Breast fibroblasts modulate epithelial cell proliferation in three-dimensional in vitro co-culture

Breast Cancer Research

Andra R Frost⁵  Danny R Welch⁵  Jaideep V Thottassery³  Grier P Page⁴  Sandra R Gault⁵  Damon B Bowe¹  Martin R Johnson¹  Zdenek Novak²  Andrea Sadlonova⁵ 

[1] Department of Pharmacology and Toxicology, The University of Alabama at Birmingham, Alabama, USA;Department of Pediatrics, The University of Alabama at Birmingham, Alabama, USA;Drug Discovery Division, Southern Research Institute, Birmingham, Alabama, USA;Department of Biostatistics, The University of Alabama at Birmingham, Alabama, USA;Department of Pathology, The University of Alabama at Birmingham, Alabama, USA

关键词: stroma;    insulin-like growth factor;    fibroblast;    breast epithelium;    breast cancer;   

Others  :  1115100
DOI  :  10.1186/bcr949

 received in 2003-12-15, accepted in 2004-09-24,  发布年份 2004

【 摘 要 】

Background

Stromal fibroblasts associated with in situ and invasive breast carcinoma differ phenotypically from fibroblasts associated with normal breast epithelium, and these alterations in carcinoma-associated fibroblasts (CAF) may promote breast carcinogenesis and cancer progression. A better understanding of the changes that occur in fibroblasts during carcinogenesis and their influence on epithelial cell growth and behavior could lead to novel strategies for the prevention and treatment of breast cancer. To this end, the effect of CAF and normal breast-associated fibroblasts (NAF) on the growth of epithelial cells representative of pre-neoplastic breast disease was assessed.

Methods

NAF and CAF were grown with the nontumorigenic MCF10A epithelial cells and their more transformed, tumorigenic derivative, MCF10AT cells, in direct three-dimensional co-cultures on basement membrane material. The proliferation and apoptosis of MCF10A cells and MCF10AT cells were assessed by 5-bromo-2'-deoxyuridine labeling and TUNEL assay, respectively. Additionally, NAF and CAF were compared for expression of insulin-like growth factor II as a potential mediator of their effects on epithelial cell growth, by ELISA and by quantitative, real-time PCR.

Results

In relatively low numbers, both NAF and CAF suppressed proliferation of MCF10A cells. However, only NAF and not CAF significantly inhibited proliferation of the more transformed MCF10AT cells. The degree of growth inhibition varied among NAF or CAF from different individuals. In greater numbers, NAF and CAF have less inhibitory effect on epithelial cell growth. The rate of epithelial cell apoptosis was not affected by NAF or CAF. Mean insulin-like growth factor II levels were not significantly different in NAF versus CAF and did not correlate with the fibroblast effect on epithelial cell proliferation.

Conclusion

Both NAF and CAF have the ability to inhibit the growth of pre-cancerous breast epithelial cells. NAF have greater inhibitory capacity than CAF, suggesting that the ability of fibroblasts to inhibit epithelial cell proliferation is lost during breast carcinogenesis. Furthermore, as the degree of transformation of the epithelial cells increased they became resistant to the growth-inhibitory effects of CAF. Insulin-like growth factor II could not be implicated as a contributor to this differential effect of NAF and CAF on epithelial cell growth.

【 授权许可】

   
2004 Sadlonova et al., licensee BioMed Central Ltd.

【 图 表 】

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