Skip to main content
SpringerLink
Log in

Hyaluronan in aged collagen matrix increases prostate epithelial cell proliferation

  • Published:
In Vitro Cellular & Developmental Biology - Animal Aims and scope Submit manuscript

Abstract

The extracellular matrix (ECM) of the prostate, which is comprised primarily of collagen, becomes increasingly disorganized with age, a property that may influence the development of hyperplasia and cancer. Collageous ECM extracted from the tails of aged mice exhibits many characteristics of collagen in aged tissues, including the prostate. When polymerized into a 3-dimensional (3D) gel, these collagen extracts can serve as models for the study of specific cell-ECM interactions. In the present study, we examined the behaviors of human prostatic epithelial cell lines representing normal prostate epithelial cells (PEC), benign prostatic hyperplasia (BPH-1), and adenocarcinoma (LNCaP) cultured in contact with 3D gels made from collagen extracts of young and aged mice. We found that proliferation of PEC, BPH-1, and LNCaP cells were all increased by culture on aged collagen gels relative to young collagen gels. In examining age-associated differences in the composition of the collagen extracts, we found that aged and young collagen had a similar amount of several collagen-associated ECM components, but aged collagen had a much greater content of the glycosaminoglycan hyaluronan (HA) than young collagen. The addition of HA (of similar size and concentration to that found in aged collagen extracts) to cells placed in young collagen elicited significantly increased proliferation in BPH-1 cells, but not in PEC or LNCaP cells, relative to controls not exposed to HA. Of note, histochemical analyses of human prostatic tissues showed significantly higher expression of HA in BPH and prostate cancer stroma relative to stroma of normal prostate. Collectively, these results suggest that changes in ECM involving increased levels of HA contribute to the growth of prostatic epithelium with aging.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1.
Figure 2.
Figure 3.
Figure 4.

Similar content being viewed by others

References

  • Afratis N, Gialeli C, Nikitovic D, Tsegenidis T, Karousou E, Theocharis AD, Pavão MS, Tzanakakis GN, Karamanos NK (2012) Glycosaminoglycans: key players in cancer cell biology and treatment. FEBS J 279:1177–1197

    Article  CAS  PubMed  Google Scholar 

  • Bartling B, Desole M, Rohrbach S, Silber RE, Simm A (2009) Age-associated changes of extracellular matrix collagen impair lung cancer cell migration. FASEB J 23:1510–1520

    Article  CAS  PubMed  Google Scholar 

  • Begley LA, Kasina S, MacDonald J, Macoska JA (2008) The inflammatory microenvironment of the aging prostate facilitates cellular proliferation and hypertrophy. Cytokine 43:194–199

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bentov I, Damodarasamy M, Plymate S, Reed MJ (2013) B16/F10 tumors in aged 3D collagen in vitro simulate tumor growth and gene expression in aged mice in vivo. In Vitro Cell Dev Biol Anim 49:395–399

    Article  CAS  PubMed  Google Scholar 

  • Bharadwaj AG, Rector K, Simpson MA (2007) Inducible hyaluronan production reveals differential effects on prostate tumor cell growth and tumor angiogenesis. J Biol Chem 282:20561–20572

    Article  CAS  PubMed  Google Scholar 

  • Bianchi-Frias D, Vakar-Lopez F, Coleman M, Plymate SR, Reed MJ, Nelson PS (2010) The effects of aging on the molecular and cellular composition of the prostate microenvironment. PLoS One 1:5–10

    Google Scholar 

  • Bradshaw AD, Baicu CF, Rentz TJ, Van Laer AO, Bonnema DD, Zile MR (2010) Age-dependent alterations in fibrillar collagen content and myocardial diastolic function: role of SPARC in post-synthetic procollagen processing. Am J Physiol Heart Circ Physiol 298:H614–H622

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cukierman E, Pankov R, Stevens DR, Yamada KM (2001) Taking cell-matrix adhesions to the third dimension. Science 294:1708–1712

