• Contact Us
  • Indexing
  • Submit Manuscript
  • Open Access
  • Journals
  • Home
  • ISSN: 2373-9436
    J Cancer Biol Res 2(1): 1031.
    Submitted: 29 January 2014; Accepted: 03 March 2014; Published: 15 March 2014
    Special Issue entitled:
    Breast Cancer Therapeutics
    Review Article
    The Effects of Obesity on Adipose-Derived Stromal Cells and Impact on Breast Cancer Tumorigenesis
    Amy L Strong1, Matthew E Burow2, Jeffrey M Gimble1,3 and Bruce A Bunnell1,4*
    1Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, USA
    2Department of Medicine, Tulane University Health Sciences Center, USA
    3LaCell LLC, USA
    4Department of Pharmacology, Tulane University School of Medicine, USA
    *Corresponding author: Bruce A Bunnell, Tulane University School of Medicine, 1430 Tulane Avenue, SL-99, New Orleans, Louisiana, USA, Tel: (504) 988-7711; Fax: (504) 988-7710; Email: @
    Obesity increases the incidence of many types of cancers, and as the incidence of obesity continues to rise, the frequency of obesity-associated cancers will likely increase. While obesity increases postmenopausal breast, endometrial, pancreatic, colorectal, and renal carcinomas, understanding the effects of obesity on postmenopausal breast cancer remains a priority, as it is the most commonly diagnosed cancer in women. Obesity is characterized by the expansion of adipose tissue, resulting in inflammation of the adipose tissue. This inflammatory environment may, in turn, alter the Adipose-derived Stromal Cells (ASCs) within adipose tissue, influencing their effects on breast cancer cells. Recent studies demonstrate that ASCs in obese patients traffic through the circulation and into the tumor more frequently compared to lean patients. Furthermore, once at the tumor site, ASCs have been shown to alter the gene expression profile of cancer cells, leading to the expansion and enhanced invasiveness of these cancer cells. Together, these results suggest that obesity alters the ASCs within the tumor stroma, which in turn alters the cancer cells and leads to the development of aggressive breast cancer. Future studies investigating the precise mechanisms by which ASCs isolated from obese patients enhance breast cancer cell growth and the development of new therapies to target these ASCs will decrease the morbidity and mortality of obesity-associated breast cancers.
    Keywords: Postmenopausal breast cancer; Obesity; BMI; Adipose-derived stromal cells; ASCs
    WAT: White Adipose Tissue; TNF-α: Tumor Necrosis Factor-alpha; IL-6: Interleukin-6; MCP-1: Monocyte Chemotactic Protein-1; MMP-2: Matrix Metalloproteinase-2; PAI-1: Plasminogen Activator Inhibitor-1; ASCs: Adipose-derived Stromal Cells
    Obesity is the excessive accumulation of adipose tissue, resulting in physical and psychological health impairments. The prevalence of obesity in the United States has tripled over the past decades, with more than one third of adults meeting the criteria for obesity [1,2]. Recently, the World Cancer Research Fund used a standardized approach to review the effects of obesity on cancer incidence and mortality [3]. This study determined that increased adiposity was associated with increased risk of multiple types of cancers, including postmenopausal breast, endometrial, pancreatic, colorectal, and renal cancers [4]. With regard to breast cancer, approximately 18-20% of postmenopausal breast cancer cases are attributable to obesity [5-7]. As postmenopausal breast cancer is the second leading cause of cancer-related deaths in women, understanding the influence of obesity on the development and progression of this disease remains a major healthcare concern.
    Expansion of adipose tissue in obesity
    The enlarged adipocytes, which is a hallmark of obesity results in increased distance between the adipocytes and the surrounding vasculature. Large adipocytes can grow an upwards of 100-200 μm in diameter often exceeding the normal diffusion distance of oxygen into tissue [8,9]. Studies have demonstrated that oxygen concentration is close to zero at 100 μm distance from the vasculature [8]. Furthermore, studies have shown that despite the substantial expansion of adipose tissue in obese humans, neither cardiac output nor total blood flow to the adipose tissue is increased [10,11]. All of these factors lead to a hypoxic environment in the adipose tissue [12-15]. Moreover, in obese mice, reduced blood perfusion and hypoxia appeared to be particularly pronounced in the White Adipose Tissue (WAT) [16]. The hypoxic environment in WAT triggers an inflammatory response in an attempt to increase blood flow and stimulate angiogenesis. However, it is insufficient to compensate for the expanding adipocytes, consequently resulting in chronic low-grade inflammation [17-19]. This chronic inflammation induces the secretion of several pro-inflammatory cytokines (tumor necrosis factor-α and IL-6), chemokines (MCP-1), proteases (MMP2), and protease inhibitor (PAI-1) by immune cells and endothelial cells, which conditions the cells within the Stromal Vascular Fraction (SVF) of adipose tissue and ultimately results in adipose tissue dysfunction [20,21].
