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Expression of tissue factor in tumor stroma correlates with progression to invasive human breast cancer: paracrine regulation by carcinoma cell-derived members of the transforming growth factor beta family.

Publication ,  Journal Article
Vrana, JA; Stang, MT; Grande, JP; Getz, MJ
Published in: Cancer Res
November 1, 1996

Tissue factor (TF), the cellular initiator of the protease blood coagulation cascade, has been shown to be expressed in a variety of solid tumors, particularly those of epithelial origin. However, the mechanisms that mediate TF expression in tumors, as well as the clinical implications of this expression, remain largely unknown. In this study, we examined the cytological distribution of TF in normal human breast tissue and breast carcinomas. Epithelial cells exhibited TF immunoreactivity with little obvious correlation with malignant progression from in situ lesions to invasive cancer. However, there was a strong correlation between progression to invasive cancer and the expression of TF antigen in cellular components of the stroma. TF-positive cells were particularly abundant in close proximity to infiltrating tumor cells and included both macrophages and myofibroblasts, as determined by double-immunofluorescent staining for TF and cell type-specific marker proteins. Double-immunofluorescent staining for TF and transforming growth factor beta (TGF-beta) revealed TGF-beta immunoreactivity both in tumor cells and in the extracellular matrix surrounding TF-positive stromal cells. To test the role of carcinoma cell-derived growth factors in the regulation of stromal cell TF activity, we examined the ability of conditioned media (CM) from breast carcinoma cell lines to stimulate TF activity in myofibroblast-like cells in vitro. Extracts from myofibroblasts exposed to CM displayed strong TF procoagulant activity. However, extracts from cells exposed to unconditioned media or CM pretreated with anti-TGF-beta antibodies did not. The induction of TF activity was also observed upon treatment of indicator cells with recombinant TGF-beta isoforms. Collectively, these data indicate that the recruitment and/or activation of TF-expressing stromal cells is an early event in progression to invasive breast cancer and likely occurs, in part, as a paracrine response to tumor cell-derived members of the TGF-beta family of growth factors.

Duke Scholars

Published In

Cancer Res

ISSN

0008-5472

Publication Date

November 1, 1996

Volume

56

Issue

21

Start / End Page

5063 / 5070

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transforming Growth Factor beta
  • Thromboplastin
  • Oncology & Carcinogenesis
  • Mice, Inbred AKR
  • Mice
  • Humans
  • Female
  • Breast Neoplasms
  • Breast
 

Citation

APA
Chicago
ICMJE
MLA
NLM

Published In

Cancer Res

ISSN

0008-5472

Publication Date

November 1, 1996

Volume

56

Issue

21

Start / End Page

5063 / 5070

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transforming Growth Factor beta
  • Thromboplastin
  • Oncology & Carcinogenesis
  • Mice, Inbred AKR
  • Mice
  • Humans
  • Female
  • Breast Neoplasms
  • Breast