indexed: 12/19/2022]
Abstract
Emerging evidence suggests that mesenchymal stem cells (MSCs) are often recruited to tumor sites but their functional significance in tumor growth and disease progression remains elusive. Herein we report that prostate cancer (PC) cell microenvironment subverts PC patient adipose-derived stem cells (pASCs) to undergo neoplastic transformation. Unlike normal ASCs, the pASCs primed with PC cell conditioned media (CM) formed prostate-like neoplastic lesions in vivo and reproduced aggressive tumors in secondary recipients. The pASC tumors acquired cytogenetic aberrations and mesenchymal-to-epithelial transition and expressed epithelial, neoplastic, and vasculogenic markers reminiscent of molecular features of PC tumor xenografts. Our mechanistic studies revealed that PC cell-derived exosomes are sufficient to recapitulate formation of prostate tumorigenic mimicry generated by CM-primed pASCs in vivo. In addition to downregulation of the large tumor suppressor homolog2 and the programmed cell death protein 4, a neoplastic transformation inhibitor, the tumorigenic reprogramming of pASCs was associated with trafficking by PC cell-derived exosomes of oncogenic factors, including H-ras and K-ras transcripts, oncomiRNAs miR-125b, miR-130b, and miR-155 as well as the Ras superfamily of GTPases Rab1a, Rab1b, and Rab11a. Our findings implicate a new role for PC cell-derived exosomes in clonal expansion of tumors through neoplastic reprogramming of tumor tropic ASCs in cancer patients.
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Affiliation(s)
- Zakaria Y Abd Elmageed
- Department of Urology, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
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36
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Stem cells from adipose tissue and breast cancer: hype, risks and hope. Br J Cancer 2015; 112:419-23. [PMID: 25584493 PMCID: PMC4453662 DOI: 10.1038/bjc.2014.657] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Revised: 10/21/2014] [Accepted: 12/03/2014] [Indexed: 12/20/2022] Open
Abstract
Several recent papers have generated new hope about the use of white adipose tissue (WAT)-derived progenitor cells for soft tissue reconstruction in a variety of diseases including breast cancer (BC), a procedure that is increasingly used worldwide. We revised the available literature about WAT cells and BC. In the BC field, we believe that the hype for the exciting results in terms of WAT progenitor cell engraftment and tissue augmentation should be tempered when considering the recent and abundant preclinical studies, indicating that WAT progenitors may promote BC growth and metastasis. White adipose tissue progenitors can contribute to tumour vessels, pericytes and adipocytes, and were found to stimulate local and metastatic BC progression in several murine models. Moreover, there are clinical retrospective data showing a significant increase in the local recurrence frequency in patients with intraepithelial neoplasia who received a lipofilling procedure for breast reconstruction compared with controls. Retrospective and prospective clinical trials are warranted to investigate in depth the safety of this procedure in BC. Preclinical models should be used to find mechanisms able to inhibit the tumour-promoting activity of WAT progenitors while sparing their tissue reconstruction potential.