    Article  CAS  PubMed  Google Scholar 

  • Damodarasamy M, Johnson RS, Bentov I, MacCoss MJ, Vernon RB, Reed MJ (2014) Hyaluronan enhances wound repair and increases collagen III in aged dermal wounds. Wound Repair Regen (in press)

  • Damodarasamy M, Vernon RB, Karres N, Chang H, Bianchi-Frias D, Nelson PS, Reed MJ (2010) Collagen extracts derived from young and aged mice demonstrate different structural properties and cellular effects in three-dimensional gels. J Gerontol A Biol Sci Med Sci 65:209–218

    Article  PubMed  Google Scholar 

  • David-Raoudi M, Tranchepain F, Deschrevel B, Vincent JC, Bogdanowicz P, Boumediene K, Pujol JP (2008) Differential effects of hyaluronan and its fragments on fibroblasts: relation to wound healing. Wound Repair Regen 16:274–287

    Article  PubMed  Google Scholar 

  • De Klerk DP (1983) The glycosaminoglycans of normal and hyperplastic prostate. Prostate 4:73–81

    Article  PubMed  Google Scholar 

  • Ershler WB, Stewart JA, Hacker P, Moore AL, Tindle BH (1984) B16 murine melanoma and aging: slower growth and longer survival in old mice. J Natl Cancer Inst 72:161–164

    CAS  PubMed  Google Scholar 

  • Ghazi K, Deng-Pichon U, Warnet JM, Rat P (2012) Hyaluronan fragments improve wound healing on in vitro cutaneous model through P2X7 purinoreceptor basal activation: role of molecular weight. PLoS One 7:e48351

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Goldberg RL, Toole BP (1987) Hyaluronate inhibition of cell proliferation. Arthritis Rheum 30:769–778

    Article  CAS  PubMed  Google Scholar 

  • Goulas A, Hatzichristou DG, Karakiulakis G, Mirtsou-Fidani V, Kalinderis A, Papakonstantinou E (2000) Benign hyperplasia of the human prostate is associated with tissue enrichment in chondroitin sulphate of wide size distribution. Prostate 44:104–110

    Article  CAS  PubMed  Google Scholar 

  • Grönberg H, Damber JE, Jonsson H, Lenner P (1994) Patient age as a prognostic factor in prostate cancer. J Urol 152:892–895

    PubMed  Google Scholar 

  • Haas TL, Davis SJ, Madri JA (1998) Three-dimensional type I collagen lattices induce coordinate expression of matrix metalloproteinases MT1-MMP and MMP-2 in microvascular endothelial cells. J Biol Chem 273:3604–3610

    Article  CAS  PubMed  Google Scholar 

  • Harrison DE, Archer JR (1978) Measurement of changes in mouse tail collagen with age: temperature dependence and procedural details. Exp Gerontol 3:75–82

    Article  Google Scholar 

  • Hayward SW, Dahiya R, Cunha GR, Bartek J, Deshpande N, Narayan P (1995) Establishment and characterization of an immortalized but non-transformed human prostate epithelial cell line: BPH-1. In Vitro Cell Dev Biol Anim 31:14–24

    Article  CAS  PubMed  Google Scholar 

  • Horoszewicz JS, Leong SS, Chu TM, Wajsman ZL, Friedman M, Papsidero L, Kim U, Chai LS, Kakati S, Arya SK, Sandberg AA (1980) The LNCaP cell line—a new model for studies on human prostatic carcinoma. Prog Clin Biol Res 37:115–132

    CAS  PubMed  Google Scholar 

  • Iozzo RV, Sanderson RD (2011) Proteoglycans in cancer biology, tumour microenvironment and angiogenesis. J Cell Mol Med 5:1013–1031

    Article  Google Scholar 

  • Jarvelainen H, Sainio A, Koulu M, Wight TN, Penttinen R (2009) Extracellular matrix molecules: potential targets in pharmacotherapy. Pharmacol Rev 61:198–223

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jiang ST, Liao KK, Liao MC, Tang MJ (2000) Age effect of type I collagen on morphogenesis of Madin-Darby canine kidney cells. Kidney Int 57:1539–1548