    Alterations to ASCs in Obesity
    The SVF of adipose tissue is composed of ASCs, preadipocytes, endothelial progenitor cells, and immune cells. As the major component of the stromal layer of tumors, ASCs have drawn significant attention. Recent studies have reported that hypoxia induced by obesity is sufficient to increase the frequency of ASCs in circulation. Obese mice demonstrated an increased circulation of ASCs isolated from WAT compared to lean mice [22]. Furthermore, Bellows et al. demonstrated that patients who were obese displayed increased mobilization of ASCs in the circulation [23]. Moreover, ASCs isolated from subcutaneous WAT of the abdomen of obese women were found to be more migratory towards breast cancer conditioned media than the ASCs from lean women of the same adipose depot site [24]. Furthermore, the mechanism by which the trafficking of these ASCs was enhanced was attributed to increases in MMP and calpain expression [24]. Together, these studies support conditioning of ASCs by the local environment, resulting in robust alterations to ASCs with respect to their ability to circulate and home to cancer cells.
    ASCs altered by obesity and breast cancer
    Recently studies have focused on understanding the potential implications of this enhanced migratory ability of ASCs on the tumor and tumor stroma. Studies have shown that once recruited to the tumor site, ASCs increase the proliferation of breast cancer cells and enhance the invasion and metastasis of cancer cells [25]. Utilizing ASCs isolated from the breast and from abdominal adipose tissue, Walter et al. demonstrated that the secretion of IL-6 from ASCs enhanced the migration and invasion of breast cancer cells [26]. Additionally, studies have shown that ASCs isolated from obese subjects further enhanced breast cancer cell proliferation and tumor volume through altered gene expression [27]. Genes involved in cell cycle regulation and apoptosis were over expressed following co-culture with ASCs from obese patients [27]. Furthermore, ASCs isolated from obese patients were found to enhance the expression of angiogenic and metastatic genes in breast cancer cells [27]. Collectively, these studies suggest that ASCs isolated from obese patients increase the aggressiveness of breast cancer cells and lead to the diagnosis of more advance staged breast cancer in obese women.
    Multiple independent studies have demonstrated that obesity is directly linked to an increased risk of developing postmenopausal breast cancer. ASCs derived from adipose tissue of obese subjects possess novel biologic properties and these altered ASCs influence the gene expression profile of breast cancer cells, contributing to enhanced tumorigenesis. In order to reduce the incidence of obesity-associated postmenopausal breast cancers, additional studies are necessary to investigate the precise mechanism(s) by which obesity alters the ASCs within the tumor stroma. By identifying the alterations in the ASCs, it may be possible to utilize these ASCs for targeted cancer therapies in obese women. Furthermore, by targeting the complex interaction between cancer cells and ASCs, it will be possible to reduce the morbidity and mortality caused by obesity-associated breast cancer.
    The research was supported by funds from Tulane University.
    Conflict of Interest
    J.M.G. is co-founder and chief scientific officer for LaCell LLC.
    1. Adult Obesity Facts, PA. Division of Nutrition, and Obesity, National Center for Chronic Disease Prevention and Health Promotion, Editor. CDC: Centers for Disease Control and Prevention: Atlanta. 2013.
    2. James PT. Obesity: the worldwide epidemic. Clin Dermatol. 2004; 22: 276-280.
    3. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective, AIfC. Research, Editor. WCRF. World Cancer Research Fund: Washington, USA. 2007.
    4. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008; 371: 569-578.
    5. Reeves KW, Carter GC, Rodabough RJ, Lane D, McNeeley SG, Stefanick ML, et al. Obesity in relation to endometrial cancer risk and disease characteristics in the Women's Health Initiative. Gynecol Oncol. 2011; 121: 376-382.
    6. Diaz ES, Karlan BY, Li AJ. Obesity-associated adipokines correlate with survival in epithelial ovarian cancer. Gynecol Oncol. 2013; 129: 353-357.
    7. Crosbie EJ, Roberts C, Qian W, Swart AM, Kitchener HC, Renehan AG. Body mass index does not influence post-treatment survival in early stage endometrial cancer: results from the MRC ASTEC trial. Eur J Cancer. 2012; 48: 853-864.
    8. Folkman J, Hahnfeldt P, Hlatky L. Cancer: looking outside the genome. Nat Rev Mol Cell Biol. 2000; 1: 76-79.
    9. Brahimi-Horn MC, Pouysségur J. Oxygen, a source of life and stress. FEBS Lett. 2007; 581: 3582-3591.
    10. Blaak EE, van Baak MA, Kemerink GJ, Pakbiers MT, Heidendal GA, Saris WH. Beta-adrenergic stimulation and abdominal subcutaneous fat blood flow in lean, obese, and reduced-obese subjects. Metabolism. 1995; 44: 183-187.