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37
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Ramcharan KS, Lip GYH, Stonelake PS, Blann AD. Effect of standard chemotherapy and antiangiogenic therapy on plasma markers and endothelial cells in colorectal cancer. Br J Cancer 2014; 111:1742-9. [PMID: 25211664 PMCID: PMC4453738 DOI: 10.1038/bjc.2014.491] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Revised: 07/29/2014] [Accepted: 08/13/2014] [Indexed: 01/04/2023] Open
Abstract
Introduction: The importance of the endothelium in angiogenesis and cancer is undisputed, and its integrity may be assessed by laboratory markers such as circulating endothelial cells (CECs), endothelial progenitor cells (EPCs), plasma von Willebrand factor (vWf), soluble E selectin, vascular endothelial growth factor (VEGF) and angiogenin. Antiantigenic therapy may be added to standard cytotoxic chemotherapy as a new treatment modality. We hypothesised that additional antiangiogenic therapy acts in a contrasting manner to that of standard chemotherapy on the laboratory markers. Methods: We recruited 68 patients with CRC, of whom 16 were treated with surgery alone, 32 were treated with surgery followed by standard chemotherapy (5-flurouracil), and 20 were treated with surgery followed by standard chemotherapy plus anti-VEGF therapy (Avastin). Peripheral blood was taken before surgery, and again 3 months and 6 months later. CD34+/CD45−/CD146+ CECs and CD34+/CD45−/CD309[KDR]+ EPCs were measured by flow cytometry, plasma markers by ELISA. Results: In each of the three groups, CECs and EPCs fell at 3 months but were back at pre-surgery levels at 6 months (P<0.05). VEGF was lower in both 3-and 6-month samples in the surgery-only and surgery plus standard chemotherapy groups (P<0.05), but in those on surgery followed by standard chemotherapy plus anti-VEGF therapy, low levels at 3 months (P<0.01) increased to pre-surgery levels at 6 months. In those having surgery and standard chemotherapy, soluble E selectin was lower, whereas angiogenin was higher at 6 months than at baseline (both P<0.05). Conclusions: We found disturbances in endotheliod cells regardless of treatment, whereas VEGF returned to levels before surgery in those on antiangiogenic therapy. These observations may have clinical and pathophysiological implications.
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Affiliation(s)
- K S Ramcharan
- 1] Department of Medicine, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Dudley Road, Birmingham B18 7QH, UK [2] Department of Surgery, Russell's Hall Hospital, Dudley DY1 2HQ, UK
| | - G Y H Lip
- Department of Medicine, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Dudley Road, Birmingham B18 7QH, UK
| | - P S Stonelake
- Department of Surgery, Russell's Hall Hospital, Dudley DY1 2HQ, UK
| | - A D Blann
- Department of Medicine, University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Dudley Road, Birmingham B18 7QH, UK
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Shah R, Jones E, Vidart V, Kuppen PJK, Conti JA, Francis NK. Biomarkers for early detection of colorectal cancer and polyps: systematic review. Cancer Epidemiol Biomarkers Prev 2014; 23:1712-28. [PMID: 25004920 DOI: 10.1158/1055-9965.epi-14-0412] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
There is growing interest in early detection of colorectal cancer as current screening modalities lack compliance and specificity. This study systematically reviewed the literature to identify biomarkers for early detection of colorectal cancer and polyps. Literature searches were conducted for relevant papers since 2007. Human studies reporting on early detection of colorectal cancer and polyps using biomarkers were included. Methodologic quality was evaluated, and sensitivity, specificity, and the positive predictive value (PPV) were reported. The search strategy identified 3,348 abstracts. A total of 44 papers, examining 67 different tumor markers, were included. Overall sensitivities for colorectal cancer detection by fecal DNA markers ranged from 53% to 87%. Combining fecal DNA markers increased the sensitivity of colorectal cancer and adenoma detection. Canine scent detection had a sensitivity of detecting colorectal cancer of 99% and specificity of 97%. The PPV of immunochemical fecal occult blood test (iFOBT) is 1.26%, compared with 0.31% for the current screening method of guaiac fecal occult blood test (gFOBT). A panel of serum protein biomarkers provides a sensitivity and specificity above 85% for all stages of colorectal cancer, and a PPV of 0.72%. Combinations of fecal and serum biomarkers produce higher sensitivities, specificities, and PPVs for early detection of colorectal cancer and adenomas. Further research is required to validate these biomarkers in a well-structured population-based study.
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Affiliation(s)
- Reena Shah
- Yeovil District Hospital NHS Trust, Yeovil, United Kingdom.
