Abstract
Excessive adiposity has long been associated with increased incidence of breast cancer in post-menopausal women, and with increased mortality from breast cancer, regardless of the menopausal status. Although adipose tissue-derived estrogen contributes to obesity-associated risk for estrogen receptor (ER)-positive breast cancer, the estrogen-independent impact of adipose tissue on tumor invasion and progression needs to be elucidated. Here, we show that adipose stromal cells (ASCs) significantly stimulate migration and invasion of ER-negative breast cancer cells in vitro and tumor invasion in a co-transplant xenograft mouse model. Our study also identifies cofilin-1, a known regulator of actin dynamics, as a determinant of the tumor-promoting activity of ASCs. The cofilin-1-dependent pathway affects the production of interleukin 6 (IL-6) in ASCs. Depletion of IL-6 from the ASC-conditioned medium abrogated the stimulatory effect of ASCs on the migration and invasion of breast tumor cells. Thus, our study uncovers a link between a cytoskeleton-based pathway in ASCs and the stromal impact on breast cancer cells.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ailhaud G . (2006). Adipose tissue as a secretory organ: from adipogenesis to the metabolic syndrome. Comptes Rendus Biologies 329: 570–577.
Amemori S, Ootani A, Aoki S, Fujise T, Shimoda R, Kakimoto T et al. (2007). Adipocytes and preadipocytes promote the proliferation of colon cancer cells in vitro. Am J Physiol 292: G923–G929.
Ara T, Song L, Shimada H, Keshelava N, Russell HV, Metelitsa LS et al. (2009). Interleukin-6 in the bone marrow microenvironment promotes the growth and survival of neuroblastoma cells. Cancer Res 68: 329–337.
Bissell MJ, Radisky DC, Rizki A, Weaver VM, Petersen OW . (2002). The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation 70: 537–546.
Bulun SE, Lin Z, Imir G, Amin S, Demura M, Yilmaz B et al. (2005). Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev 57: 359–383.
Carmichael AR . (2006a). Obesity and prognosis of breast cancer. Obesity Rev 7: 333–340.
Carmichael AR . (2006b). Obesity as a risk factor for development and poor prognosis of breast cancer. BJOG 113: 1160–1166.
Celis JE, Moreira JMA, Cabezon T, Gromov P, Friis E, Rank F et al. (2005). Identification of extracellular and intracellular signaling components of the mammary adipose tissue and its interstitial fluid in high risk breast cancer patients. Mol Cell Prot 4: 492–522.
Cooke PS, Naaz A . (2004). Role of estrogens in adipocyte development and function. Exp Biol Med 229: 1127–1135.
Dawood S, Broglio K, Gonzalez-Angulo AM, Kau SW, Islam R, Hortobagyi GN et al. (2008). Prognostic value of body mass index in locally advanced breast cancer. Clin Cancer Res 14: 1718–1725.
Ferrante AWJ . (2007). Obesity-induced inflammation: a metabolic dialogue in the language of inflammation. J Int Medicine 262: 408–414.
Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K et al. (2007). Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol 9: 1392–1400.
Gao SP, Mark KG, Leslie K, Pao W, Motoi N, Gerald WL et al. (2007). Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung carcinomas. J Clin Invest 117: 3846–3856.
Ghosh S, Lu Y, Katz A, Hu Y, Li R . (2007). Tumor suppressor BRCA1 inhibits a breast cancer-associated promoter of the aromatase gene (CYP19) in human adipose stromal cells. Am J Physiol Endocrinol Metab 292: E246–E252.
Gimble JM, Katz AJ, Bunnell BA . (2007). Adipose-derived stem cells for regenerative medicine. Circ Res 100: 1249–1260.
Hennighausen L, Robinson GW . (2005). Information networks in the mammary gland. Nat Rev Mol Cell Biol 6: 715–725.
Hjartaeker A, Langseth H, Weiderpass E . (2008). Obesity and diabetes epidemics: cancer repercussions. Adv Exp Med Biol 630: 72–93.
Hoene M, Weigert C . (2008). The role of interleukin-6 in insulin resistance, body fat distribution and energy balance. Obesity Rev 9: 20–29.
Hong DS, Angelo LS, Kurzrock R . (2007). Interleukin-6 and its receptor in cancer. Cancer 110: 1911–1928.
Kamat A, Hinshelwood MM, Murry BA, Mendelson CR . (2002). Mechanisms in tissue-specific regulation of estrogen biosynthesis in humans. Trends Endo Metab 13: 122–128.
Karnoub A, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW et al. (2007). Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449: 557–563.
Katz AJ, Tholpady A, Tholpady SS, Shang H, Ogle RC . (2005). Cell surface and transcriptional characterization of human adipose-derived adherent stromal (hADAS) cells. Stem Cells 23: 412–423.
Kilroy GE, Foster SJ, Wu X, Ruiz J, Sherwood S, Heifetz A et al. (2007). Cytokine profile of human adipose-derived stem cells: expression of angiogenic, hematopoietic, and pro-inflammatory factors. J Cell Physiol 212: 707–709.
Knuepfer H, Preiss R . (2007). Significance of interleukin-6 (IL-6) in breast cancer. Breast Cancer Res Treatment 102: 129–135.
La Vecchia C, Negri E, Franceschi S, Talamini R, Bruzzi P, Palli D et al. (1997). Body mass index and post-menopausal breast cancer: an age-specific analysis. Br J Cancer 75: 441–444.
Li Z, Bowerman S, Heber D . (2005). Health ramifications of the obesity epidemic. Surg Clin North Am 85: 681–701.
