Regular Article
Lactate Stimulates Fibroblast Expression of Hyaluronan and CD44: The Warburg Effect Revisited

https://doi.org/10.1006/excr.2002.5508Get rights and content

Abstract

Hyaluronan, a high-molecular-weight glycosaminoglycan of the extracellular matrix, is prominent during rapid tissue growth and repair. It stimulates cell motility and hydrates tissue, providing an environment that facilitates cell movement. Markedly enhanced levels of hyaluronan also occur in the stroma surrounding human cancers, thus providing an environment that promotes spread of cancer cells. The ability of malignant tumors to generate lactate, even in the presence of adequate oxygen, is known as the Warburg effect. Early in wound healing as blood and oxygen supply decrease, lactate levels increase, as does stromal hyaluronan, suggesting a cause-and-effect relationship. Similarly, peritumor stromal fibroblast hyaluronan may be a response to cancer cell lactate. To test this, fibroblasts were cultured in the presence of lactate. With increasing lactate, higher levels of hyaluronan were observed, as were levels of CD44 expression, the predominant receptor for hyaluronan. The ability of tumor cells to utilize anaerobic metabolism and to generate lactate, even in the presence of adequate supplies of oxygen, may be one of the mechanisms used to recruit host fibroblasts to deposit hyaluronan and to express CD44, thereby participating in the process of cancer invasion and metastasis.

References (58)

  • P.D. Kittlick et al.

    Hypoxia in fibroblast cultures. 2. Influence of pH on the distribution pattern of acid mucopolysaccharides

    Exp. Pathol. (Jena)

    (1975)
  • R Stern et al.

    Hyaluronidase can modulate expression of CD44

    Exp. Cell Res.

    (2001)
  • K. Kuroda et al.

    Up-regulation of putative hyaluronan synthase mRNA by basic fibroblast growth factor and insulin-like growth factor-1 in human skin fibroblasts

    J. Dermatol. Sci.

    (2001)
  • I.R. Ellis et al.

    Differential motogenic and biosynthetic response of fetal and adult skin fibroblasts to TGF-beta isoforms

    Cytokine

    (1998)
  • Y. Sugiyama et al.

    Putative hyaluronan synthase mRNA are expressed in mouse skin and TGF-beta upregulates their expression in cultured human skin cells

    J. Invest. Dermatol.

    (1998)
  • B.P. Toole

    Proteoglycans and hyaluronan in morphogenesis and differentiation

  • T.C. Laurent et al.

    Hyaluronan

    FASEB J.

    (1992)
  • T.C. Laurent

    The Chemistry, Biology and Medical Applications of Hyaluronan and Its Derivatives

    (1998)
  • B. Delpech et al.

    The origin of hyaluronectin in human tumors

    J. Intern. Med.

    (1997)
  • C.L. Hall et al.

    Hyaluronan: RHAMM mediated cell locomotion and signaling in tumorigenesis

    J. Neurooncol.

    (1995)
  • Granger, H. J., Laine, G. A., Barnes, G. E., and Lewis, R. E.1984. Dynamics and control of transmicrovascular fluid...
  • J. Bajorath

    Structure and function of CD44: Characteristic molecular features and analysis of the hyaluronan binding site

    Results Probl. Cell Differ.

    (2001)
  • J. Lesley et al.

    CD44 structure and function Front

    Biosci.

    (1998)
  • D. Zhu et al.

    Interaction between CD44 and the repeat domain of ankyrin promotes hyaluronic acid-mediated ovarian tumor cell migration

    J. Cell Physiol.

    (2000)
  • J. Entwistle et al.

    HA receptors: Regulators of signalling to the cytoskeleton

    J. Cell. Biochem.

    (1996)
  • L.Y. Bourguignon et al.

    CD44 isoform–cytoskeleton interaction in oncogenic signaling and tumor progression

    Front. Biosci.

    (1998)
  • M.T. Longaker et al.

    Studies in fetal wound healing. V prolonged presence of hyaluronic acid in fetal wound fluid

    Ann. Surg.

    (1991)
  • W. Knudson

    Tumor-associated hyaluronan. Providing an extracellular matrix that facilitates invasion

    Am. J. Pathol.

    (1996)
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