Mesenchymal CD44 expression contributes to the acquisition of an activated fibroblast phenotype via TWIST activation in the tumor microenvironment

Cancer Res. 2013 Sep 1;73(17):5347-59. doi: 10.1158/0008-5472.CAN-13-0087. Epub 2013 Jul 9.


Tumor-stroma interactions play a crucial role in cancer progression by eliciting factors that promote proliferative, angiogenic, and invasive supports to the tumor microenvironment. Mesenchymal stromal/stem cells (MSC) contribute to stroma in part as cancer-associated fibroblasts (CAF), but a complete understanding of how MSC contribute to the tumor stroma is lacking. In this study, we show how CAF phenotypes rely upon MSC expression of the multifunctional cell surface glycoprotein CD44, a putative stem cell marker. Through bone marrow transplantation experiments in a transgenic mouse model of cancer, we determined that CD44 deficiency leads to a relative reduction in the contribution of bone marrow-derived cells to tumor stroma. CD44 attenuation in MSC limited their expression of CAF markers induced by tumor conditioning, and these MSC migrated poorly and provided weak angiogenic support compared with wild-type MSC. These defects were linked to deficiencies in the ability of CD44-attenuated MSC to transcriptionally upregulate Twist expression. Together, our results establish that CD44 expression contributes to critical functions in the tumor stroma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Cell Differentiation
  • Cell Movement
  • Cell Proliferation
  • Chromatin Immunoprecipitation
  • Culture Media, Conditioned / pharmacology
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Humans
  • Hyaluronan Receptors / physiology*
  • Immunoenzyme Techniques
  • Mammary Neoplasms, Animal / genetics
  • Mammary Neoplasms, Animal / metabolism
  • Mammary Neoplasms, Animal / pathology*
  • Mesenchymal Stem Cells / metabolism
  • Mesenchymal Stem Cells / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Phenotype
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Microenvironment*
  • Twist-Related Protein 1 / genetics
  • Twist-Related Protein 1 / metabolism*


  • Cd44 protein, mouse
  • Culture Media, Conditioned
  • Hyaluronan Receptors
  • RNA, Messenger
  • Twist-Related Protein 1