| | - Emma Jones
- University of Leicester, Leicester, United Kingdom
| | | | - Peter J K Kuppen
- Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
| | - John A Conti
- Portsmouth Hospital NHS Trust, Portsmouth, United Kingdom. University of Southampton, Southampton, United Kingdom
| | - Nader K Francis
- Yeovil District Hospital NHS Trust, Yeovil, United Kingdom. University of Bristol, Bristol, United Kingdom
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Yamaguchi DT. “Ins” and “Outs” of mesenchymal stem cell osteogenesis in regenerative medicine. World J Stem Cells 2014; 6:94-110. [PMID: 24772237 PMCID: PMC3999785 DOI: 10.4252/wjsc.v6.i2.94] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Repair and regeneration of bone requires mesenchymal stem cells that by self-renewal, are able to generate a critical mass of cells with the ability to differentiate into osteoblasts that can produce bone protein matrix (osteoid) and enable its mineralization. The number of human mesenchymal stem cells (hMSCs) diminishes with age and ex vivo replication of hMSCs has limited potential. While propagating hMSCs under hypoxic conditions may maintain their ability to self-renew, the strategy of using human telomerase reverse transcriptase (hTERT) to allow for hMSCs to prolong their replicative lifespan is an attractive means of ensuring a critical mass of cells with the potential to differentiate into various mesodermal structural tissues including bone. However, this strategy must be tempered by the oncogenic potential of TERT-transformed cells, or their ability to enhance already established cancers, the unknown differentiating potential of high population doubling hMSCs and the source of hMSCs (e.g., bone marrow, adipose-derived, muscle-derived, umbilical cord blood, etc.) that may provide peculiarities to self-renewal, differentiation, and physiologic function that may differ from non-transformed native cells. Tissue engineering approaches to use hMSCs to repair bone defects utilize the growth of hMSCs on three-dimensional scaffolds that can either be a base on which hMSCs can attach and grow or as a means of sequestering growth factors to assist in the chemoattraction and differentiation of native hMSCs. The use of whole native extracellular matrix (ECM) produced by hMSCs, rather than individual ECM components, appear to be advantageous in not only being utilized as a three-dimensional attachment base but also in appropriate orientation of cells and their differentiation through the growth factors that native ECM harbor or in simulating growth factor motifs. The origin of native ECM, whether from hMSCs from young or old individuals is a critical factor in “rejuvenating” hMSCs from older individuals grown on ECM from younger individuals.
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40
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A module of human peripheral blood mononuclear cell transcriptional network containing primitive and differentiation markers is related to specific cardiovascular health variables. PLoS One 2014; 9:e95124. [PMID: 24759906 PMCID: PMC3997360 DOI: 10.1371/journal.pone.0095124] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 03/24/2014] [Indexed: 12/30/2022] Open
Abstract
Peripheral blood mononuclear cells (PBMCs), including rare circulating stem and progenitor cells (CSPCs), have important yet poorly understood roles in the maintenance and repair of blood vessels and perfused organs. Our hypothesis was that the identities and functions of CSPCs in cardiovascular health could be ascertained by analyzing the patterns of their co-expressed markers in unselected PBMC samples. Because gene microarrays had failed to detect many stem cell-associated genes, we performed quantitative real-time PCR to measure the expression of 45 primitive and tissue differentiation markers in PBMCs from healthy and hypertensive human subjects. We compared these expression levels to the subjects' demographic and cardiovascular risk factors, including vascular stiffness. The tested marker genes were expressed in all of samples and organized in hierarchical transcriptional network modules, constructed by a bottom-up approach. An index of gene expression in one of these modules (metagene), defined as the average standardized relative copy numbers of 15 pluripotency and cardiovascular differentiation markers, was negatively correlated (all p<0.03) with age (R2 = −0.23), vascular stiffness (R2 = −0.24), and central aortic pressure (R2 = −0.19) and positively correlated with body mass index (R2 = 0.72, in women). The co-expression of three neovascular markers was validated at the single-cell level using mRNA in situ hybridization and immunocytochemistry. The overall gene expression in this cardiovascular module was reduced by 72±22% in the patients compared with controls. However, the compactness of both modules was increased in the patients' samples, which was reflected in reduced dispersion of their nodes' degrees of connectivity, suggesting a more primitive character of the patients' CSPCs. In conclusion, our results show that the relationship between CSPCs and vascular function is encoded in modules of the PBMCs transcriptional network. Furthermore, the coordinated gene expression in these modules can be linked to cardiovascular risk factors and subclinical cardiovascular disease; thus, this measure may be useful for their diagnosis and prognosis.
