|
1
|
Obesity and main urologic cancers: Current systematic evidence, novel biological mechanisms, perspectives and challenges. Semin Cancer Biol 2023; 91:70-98. [PMID: 36893965 DOI: 10.1016/j.semcancer.2023.03.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/06/2023] [Accepted: 03/06/2023] [Indexed: 03/09/2023]
Abstract
Urologic cancers (UC) account for 13.1% of all new cancer cases and 7.9% of all cancer-related deaths. A growing body of evidence has indicated a potential causal link between obesity and UC. The aim of the present review is to appraise in a critical and integrative manner evidence from meta-analyses and mechanistic studies on the role of obesity in four prevalent UC (kidney-KC, prostate-PC, urinary bladder-UBC, and testicular cancer-TC). Special emphasis is given on Mendelian Randomization Studies (MRS) corroborating a genetic causal association between obesity and UC, as well as on the role of classical and novel adipocytokines. Furthermore, the molecular pathways that link obesity to the development and progression of these cancers are reviewed. Available evidence indicates that obesity confers increased risk for KC, UBC, and advanced PC (20-82%, 10-19%, and 6-14%, respectively), whereas for TC adult height (5-cm increase) may increase the risk by 13%. Obese females tend to be more susceptible to UBC and KC than obese males. MRS have shown that a higher genetic-predicted BMI may be causally linked to KC and UBC but not PC and TC. Biological mechanisms that are involved in the association between excess body weight and UC include the Insulin-like Growth Factor axis, altered availability of sex hormones, chronic inflammation and oxidative stress, abnormal secretion of adipocytokines, ectopic fat deposition, dysbiosis of the gastrointestinal and urinary tract microbiomes and circadian rhythm dysregulation. Anti-hyperglycemic and non-steroidal anti-inflammatory drugs, statins, and adipokine receptor agonists/antagonists show potential as adjuvant cancer therapies. Identifying obesity as a modifiable risk factor for UC may have significant public health implications, allowing clinicians to tailor individualized prevention strategies for patients with excess body weight.
Collapse
|
|
2
|
Pérez-Pérez A, Sánchez-Jiménez F, Vilariño-García T, Sánchez-Margalet V. Role of Leptin in Inflammation and Vice Versa. Int J Mol Sci 2020; 21:E5887. [PMID: 32824322 PMCID: PMC7460646 DOI: 10.3390/ijms21165887] [Citation(s) in RCA: 171] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/07/2020] [Accepted: 08/14/2020] [Indexed: 12/15/2022] Open
Abstract
Inflammation is an essential immune response for the maintenance of tissue homeostasis. In a general sense, acute and chronic inflammation are different types of adaptive response that are called into action when other homeostatic mechanisms are insufficient. Although considerable progress has been made in understanding the cellular and molecular events that are involved in the acute inflammatory response to infection and tissue injury, the causes and mechanisms of systemic chronic inflammation are much less known. The pathogenic capacity of this type of inflammation is puzzling and represents a common link of the multifactorial diseases, such as cardiovascular diseases and type 2 diabetes. In recent years, interest has been raised by the discovery of novel mediators of inflammation, such as microRNAs and adipokines, with different effects on target tissues. In the present review, we discuss the data emerged from research of leptin in obesity as an inflammatory mediator sustaining multifactorial diseases and how this knowledge could be instrumental in the design of leptin-based manipulation strategies to help restoration of abnormal immune responses. On the other direction, chronic inflammation, either from autoimmune or infectious diseases, or impaired microbiota (dysbiosis) may impair the leptin response inducing resistance to the weight control, and therefore it may be a cause of obesity. Thus, we are reviewing the published data regarding the role of leptin in inflammation, and the other way around, the role of inflammation on the development of leptin resistance and obesity.