Lin S, Yang J, Everett AD, Clevenger CV, Koneru M, Mishra PJ et al. (2008). The isolation of novel mesenchymal stromal cell chemotactic factors from the conditioned medium of tumor cells. Exp Cell Res 314: 3107–3117.
Lin Y, Chen X, Yan Z, Liu L, Tang W, Zheng X et al. (2006). Multilineage differentiation of adipose-derived stromal cells from GFP transgenic mice. Mol Cell Biochem 285: 69–78.
Liu D, Hornsby PJ . (2007a). Fibroblast stimulation of blood vessel development and cancer cell invasion in a subrenal capsule xenograft model: stress-induced premature senescence does not increase effect. Neoplasia 9: 418–426.
Liu D, Hornsby PJ . (2007b). Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res 67: 3117–3126.
Manabe Y, Toda S, Miyazaki K, Sugihara H . (2003). Mature adipocytes, but not preadipocytes, promote the growth of breast carcinoma cells in collagen gel matrix cuture through cancer-stromal interactions. J Path 201: 221–228.
Marcoux N, Vuori K . (2005). EGF receptor activity is essential for adhesion-induced stress fiber formation and cofilin phosphorylation. Cellular Signalling 17: 1449–1455.
Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R et al. (2005). Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCl12 secretion. Cell 121: 335–348.
Paduch R, Kandefer-Szerszen M . (2005). Vitamin D, tamoxifen, and β-estradiol modulate breast cancer cell growth and interleukin-6 and metalloproteinase-2 production in three-dimensional co-cultures of tumor cell spheroids with endothelium. Cell Biol Toxicol 21: 247–256.
Pederson T . (2008). As functional actin comes into view, is it globular, filamentous, or both? J Cell Biol 180: 1061–1064.
Pollard TD, Borisy GG . (2003). Cellular motility driven by assembly and disassembly of actin filaments. Cell 112: 453–465.
Pupa SM, Menard S, Forti S, Tagliabue E . (2002). New insights into the role of extracellular matrix during tumor onset and progression. J Cell Physiol 192: 259–267.
Raman D, Baugher PJ, Thu YM, Richmond A . (2007). Role of chemokines in tumor growth. Cancer Lett 256: 137–165.
Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M et al. (2007). IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 117: 3988–4002.
Sasser KA, Sullivan NJ, Studebaker AW, Hendey LF, Axel AE, Hall BM . (2007). Interleukin-6 is a potent growth factor for ER-α-positive human breast cancer. FASEB J 21: 3763–3770.
Schaeffler A, Schoelmerich J, Buechler C . (2007). Mechanisms of disease: adipokines and breast cancer—endocrine and paracrine mechanisms that connect adiposity and breast cancer. Nat Clin Practice 3: 345–354.
Song X, Chen X, Yamaguchi H, Mouneimme G, Condeelis JS, Eddy RJ . (2006). Initiation of cofilin activity in response to EGF is uncoupled from cofilin phosphorylation and dephosphorylation in carcinoma cells. J Cell Sci 119: 2871–2881.
Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O et al. (2008). Dynamics of fat cell turnover in humans. Nature 453: 783–787.
Tang W, Zeve D, Suh JM, Bosnakovski D, Kyba M, Hammer RE et al. (2008). White fat progenitor cells reside in the adipose vasculature. Science 322: 583–586.
Tessitore L, Vizio B, Pesola D, Cecchini F, Mussa A, Argiles JM et al. (2004). Adipocyte expression and circulating levels of leptin increase in both gynaecological and breast cancer patients. Int J Oncol 24: 1529–1535.
Tholpady SS, Llull R, Ogle RC, Rubin JP, Futrell JW, Katz AJ . (2006). Adipose tissue: stem cells and beyond. Clin Plast Surg 33: 55–62.
Wang W, Eddy RJ, Condeelis JS . (2007). The cofilin pathway in breast cancer invasion and metastasis. Nat Rev Cancer 7: 429–440.
Whiteman MK, Hillis SD, Curtis KM, McDonald JA, Wingo PA, Marchbanks PA . (2005). Body mass and mortality after breast cancer diagnosis. Cancer Epidemiol Biomarkers Prev 14: 2009–2014.
Zalesin KC, Franklin BA, Miller WM, Peterson ED, McCullough PA . (2008). Impact of obesity on cardiovascular disease. Endocrinol Metab Clinics of North Am 37: 663–684.
Acknowledgements
We thank Dr Adam Katz for ASCs. The work was supported by grants to RL from the NCI (CA93506) and DOD (W81XWH-06-1-034), and by grants to PJH from the NIA, the Owens Medical Research Foundation, and the Glenn Foundation for Medical Research.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
Rights and permissions
About this article
Cite this article
Walter, M., Liang, S., Ghosh, S. et al. Interleukin 6 secreted from adipose stromal cells promotes migration and invasion of breast cancer cells. Oncogene 28, 2745–2755 (2009). https://doi.org/10.1038/onc.2009.130
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2009.130
Keywords
This article is cited by
-
The inhibitory effect of Gremlin-2 on adipogenesis suppresses breast cancer cell growth and metastasis
Breast Cancer Research (2023)
-
ULBP2 is a biomarker related to prognosis and immunity in colon cancer
Molecular and Cellular Biochemistry (2023)
-
Adipose Stroma Accelerates the Invasion and Escape of Human Breast Cancer Cells from an Engineered Microtumor
Cellular and Molecular Bioengineering (2022)
-
Operative invasiveness does not affect the prognosis of patients with non-small cell lung cancer
BMC Pulmonary Medicine (2020)
-
Omental adipocytes promote peritoneal metastasis of gastric cancer through the CXCL2–VEGFA axis
British Journal of Cancer (2020)