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41
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Ghosh S, Hughes D, Parma DL, Ramirez A, Li R. Association of obesity and circulating adipose stromal cells among breast cancer survivors. Mol Biol Rep 2014; 41:2907-16. [PMID: 24458825 DOI: 10.1007/s11033-014-3146-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Accepted: 01/13/2014] [Indexed: 12/26/2022]
Abstract
A positive association of obesity with breast cancer incidence and mortality is well established. Recent reports indicate that adipose stromal cells (ASCs) play an important role in breast cancer development and progression by producing estrogens and tumor-promoting cytokines. Furthermore, circulating ASCs have been uniquely detected in obese individuals, which is likely due to increased tissue remodeling and cell mobilization. The number of circulating ASCs is even more prominent in obese patients with colon and prostate cancers, both of which are exacerbated by obesity. To determine whether a similar association exists for breast cancer, we collected blood samples from a cohort of breast cancer survivors and enumerated circulating ASCs by flow cytometry on the basis of the previously established ASC-associated immunophenotype (CD34+/CD31-/CD45-). We found significantly higher levels of circulating ASCs (p<0.001) in breast cancer survivors with body mass index (BMI)≥30 kg/m2 than their non-obese counterparts (BMI<30). We also compared circulating ASCs before and after exercise of only the obese subjects enrolled in a 6-month individualized exercise program, but found no statistically significant difference, likely due to limited number of subjects in the study. Our findings suggest that circulating ASCs can serve as a potential biomarker for future studies of the impacts of obesity and physical activity on breast cancer recurrence and survival.
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Affiliation(s)
- Sagar Ghosh
- Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA
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De Wever O, Van Bockstal M, Mareel M, Hendrix A, Bracke M. Carcinoma-associated fibroblasts provide operational flexibility in metastasis. Semin Cancer Biol 2014; 25:33-46. [PMID: 24406210 DOI: 10.1016/j.semcancer.2013.12.009] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Revised: 12/20/2013] [Accepted: 12/30/2013] [Indexed: 01/11/2023]
Abstract
Malignant cancer cells do not act as lone wolves to achieve metastasis, as they exist within a complex ecosystem consisting of an extracellular matrix scaffold populated by carcinoma-associated fibroblasts (CAFs), endothelial cells and immune cells. We recognize local (primary tumor) and distant ecosystems (metastasis). CAFs, also termed myofibroblasts, may have other functions in the primary tumor versus the metastasis. Cellular origin and tumor heterogeneity lead to the expression of specific markers. The molecular characteristics of a CAF remain in evolution since CAFs show operational flexibility. CAFs respond dynamically to a cancer cell's fluctuating demands by shifting profitable signals necessary in metastasis. Local, tissue-resident fibroblasts and mesenchymal stem cells (MSCs) coming from reservoir sites such as bone marrow and adipose tissue are the main progenitor cells of CAFs. CAFs may induce awakening from metastatic dormancy, a major cause of cancer-specific death. Cancer management protocols influence CAF precursor recruitment and CAF activation. Since CAF signatures represent early changes in metastasis, including formation of pre-metastatic niches, we discuss whether liquid biopsies, including exosomes, may detect and monitor CAF reactions allowing optimized prognosis of cancer patients.
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Affiliation(s)
- Olivier De Wever
- Laboratory of Experimental Cancer Research, Department of Radiotherapy and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium.