Collapse
Affiliation(s)
- Antonio Pérez-Pérez
- Department of Medical Biochemistry and Molecular Biology, and Immunology, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain; (F.S.-J.); (T.V.-G.)
| | | | | | - Víctor Sánchez-Margalet
- Department of Medical Biochemistry and Molecular Biology, and Immunology, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain; (F.S.-J.); (T.V.-G.)
| |
Collapse
|
|
3
|
Sánchez-Jiménez F, Pérez-Pérez A, de la Cruz-Merino L, Sánchez-Margalet V. Obesity and Breast Cancer: Role of Leptin. Front Oncol 2019; 9:596. [PMID: 31380268 PMCID: PMC6657346 DOI: 10.3389/fonc.2019.00596] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 06/17/2019] [Indexed: 01/08/2023] Open
Abstract
Obesity-related breast cancer is an important threat that affects especially post-menopausal women. The link between obesity and breast cancer seems to be relying on the microenvironment generated at adipose tissue level, which includes inflammatory cytokines. In addition, its association with systemic endocrine changes, including hyperinsulinemia, increased estrogens levels, and hyperleptinemia may be key factors for tumor development. These factors may promote tumor initiation, tumor primary growth, tissue invasion, and metastatic progression. Although the relationship between obesity and breast cancer is already established, the different pathophysiological mechanisms involved are not clear. Obesity-related insulin resistance is a well-known risk factor for breast cancer development in post-menopausal women. However, the role of inflammation and other adipokines, especially leptin, is less studied. Leptin, like insulin, appears to be a growth factor for breast cancer cells. There exists a link between leptin and metabolism of estrogens and between leptin and other factors in a more complex network. As a result, obesity-associated hyperleptinemia has been suggested as an important mediator in the pathophysiology of breast cancer. On the other hand, recent data on the paradoxical effect of obesity on cancer immunotherapy efficacy has brought some controversy, since the proinflammatory effect of leptin may help the effect of immune checkpoint inhibitors. Therefore, a better knowledge of the molecular mechanisms that mediate leptin action may be helpful to understand the underlying processes which link obesity to breast cancer in post-menopausal women, as well as the possible role of leptin in the response to immunotherapy in obese patients.
Collapse
Affiliation(s)
- Flora Sánchez-Jiménez
- Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, Virgen Macarena University Hospital, University of Seville, Seville, Spain
| | - Antonio Pérez-Pérez
- Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, Virgen Macarena University Hospital, University of Seville, Seville, Spain
| | - Luis de la Cruz-Merino
- Department of Clinical Oncology, Virgen Macarena University Hospital, University of Seville, Seville, Spain
| | - Víctor Sánchez-Margalet
- Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, Virgen Macarena University Hospital, University of Seville, Seville, Spain
| |
Collapse
|
|
4
|
Foglesong GD, Queen NJ, Huang W, Widstrom KJ, Cao L. Enriched environment inhibits breast cancer progression in obese models with intact leptin signaling. Endocr Relat Cancer 2019; 26:483-495. [PMID: 30856610 PMCID: PMC6717689 DOI: 10.1530/erc-19-0075] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 03/11/2019] [Indexed: 12/11/2022]
Abstract
Obesity is becoming a global epidemic and is a risk factor for breast cancer. Environmental enrichment (EE), a model recapitulating an active lifestyle, leads to leanness, resistance to diet-induced obesity (DIO) and cancer. One mechanism is the activation of the hypothalamic-sympathoneural-adipocyte (HSA) axis. This results in the release of norepinephrine onto adipose tissue inducing a drop of leptin. This study aimed to test the effects of EE on breast cancer onset and progression while considering the effect of leptin by utilizing the transgenic MMTV-PyMT model as well as several models of varied leptin signaling. EE was highly effective at reducing weight gain, regardless of the presence of leptin. However, the effects of EE on tumor progression were dependent on leptin signaling. EE decreased leptin and reduced mammary tumor growth rate in MMTV-PyMT spontaneous and DIO transplantation models; in contrast, the absence of leptin in ob/ob mice resulted in increased tumor growth likely due to elevated norepinephrine levels. Our results suggest that the microenvironment is critical in breast tumorigenesis and that the drop in leptin is an important peripheral mediator of the EE anti-breast cancer effects, offsetting the potential pro-tumorigenic effects of norepinephrine responding to a complex environment.
