Lactate stimulates fibroblast expression of hyaluronan and CD44: the Warburg effect revisited

Exp Cell Res. 2002 May 15;276(1):24-31. doi: 10.1006/excr.2002.5508.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Breast Neoplasms / metabolism
  • Carcinoma, Ductal, Breast / metabolism
  • Cell Line
  • Culture Media
  • Dose-Response Relationship, Drug
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Humans
  • Hyaluronan Receptors / biosynthesis*
  • Hyaluronan Receptors / genetics
  • Hyaluronic Acid / biosynthesis*
  • Hyaluronic Acid / genetics
  • Lactic Acid / pharmacology*
  • Models, Biological*
  • RNA, Messenger / biosynthesis
  • Transcriptional Activation


  • Culture Media
  • Hyaluronan Receptors
  • RNA, Messenger
  • Lactic Acid
  • Hyaluronic Acid