| | | | - Marc Mareel
- Laboratory of Experimental Cancer Research, Department of Radiotherapy and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium
| | - An Hendrix
- Laboratory of Experimental Cancer Research, Department of Radiotherapy and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium
| | - Marc Bracke
- Laboratory of Experimental Cancer Research, Department of Radiotherapy and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium
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43
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Stolzenberg-Solomon RZ, Schairer C, Moore S, Hollenbeck A, Silverman DT. Lifetime adiposity and risk of pancreatic cancer in the NIH-AARP Diet and Health Study cohort. Am J Clin Nutr 2013; 98:1057-65. [PMID: 23985810 PMCID: PMC3778860 DOI: 10.3945/ajcn.113.058123] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The association of excess body weight across a lifetime with pancreatic cancer has not been examined extensively. OBJECTIVE We determined the association for body mass index (BMI) at different ages and adiposity duration and gain with incident pancreatic adenocarcinoma in the NIH-AARP Diet and Health Study cohort. DESIGN Participants aged 50-71 y completed questionnaires at baseline (1995-1996) and 6 months later that queried height and weight history. We calculated HRs and 95% CIs by using Cox proportional hazards models adjusted for age, smoking, sex, and intakes of energy and total fat. RESULTS Over an average follow-up of 10.5 y, 1206 and 2122 pancreatic cancer cases were identified in the subcohort who completed the second questionnaire (n = 273,975) and the baseline cohort (n = 501,698), respectively. Compared with normal weight, overweight or obesity at ages 18, 35, 50, or >50 y (baseline BMI) was significantly associated with pancreatic cancer, with HRs ranging from 1.15 to 1.53. A longer duration of BMI (in kg/m(2)) >25.0 was significantly associated with pancreatic cancer (overall HR per 10-y increment of duration: 1.06; 95% CI: 1.02, 1.09), with individuals who reported diabetes having the greatest risk (HR per 10-y increment of duration: 1.18; 95% CI: 1.05, 1.32; P-interaction = 0.01) and rates. A substantial gain in adiposity (>10 kg/m(2)) after age 50 y was significantly associated with increased pancreatic cancer risk. The etiologic fraction of pancreatic cancer explained by adiposity at any age was 14% overall and 21% in never smokers. CONCLUSION Overweight and obesity at any age are associated with increased pancreatic cancer.
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Affiliation(s)
- Rachael Z Stolzenberg-Solomon
- Branches of Nutritional Epidemiology, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD
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44
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Strong AL, Semon JA, Strong TA, Santoke TT, Zhang S, McFerrin HE, Gimble JM, Bunnell BA. Obesity-associated dysregulation of calpastatin and MMP-15 in adipose-derived stromal cells results in their enhanced invasion. Stem Cells 2013; 30:2774-83. [PMID: 22969001 DOI: 10.1002/stem.1229] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 08/21/2012] [Indexed: 01/29/2023]
Abstract
Adipose tissue maintains a subpopulation of cells, referred to as adipose-derived stromal/stem cells (ASCs), which have been associated with increased breast cancer tumorigenesis and metastasis. For ASCs to affect breast cancer cells, it is necessary to delineate how they mobilize and home to cancer cells, which requires mobilization and invasion through extracellular matrix barriers. In this study, ASCs were separated into four different categories based on the donor's obesity status and depot site of origin. ASCs isolated from the subcutaneous abdominal adipose tissue of obese patients (Ob(+)Ab(+)) demonstrated increased invasion through Matrigel as well as a chick chorioallantoic membrane, a type I collagen-rich extracellular matrix barrier. Detailed mRNA and protein analyses revealed that calpain-4, calpastatin, and MMP-15 were associated with increased invasion, and the silencing of each protease or protease inhibitor confirmed their role in ASC invasion. Thus, the data indicate that both the donor's obesity status and depot site of origin distinguishes the properties of subcutaneous-derived ASCs with respect to enhanced invasion and this is associated with the dysregulation of calpain-4, calpastatin, and MMP-15.