Collapse
Affiliation(s)
- Grant D Foglesong
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Nicholas J Queen
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Wei Huang
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Kyle J Widstrom
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Lei Cao
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
- The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| |
Collapse
|
|
5
|
Lipsey CC, Harbuzariu A, Daley-Brown D, Gonzalez-Perez RR. Oncogenic role of leptin and Notch interleukin-1 leptin crosstalk outcome in cancer. World J Methodol 2016; 6:43-55. [PMID: 27019796 PMCID: PMC4804251 DOI: 10.5662/wjm.v6.i1.43] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 11/11/2015] [Accepted: 03/09/2016] [Indexed: 02/06/2023] Open
Abstract
Obesity is a global pandemic characterized by high levels of body fat (adiposity) and derived-cytokines (i.e., leptin). Research shows that adiposity and leptin provide insight on the link between obesity and cancer progression. Leptin’s main function is to regulate energy balance. However, obese individuals routinely develop leptin resistance, which is the consequence of the breakdown in the signaling mechanism controlling satiety resulting in the accumulation of leptin. Therefore, leptin levels are often chronically elevated in human obesity. Elevated leptin levels are related to higher incidence, increased progression and poor prognosis of several human cancers. In addition to adipose tissue, cancer cells can also secrete leptin and overexpress leptin receptors. Leptin is known to act as a mitogen, inflammatory and pro-angiogenic factor that induces cancer cell proliferation and tumor angiogenesis. Moreover, leptin signaling induces cancer stem cells, which are involved in cancer recurrence and drug resistance. A novel and complex signaling crosstalk between leptin, Notch and interleukin-1 (IL-1) [Notch, IL-1 and leptin crosstalk outcome (NILCO)] seems to be an important driver of leptin-induced oncogenic actions. Leptin and NILCO signaling mediate the activation of cancer stem cells that can affect drug resistance. Thus, leptin and NILCO signaling are key links between obesity and cancer progression. This review presents updated data suggesting that adiposity affects cancer incidence, progression, and response to treatment. Here we show data supporting the oncogenic role of leptin in breast, endometrial, and pancreatic cancers.
Collapse
|
|
6
|
Activated FXR Inhibits Leptin Signaling and Counteracts Tumor-promoting Activities of Cancer-Associated Fibroblasts in Breast Malignancy. Sci Rep 2016; 6:21782. [PMID: 26899873 PMCID: PMC4761870 DOI: 10.1038/srep21782] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 02/01/2016] [Indexed: 12/21/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs), the principal components of the tumor stroma, play a central role in cancer development and progression. As an important regulator of the crosstalk between breast cancer cells and CAFs, the cytokine leptin has been associated to breast carcinogenesis. The nuclear Farnesoid X Receptor-(FXR) seems to exert an oncosuppressive role in different tumors, including breast cancer. Herein, we demonstrated, for the first time, that the synthetic FXR agonist GW4064, inhibiting leptin signaling, affects the tumor-promoting activities of CAFs in breast malignancy. GW4064 inhibited growth, motility and invasiveness induced by leptin as well as by CAF-conditioned media in different breast cancer cell lines. These effects rely on the ability of activated FXR to increase the expression of the suppressor of the cytokine signaling 3 (SOCS3) leading to inhibition of leptin-activated signaling and downregulation of leptin-target genes. In vivo xenograft studies, using MCF-7 cells alone or co-injected with CAFs, showed that GW4064 administration markedly reduced tumor growth. Interestingly, GW4064-treated tumors exhibited decreased levels of leptin-regulated proteins along with a strong staining intensity for SOCS3. Thus, FXR ligands might represent an emerging potential anti-cancer therapy able to block the tumor supportive role of activated fibroblasts within the breast microenvironment.
Collapse
|
|
7
|
Esper RM, Dame M, McClintock S, Holt PR, Dannenberg AJ, Wicha MS, Brenner DE. Leptin and Adiponectin Modulate the Self-renewal of Normal Human Breast Epithelial Stem Cells. Cancer Prev Res (Phila) 2015; 8:1174-83. [PMID: 26487401 DOI: 10.1158/1940-6207.capr-14-0334] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Accepted: 10/09/2015] [Indexed: 12/23/2022]
Abstract
Multiple mechanisms are likely to account for the link between obesity and increased risk of postmenopausal breast cancer. Two adipokines, leptin and adiponectin, are of particular interest due to their opposing biologic functions and associations with breast cancer risk. In the current study, we investigated the effects of leptin and adiponectin on normal breast epithelial stem cells. Levels of leptin in human adipose explant-derived conditioned media positively correlated with the size of the normal breast stem cell pool. In contrast, an inverse relationship was found for adiponectin. Moreover, a strong linear relationship was observed between the leptin/adiponectin ratio in adipose conditioned media and breast stem cell self-renewal. Consistent with these findings, exogenous leptin stimulated whereas adiponectin suppressed breast stem cell self-renewal. In addition to local in-breast effects, circulating factors, including leptin and adiponectin, may contribute to the link between obesity and breast cancer. Increased levels of leptin and reduced amounts of adiponectin were found in serum from obese compared with age-matched lean postmenopausal women. Interestingly, serum from obese women increased stem cell self-renewal by 30% compared with only 7% for lean control serum. Taken together, these data suggest a plausible explanation for the obesity-driven increase in postmenopausal breast cancer risk. Leptin and adiponectin may function as both endocrine and paracrine/juxtacrine factors to modulate the size of the normal stem cell pool. Interventions that disrupt this axis and thereby normalize breast stem cell self-renewal could reduce the risk of breast cancer.