    Article  CAS  PubMed  Google Scholar 

  • Kovar JL, Johnson MA, Volcheck WM, Chen J, Simpson MA (2006) Hyaluronidase expression induces prostate tumor metastasis in an orthotopic mouse model. Am J Pathol 169:1415–1426

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee GY, Kenny PA, Lee EH, Bissell MJ (2007) Three-dimensional culture models of normal and malignant breast epithelial cells. Nat Methods 4:359–365

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Leventhal KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W, Yamauchi M, Gasser DL, Weaver VM (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891–906

    Article  Google Scholar 

  • Lokeshwar VB, Lokeshwar BL, Pham HT, Block NL (1996) Association of elevated levels of hyaluronidase, a matrix-degrading enzyme, with prostate cancer progression. Cancer Res 56:651–657

    CAS  PubMed  Google Scholar 

  • Lokeshwar VB, Rubinowicz D, Schroeder GL, Forgacs E, Minna JD, Block NL, Nadji M, Lokeshwar BL (2001) Stromal and epithelial expression of tumor markers hyaluronic acid and HYAL1 hyaluronidase in prostate cancer. J Biol Chem 276:11922–11932

    Article  CAS  PubMed  Google Scholar 

  • Maharjan A, Pilling D, Gomer RH (2011) High and low molecular weight hyaluronic acid differentially regulate human fibrocyte differentiation. PLoS One 6:e26078

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Miron-Mendoza M, Seemann J, Grinnell F (2010) The differential regulation of cell motile activity through matrix stiffness and porosity in three dimensional collagen matrices. Biomaterials 31:6425–6435

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Misra S, Toole BP, Ghatak S (2006) Hyaluronan constitutively regulates activation of multiple receptor tyrosine kinases in epithelial and carcinoma cells. J Biol Chem 281:34936–34941

    Article  CAS  PubMed  Google Scholar 

  • Ng MR, Brugge JS (2009) A stiff blow from the stroma: collagen crosslinking drives tumor progression. Cancer Cell 16:455–457

    Article  CAS  PubMed  Google Scholar 

  • Orgel JP, San Antonio JD, Antipova O (2011) Molecular and structural mapping of collagen fibril interactions. Connect Tissue Res 52:2–17

    Article  CAS  PubMed  Google Scholar 

  • Petrie RJ, Gavara N, Chadwick RS, Yamada KM (2012) Nonpolarized signaling reveals two distinct modes of 3D cell migration. J Cell Biol 197:439–455

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, White JG, Keely PJ (2008) Collagen density promotes mammary tumor initiation and progression. BMC Med 6:11–22

    Article  PubMed Central  PubMed  Google Scholar 

  • Pullen M, Thomas K, Wu H, Nambi P (2001) Stimulation of hyaluronan synthetase by platelet-derived growth factor bb in human prostate smooth muscle cells. Pharmacology 62:103–106

    Article  CAS  PubMed  Google Scholar 

  • Reed MJ, Damodarasamy M, Chan CK, Johnson MN, Wight TN, Vernon RB (2013) Cleavage of hyaluronan is impaired in aged dermal wounds. Matrix Biol 32:45–51

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Roughley PJ, Lamplugh L, Lee ER, Matsumoto K, Yamaguchi Y (2011) The role of hyaluronan produced by Has2 gene expression in development of the spine. Spine 36:E914–E920

    Article  PubMed  Google Scholar 

  • Saad M, Abdel-Rahim M, Abol-Enein H, Ghoneim MA (2008) Concomitant pathology in the prostate in cystoprostatectomy specimens: a prospective study and review. BJU Int 102:1544–1550

    Article  PubMed  Google Scholar 

  • Sadoun E, Reed MJ (2003) Impaired angiogenesis in aging is associated with alterations in vessel density, matrix composition, inflammatory response, and growth factor expression. J Histochem Cytochem 51:1119–1130