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Affiliation(s)
- Amy L Strong
- Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
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45
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Ramcharan SK, Lip GYH, Stonelake PS, Blann AD. Angiogenin outperforms VEGF, EPCs and CECs in predicting Dukes' and AJCC stage in colorectal cancer. Eur J Clin Invest 2013; 43:801-8. [PMID: 23683169 DOI: 10.1111/eci.12108] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2012] [Accepted: 04/22/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND Circulating endothelial cells (CECs), endothelial progenitor cells (EPCs), Willebrand factor (vWf), soluble E-selectin, vascular endothelial growth factor (VEGF) and angiogenin are of interest in cancer vascular biology. However, few studies have looked at more than one in combination. We set out to determine which would be best in predicting the Dukes' and American Joint Committee on Cancer (AJCC) scores in colorectal cancer patients. METHODS We recruited 154 patients with colorectal cancer, 29 healthy controls and 26 patients with benign bowel disease. CD34(+) /CD45(-) /CD146(+) CECs and CD34(+) /CD45(-) /CD309[KDR](+) EPCs were measured by flow cytometry, plasma markers by ELISA. RESULTS All research indices were raised in colorectal cancer (P < 0·05) compared to control groups. Although CECs (P < 0·05), EPCs (P < 0·01) and angiogenin (P < 0·01) increased stepwise across the four Dukes' stages and four AJCC stages, only angiogenin remained significant in multiple regression analysis (P = 0·003 for Dukes, P = 0·01 for AJCC). Angiogenin levels were higher in Dukes' stages C and D compared to stage A, and AJCC stages 4-6 and 7-10 compared to stage 1 (all P < 0·05). Adding a second research marker to angiogenin did not markedly improve this relationship. CONCLUSION Although we found disturbances in endotheliod cells and plasma markers of the endothelium and growth factors, only angiogenin levels were independently associated with progression of the Dukes' stage and AJCC stage, with the association with Duke's stage being stronger. We suggest that angiogenin is a potential biomarker in risk stratification for colorectal cancer, and may aid clinical decision making.
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Affiliation(s)
- Sean K Ramcharan
- Department of Medicine, Centre for Cardiovascular Sciences, City Hospital, University of Birmingham, Birmingham, UK
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46
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Sirin O, Kolonin MG. Treatment of obesity as a potential complementary approach to cancer therapy. Drug Discov Today 2013; 18:567-73. [DOI: 10.1016/j.drudis.2012.05.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Revised: 03/27/2012] [Accepted: 05/11/2012] [Indexed: 11/17/2022]
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Berstein LM. Cancer and heterogeneity of obesity: a potential contribution of brown fat. Future Oncol 2013; 8:1537-48. [PMID: 23231516 DOI: 10.2217/fon.12.150] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Obesity has lately been drawing additional attention as a potential cancer risk and, with some exceptions as a prognostic factor. As obesity is a complex issue characterized by different variants, mechanisms and manifestations, its role in cancer development is also a complex problem exceeding the basic fact of the fat content rising above certain limits. Therefore, in the present paper obesity is viewed as a heterogeneous entity, which has distinct connections with cancer pathogenesis. Among other issues, emphasis is made on the state of white and brown adipose tissue, in particular the association of specific brown fat features and the so-called white fat browning with the functions of normal and mutated tumor suppressor genes, such as PTEN and BRCA1. These connections are considered from the viewpoint implying the existence of two types of hormonal carcinogenesis and of hormonal mediation of the genetic predisposition to tumor development, and should be accounted for in prevention and treatment of both obesity and cancer.
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Affiliation(s)
- Lev M Berstein
- Laboratory of Oncoendocrinology, N.N. Petrov Research Institute of Oncology, St. Petersburg 197758, Russia.
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48
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Zhang Y, Young ED, Bill K, Belousov R, Peng T, Lazar AJ, Pollock RE, Simmons PJ, Lev D, Kolonin MG. Heterogeneity and immunophenotypic plasticity of malignant cells in human liposarcomas. Stem Cell Res 2013; 11:772-81. [PMID: 23770802 DOI: 10.1016/j.scr.2013.04.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Revised: 02/15/2013] [Accepted: 04/26/2013] [Indexed: 12/28/2022] Open
Abstract
Liposarcomas are tumors arising in white adipose tissue (WAT) with avidity for local recurrence. Aggressive dedifferentiated liposarcomas (DDLS) may arise from well-differentiated subtypes (WDLS) upon disease progression, however, this key issue is unresolved due in large part to knowledge gaps about liposarcoma cellular composition. Here, we wished to improve insights into liposarcoma cellular hierarchy. Tumor section analysis indicated that the populations, distinguishable based on the expression of CD34 (a marker of adipocyte progenitors) and CD36 (a marker of adipocyte differentiation), occupy distinct intra-tumoral locations in both WDLS and DDLS. Taking advantage of these markers, we separated cells from a panel of fresh human surgical specimens by fluorescence-activated cell sorting (FACS). Based on chromosome analysis and the culture phenotypes of the composing populations, we demonstrate that malignant cells comprise four mesenchymal populations distinguished by the expression of CD34 and CD36, while vascular (CD31+) and hematopoietic (CD45+) components are non-neoplastic. Finally, we show that mouse xenografts are derivable from both CD36-negative and CD36-positive DDLS cells, and that each population recreates the heterogeneity of CD36 expression in vivo. Combined, our results show that malignant cells in WDLS and DDLS can be classified according to distinct stages of adipogenesis and indicate immunophenotypic plasticity of malignant liposarcoma cells.