Collapse
Affiliation(s)
- Raymond M Esper
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
| | - Michael Dame
- Department of Internal Medicine Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Shannon McClintock
- Department of Internal Medicine Pathology, University of Michigan Medical School, Ann Arbor, Michigan
| | | | | | - Max S Wicha
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Dean E Brenner
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan. Department of Internal Medicine Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan. VA Medical Center, Ann Arbor, Michigan
| |
Collapse
|
|
8
|
|
|
9
|
Londraville RL, Macotela Y, Duff RJ, Easterling MR, Liu Q, Crespi EJ. Comparative endocrinology of leptin: assessing function in a phylogenetic context. Gen Comp Endocrinol 2014; 203:146-57. [PMID: 24525452 PMCID: PMC4128956 DOI: 10.1016/j.ygcen.2014.02.002] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Revised: 01/31/2014] [Accepted: 02/03/2014] [Indexed: 12/11/2022]
Abstract
As we approach the end of two decades of leptin research, the comparative biology of leptin is just beginning. We now have several leptin orthologs described from nearly every major clade among vertebrates, and are moving beyond gene descriptions to functional studies. Even at this early stage, it is clear that non-mammals display clear functional similarities and differences with their better-studied mammalian counterparts. This review assesses what we know about leptin function in mammals and non-mammals, and gives examples of how these data can inform leptin biology in humans.
Collapse
Affiliation(s)
- Richard L Londraville
- Department of Biology and Program in Integrated Biosciences, University of Akron, Akron, OH, USA.
| | - Yazmin Macotela
- Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Mexico
| | - Robert J Duff
- Department of Biology and Program in Integrated Biosciences, University of Akron, Akron, OH, USA
| | - Marietta R Easterling
- School of Biological Sciences and Center for Reproductive Biology, Washington State University, Pullman, WA 99164, USA
| | - Qin Liu
- Department of Biology and Program in Integrated Biosciences, University of Akron, Akron, OH, USA
| | - Erica J Crespi
- School of Biological Sciences and Center for Reproductive Biology, Washington State University, Pullman, WA 99164, USA
| |
Collapse
|
|
10
|
Rőszer T, Józsa T, Kiss-Tóth ED, De Clerck N, Balogh L. Leptin receptor deficient diabetic (db/db) mice are compromised in postnatal bone regeneration. Cell Tissue Res 2013; 356:195-206. [PMID: 24343796 DOI: 10.1007/s00441-013-1768-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Accepted: 11/04/2013] [Indexed: 12/24/2022]
Abstract
Increased fragility fracture risk with improper healing is a frequent and severe complication of insulin resistance (IR). The mechanisms impairing bone health in IR are still not fully appreciated, which gives importance to studies on bone pathologies in animal models of diabetes. Mice deficient in leptin signaling are widely used models of IR and its comorbidities. Leptin was first recognized as a hormone, regulating appetite and energy balance; however, recent studies have expanded its role showing that leptin is a link between insulin-dependent metabolism and bone homeostasis. In the light of these findings, it is intriguing to consider the role of leptin resistance in bone regeneration. In this study, we show that obese diabetic mice lacking leptin receptor (db/db) are deficient in postnatal regenerative osteogenesis. We apply an ectopic osteogenesis and a fracture healing model, both showing that db/db mice display compromised bone acquisition and regeneration capacity. The underlying mechanisms include delayed periosteal mesenchymatic osteogenesis, premature apoptosis of the cartilage callus and impaired microvascular invasion of the healing tissue. Our study supports the use of the db/db mouse as a model of IR associated bone-healing deficits and can aid further studies of mesenchymatic cell homing and differentiation, microvascular invasion, cartilage to bone transition and callus remodeling in diabetic fracture healing.