    11. Jansson PA, Larsson A, Lönnroth PN. Relationship between blood pressure, metabolic variables and blood flow in obese subjects with or without non-insulin-dependent diabetes mellitus. Eur J Clin Invest. 1998; 28: 813-818.
    12. Yin J, Gao Z, He Q, Zhou D, Guo Z, Ye J. Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue. Am J Physiol Endocrinol Metab. 2009; 296: E333-342.
    13. Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int J Obes (Lond). 2009; 33: 54-66.
    14. Pasarica M, Rood J, Ravussin E, Schwarz JM, Smith SR, Redman LM. Reduced oxygenation in human obese adipose tissue is associated with impaired insulin suppression of lipolysis. J Clin Endocrinol Metab. 2010; 95: 4052-4055.
    15. Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan LE, et al. Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes. 2009; 58: 718-725.
    16. West DB, Prinz WA, Francendese AA, Greenwood MR. Adipocyte blood flow is decreased in obese Zucker rats. Am J Physiol. 1987; 253: R228-233.
    17. Trayhurn P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev. 2013; 93: 1-21.
    18. Carroll VA, Ashcroft M. Targeting the molecular basis for tumour hypoxia. Expert Rev Mol Med. 2005; 7: 1-16.
    19. Oñate B, Vilahur G, Camino-López S, Díez-Caballero A, Ballesta-López C, Ybarra J, et al. Stem cells isolated from adipose tissue of obese patients show changes in their transcriptomic profile that indicate loss in stemcellness and increased commitment to an adipocyte-like phenotype. BMC Genomics. 2013; 14: 625.
    20. Prieto-Hontoria PL, Pérez-Matute P, Fernández-Galilea M, Bustos M, Martínez JA, Moreno-Aliaga MJ. Role of obesity-associated dysfunctional adipose tissue in cancer: a molecular nutrition approach. Biochim Biophys Acta. 2011; 1807: 664-678.
    21. Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol. 2011; 11: 85-97.
    22. 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: 5198-5208.
    23. Bellows CF, Zhang Y, Simmons PJ, Khalsa AS, Kolonin MG. Influence of BMI on level of circulating progenitor cells. Obesity (Silver Spring). 2011; 19: 1722-1726.
    24. Strong AL, Semon JA, Strong TA, Santoke TT, Zhang S, McFerrin HE, et al. Obesity-associated dysregulation of calpastatin and MMP-15 in adipose-derived stromal cells results in their enhanced invasion. Stem Cells. 2012; 30: 2774-2783.
    25. Muehlberg FL, Song YH, Krohn A, Pinilla SP, Droll LH, Leng X, et al. Tissue-resident stem cells promote breast cancer growth and metastasis. Carcinogenesis. 2009; 30: 589-597.
    26. Walter M, Liang S, Ghosh S, Hornsby PJ, Li R. Interleukin 6 secreted from adipose stromal cells promotes migration and invasion of breast cancer cells. Oncogene. 2009; 28: 2745-2755.
    27. Strong AL, Strong TA, Rhodes LV, Semon JA, Zhang X, Shi Z, et al. Obesity associated alterations in the biology of adipose stem cells mediate enhanced tumorigenesis by estrogen dependent pathways. Breast Cancer Res. 2013; 15: R102.
    Cite this article: Strong AL, Burow ME, Gimble JM, Bunnell BA (2014) The Effects of Obesity on Adipose-Derived Stromal Cells and Impact on Breast Cancer Tumorigenesis. J Cancer Biol Res 2(1): 1031.
  • Current Issue Highlights
  • BRAT1 was originally identified as a BRCA1 interacting protein [1], however, subsequent studies showed that it also binds to ATM, DNA-PK, and SMC1,

    Mechanisms of detecting and repairing damaged DNA are conserved and controlled through the DNA damage response (DDR).

    JSciMed Central Peer-reviewed Open Access Journals
    10120 S Eastern Ave, Henderson,
    Nevada 89052, USA
    Tel: (702)-751-7806
    Toll free number: 1-800-762-9856
    Fax: (844)-572-4633 (844-JSCIMED)
    E-mail: cancerbiology@jscimedcentral.com
    1455 Frazee Road, Suite 570
    San Diego, California 92108, USA
    Tel: (619)-373-8720
    Toll free number: 1-800-762-9856
    Fax: (844)-572-4633 (844-JSCIMED)
    E-mail: cancerbiology@jscimedcentral.com
    About      |      Journals      |      Open Access      |      Special Issue Proposals      |      Guidelines      |      Submit Manuscript      |      Contacts
    Copyright © 2016 JSciMed Central All Rights Reserved
    Creative Commons Licence Open Access Publication by JSciMed Central is licensed under a Creative Commons Attribution 4.0 International License.
    Based on a work at https://jscimedcentral.com/. Permissions beyond the scope of this license may be available at https://creativecommons.org/.