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Affiliation(s)
- Yan Zhang
- Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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De Pergola G, Silvestris F. Obesity as a major risk factor for cancer. J Obes 2013; 2013:291546. [PMID: 24073332 PMCID: PMC3773450 DOI: 10.1155/2013/291546] [Citation(s) in RCA: 576] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Revised: 07/17/2013] [Accepted: 07/25/2013] [Indexed: 02/07/2023] Open
Abstract
The number of cancer cases caused by being obese is estimated to be 20% with the increased risk of malignancies being influenced by diet, weight change, and body fat distribution together with physical activity. Reports from the International Agency for Research into Cancer and the World Cancer Research Fund (WCRF) have shown that the strongest evidence exists for an association of obesity with the following cancer types: endometrial, esophageal adenocarcinoma, colorectal, postmenopausal breast, prostate, and renal, whereas the less common malignancies are leukemia, non-Hodgkin's lymphoma, multiple myeloma, malignant melanoma, and thyroid tumours. To be able to develop novel methods in prevention and treatment, we first must understand the underlying processes which link cancer to obesity. Four main systems have been identified as potential producers of cancer in obesity: insulin, insulin-like growth factor-I, sex steroids, and adipokines. Various novel candidate mechanisms have been proposed: chronic inflammation, oxidative stress, crosstalk between tumour cells and surrounding adipocytes, migrating adipose stromal cells, obesity-induced hypoxia, shared genetic susceptibility, and the functional defeat of immune function. Herein, we review the major pathogenic links between obesity and susceptibility to cancer.
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Affiliation(s)
- Giovanni De Pergola
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Oncology, University of Bari "Aldo Moro", School of Medicine, Policlinico, Piazza Giulio Cesare 11, 70124 Bari, Italy.
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50
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Zhang Y, Daquinag AC, Amaya-Manzanares F, Sirin O, Tseng C, Kolonin MG. Stromal progenitor cells from endogenous adipose tissue contribute to pericytes and adipocytes that populate the tumor microenvironment. Cancer Res 2012; 72:5198-208. [PMID: 23071132 DOI: 10.1158/0008-5472.can-12-0294] [Citation(s) in RCA: 180] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Epidemiologic studies associate cancer with obesity, but the pathophysiologic connections remain obscure. In this study, we show that obesity facilitates tumor growth in mice irrespective of concurrent diet, suggesting a direct effect of excess white adipose tissue (WAT). When transplanted into mice, adipose stromal cells (ASC) can serve as perivascular adipocyte progenitors that promote tumor growth, perhaps helping explain the obesity-cancer link. In developing this hypothesis, we showed that ASCs are expanded in obesity and that they traffic from endogenous WAT to tumors in several mouse models of cancer. Strikingly, a comparison of circulating and tumor-infiltrating cell populations in lean, and obese mice revealed that cancer induces a six-fold increase of ASC frequency in the systemic circulation. We obtained evidence that ASCs mobilized in this way can be recruited into tumors, where they can be incorporated into blood vessels as pericytes and they can differentiate into adipocytes in an obesity-dependent manner. Extending this evidence, we found that increased tumor vascularization (reflected by changes in tumor vascular morphology and a two-fold increase in vascular density) was associated with intratumoral adipocytes and elevated proliferation of neighboring malignant cells. Taken together, our results suggest that ASCs recruited from endogenous adipose tissue can be recruited by tumors to potentiate the supportive properties of the tumor microenvironment.
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Affiliation(s)
- Yan Zhang
- Center for Stem Cell and Regenerative Medicine, Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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