Collapse
Affiliation(s)
- Tamás Rőszer
- Department of Cardiovascular Development and Repair, Spanish National Cardiovascular Research Center (Centro Nacional de Investigaciones Cardiovasculares Carlos III), Calle Melchor Fernández Almagro 3, 28029, Madrid, Spain,
| | | | | | | | | |
Collapse
|
|
11
|
Surmacz E. Leptin and adiponectin: emerging therapeutic targets in breast cancer. J Mammary Gland Biol Neoplasia 2013; 18:321-32. [PMID: 24136336 DOI: 10.1007/s10911-013-9302-8] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Accepted: 09/24/2013] [Indexed: 12/13/2022] Open
Abstract
Obesity is a recognized risk factor for breast cancer development and poorer response to therapy. Two major fat tissue-derived adipokines, leptin and adiponectin have been implicated in mammary carcinogenesis. Leptin appears to promote breast cancer progression through activation of mitogenic, antiapoptotic, and metastatic pathways, while adiponectin may restrict tumorigenic processes primarily by inhibiting cell metabolism. Furthermore, adiponectin is known to counteract detrimental leptin effects in breast cancer models. Thus, therapeutic inhibition of pro-neoplastic leptin pathways and reactivation of anti-neoplastic adiponectin signaling may benefit breast cancer patients, especially the obese subpopulation. This review focuses on current experimental strategies aiming at leptin and adiponectin pathways in breast cancer models. Novel leptin receptor antagonists and adiponectin receptor agonists as well as other compounds for therapeutic modulation of adipokine pathways are discussed in detail, including potential pharmacological advantages and limitations of these approaches.
Collapse
Affiliation(s)
- Eva Surmacz
- Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, 1900 N12th Street, BioLife Bldg. Rm 425, Philadelphia, PA, 19122, USA,
| |
Collapse
|
|
12
|
Saxena NK, Sharma D. Multifaceted leptin network: the molecular connection between obesity and breast cancer. J Mammary Gland Biol Neoplasia 2013; 18:309-20. [PMID: 24214584 PMCID: PMC4747028 DOI: 10.1007/s10911-013-9308-2] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 10/24/2013] [Indexed: 12/21/2022] Open
Abstract
High plasma levels of leptin, a major adipocytokine produced by adipocytes, are correlated with increased fat mass in obese state. Leptin is emerging as a key candidate molecule linking obesity with breast cancer. Acting via endocrine, paracrine, and autocrine manner, leptin impacts various stages of breast tumorigenesis from initiation and primary tumor growth to metastatic progression. Leptin also modulates the tumor microenvironment mainly through supporting migration of endothelial cells, neo-angiogenesis and sustaining recruitment of macrophage and monocytes. Various studies have shown that hyperactive leptin-signaling network leads to concurrent activation of multiple oncogenic pathways resulting in enhanced proliferation, decreased apoptosis, acquisition of mesenchymal phenotype, potentiated migration and enhanced invasion potential of tumor cells. Furthermore, the capability of leptin to interact with other molecular effectors of obese state including, estrogen, IGF-1, insulin, VEGF and inflammatory cytokines further increases its impact on breast tumor progression in obese state. This article presents an overview of the studies investigating the involvement of leptin in breast cancer.