    Article  CAS  PubMed  Google Scholar 

  • Sakr SW, Potter-Perigo S, Kinsella MG, Johnson PY, Braun KR, Goueffic Y, Rosenfeld ME, Wight TN (2008) Hyaluronan accumulation is elevated in cultures of low density lipoprotein receptor-deficient cells and is altered by manipulation of cell cholesterol content. J Biol Chem 283:36195–36204

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shi ZD, Wang H, Tarbell JM (2011) Heparan sulfate proteoglycans mediate interstitial flow mechanotransduction regulating MMP-13 expression and cell motility via FAK-ERK in 3D collagen. PLoS One 6:15956

    Article  Google Scholar 

  • Simpson MA, Lokeshwar VB (2008) Hyaluronan and hyaluronidase in genitourinary tumors. Front Biosci 13:5664–5680

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sprenger CC, Plymate SR, Reed MJ (2010) Aging-related alterations in the extracellular matrix modulate the microenvironment and influence tumor progression. Int J Cancer 127:2739–2748

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stern R, Maibach HI (2008) Hyaluronan in skin: aspects of aging and its pharmacologic modulation. Clin Dermatol 26:106–122

    Article  PubMed  Google Scholar 

  • Tian X, Azpurua J, Hine C, Vaidya A, Myakishev-Rempel M, Ablaeva J, Mao Z, Nevo E, Gorbunova V, Seluanov A (2013) High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499:346–349

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Toole BP (2004) Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer 4:528–539

    Article  CAS  PubMed  Google Scholar 

  • Underhill CB (1993) Hyaluronan is inversely correlated with the expression of CD44 in the dermal condensation of the embryonic hair follicle. J Invest Dermatol 101:820–826

    Article  CAS  PubMed  Google Scholar 

  • Vernon RB, Sage EH (1999) A novel quantitative model for study of endothelial cell migration and sprout formation within three-dimensional collagen matrices. Microvasc Res 57:118–133

    Article  CAS  PubMed  Google Scholar 

  • Wilkinson TS, Potter-Perigo S, Tsoi C, Altman LC, Wight TN (2004) Pro- and anti-inflammatory factors cooperate to control hyaluronan synthesis in lung fibroblasts. Am J Respir Cell Mol Biol 31:92–99

    Article  CAS  PubMed  Google Scholar 

  • Wu CC, Ding SJ, Wang YH, Tang MJ, Chang HC (2005) Mechanical properties of collagen gels derived from rats of different ages. J Biomater Sci Polym Ed 16:1261–1275

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Drs. Daniella Bianchi-Frias, Cynthia Sprenger, and Amy Bradshaw for helpful discussions, and Virginia M. Green, PhD, for editorial review of the manuscript.

Conflict of interest

The authors have no conflicts of interest to declare.

Contract/grant sponsor

R21 AG033391 NIA/NIH (M.J.R.); R01 EB012558, NIBIB/NIH (R.B.V./T.N.W)

Author information

Authors and Affiliations

  1. Department of Medicine, University of Washington, Harborview Medical Center, 325 9th Avenue, Box 359625, Seattle, WA, 98104, USA

    Mamatha Damodarasamy, Stephen R. Plymate & May J. Reed

  2. Matrix Biology Program, Benaroya Research Institute at Virginia Mason, 1201 9th Avenue, Seattle, WA, 98101, USA

    Robert B. Vernon, Christina K. Chan & Thomas N. Wight

  3. Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA

    Stephen R. Plymate

Authors
  1. Mamatha Damodarasamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert B. Vernon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christina K. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephen R. Plymate
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas N. Wight
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. May J. Reed
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to May J. Reed.

Additional information

Editor: T. Okamoto

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Damodarasamy, M., Vernon, R.B., Chan, C.K. et al. Hyaluronan in aged collagen matrix increases prostate epithelial cell proliferation. In Vitro Cell.Dev.Biol.-Animal 51, 50–58 (2015). https://doi.org/10.1007/s11626-014-9800-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11626-014-9800-z

Keywords

Search

Navigation