Collapse
Affiliation(s)
- Neeraj K. Saxena
- Department of Medicine, University of Maryland School of Medicine, Baltimore MD 21201
- Corresponding author: Dipali Sharma, Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB 1, Rm 145, Baltimore, MD 21231, Office: 410-455-1345, FAX: 410-614-4073, . Neeraj K. Saxena, Department of Medicine, University of Maryland School of Medicine, 660 W Redwood St., Howard Hall, Rm 301, Baltimore, MD 21201,
| | - Dipali Sharma
- Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore MD 21231
- Corresponding author: Dipali Sharma, Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB 1, Rm 145, Baltimore, MD 21231, Office: 410-455-1345, FAX: 410-614-4073, . Neeraj K. Saxena, Department of Medicine, University of Maryland School of Medicine, 660 W Redwood St., Howard Hall, Rm 301, Baltimore, MD 21201,
| |
Collapse
|
|
13
|
Integral role of PTP1B in adiponectin-mediated inhibition of oncogenic actions of leptin in breast carcinogenesis. Neoplasia 2013; 15:23-38. [PMID: 23358729 DOI: 10.1593/neo.121502] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2012] [Revised: 11/21/2012] [Accepted: 12/03/2012] [Indexed: 01/07/2023] Open
Abstract
The molecular effects of obesity are mediated by alterations in the levels of adipocytokines. High leptin level associated with obese state is a major cause of breast cancer progression and metastasis, whereas adiponectin is considered a "guardian angel adipocytokine" for its protective role against various obesity-related pathogenesis including breast cancer. In the present study, investigating the role of adiponectin as a potential inhibitor of leptin, we show that adiponectin treatment inhibits leptin-induced clonogenicity and anchorage-independent growth. Leptin-stimulated migration and invasion of breast cancer cells is also effectively inhibited by adiponectin. Analyses of the underlying molecular mechanisms reveal that adiponectin suppresses activation of two canonical signaling molecules of leptin signaling axis: extracellular signal-regulated kinase (ERK) and Akt. Pretreatment of breast cancer cells with adiponectin protects against leptin-induced activation of ERK and Akt. Adiponectin increases expression and activity of the physiological inhibitor of leptin signaling, protein tyrosine phosphatase 1B (PTP1B), which is found to be integral to leptin-antagonist function of adiponectin. Inhibition of PTP1B blocks adiponectin-mediated inhibition of leptin-induced breast cancer growth. Our in vivo studies show that adenovirus-mediated adiponectin treatment substantially reduces leptin-induced mammary tumorigenesis in nude mice. Exploring therapeutic strategies, we demonstrate that treatment of breast cancer cells with rosiglitazone results in increased adiponectin expression and inhibition of migration and invasion. Rosiglitazone treatment also inhibits leptin-induced growth of breast cancer cells. Taken together, these data show that adiponectin treatment can inhibit the oncogenic actions of leptin through blocking its downstream signaling molecules and raising adiponectin levels could be a rational therapeutic strategy for breast carcinoma in obese patients with high leptin levels.
Collapse
|
|
14
|
Sasaki A, Nakajo T, Tsunoda Y, Yamamoto G, Kobayashi Y, Tsuji M, Udaka Y, Mizutani T, Oguchi K. Gene analysis and dynamics of tumor stem cells in human glioblastoma cells after radiation. Hum Cell 2013; 26:73-9. [PMID: 23475320 DOI: 10.1007/s13577-013-0060-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Accepted: 01/18/2013] [Indexed: 01/10/2023]
Abstract
Glioblastoma is the most malignant central nervous system tumor. Patients with glioblastoma are treated with a combination of surgery, radiotherapy and chemotherapy; however, this effect is not satisfactory with regard to the prognosis. It is reported that the tumor stem cells affect recurrence, and radio- and chemotherapy resistance of the tumor, and that these cells play an important role in tumorigenesis and tumor progression. Using human glioblastoma cell lines (T98G and A172), irradiated (0, 30, 60 Gy) glioblastoma cells were prepared under the same conditions as clinical therapy. We analyzed cell proliferation rate, side population analysis by fluorescence-activated cell sorting and isolation of CD133⁺ cells, and performed genetic analysis (human stem cells) on these cells. We also investigated the difference in gene expression in the cells after radiation. The stem cell-related genes were highly expressed in the CD133⁺ cells compared with the CD133⁻ cells, suggesting that the cancer stem cells may be located in these CD133⁺ cells. In the T98G cell line, the cell proliferation rate of 30-Gy irradiated cells was higher than those of non-irradiated cells and 60-Gy irradiated cells. Stem cell-related genes were highly expressed in 30-Gy irradiated CD133⁺ T98G cells. In conclusion, we suggest that CD133⁺ cells may strongly affect tumor proliferation and the resistance against radiation therapy.
Collapse
Affiliation(s)
- Akiko Sasaki
- Department of Pharmacology, School of Medicine, Showa University, Hatanodai 1-5-8, Shinagawaku, Tokyo 142-8666, Japan.
| | | | | | | | | | | | | | | | | |
Collapse
|