Breast cancer normalization induced by embryonic mesenchyme is mediated by extracellular matrix biglycan. Integr Biol (Camb) 2013 Aug;5(8):1045-56
Date
07/03/2013Pubmed ID
23817524DOI
10.1039/c3ib40103kScopus ID
2-s2.0-84893450991 (requires institutional sign-in at Scopus site) 33 CitationsAbstract
Some epithelial cancers can be induced to revert to quiescent differentiated tissue when combined with embryonic mesenchyme; however, the mechanism of this induction is unknown. Here we combine tissue engineering, developmental biology, biochemistry and proteomics approaches to attack this problem. Using a synthetic reconstitution system, we show that co-culture of breast cancer cells with embryonic mesenchyme from early stage (E12.5-13.5) mammary glands decreases tumor cell proliferation while stimulating acinus differentiation, whereas cancer-associated fibroblasts (CAFs) fail to produce these normalizing effects. When insoluble extracellular matrices (ECMs) were isolated from cultured early stage (E12.5-13.5) embryonic mammary mesenchyme cells or E10 tooth mesenchyme and recombined with mammary tumor cells, they were found to be sufficient to induce breast cancer normalization including enhanced expression of estrogen receptor-α (ER-α). In contrast, ECM from later stage (E14.5) mammary mesenchyme and conditioned medium isolated from mesenchymal cell cultures were ineffective. Importantly, when the inductive ECMs produced by early stage embryonic mammary mesenchyme were scraped from dishes and injected into fast-growing breast tumors in mice, they significantly inhibited cancer expansion. Proteomics analysis of the detergent insoluble ECM material revealed several matrix components that were preferentially expressed in the embryonic ECMs. Analysis of two of these molecules previously implicated in cancer regulation--biglycan and tenascin C--revealed that addition of biglyan can mimic the tumor normalization response, and that siRNA knockdown of its expression in cultured embryonic mesenchyme results in loss of the ECM's inductive activity. These studies confirm that embryonic mesenchyme retains the ability to induce partial breast cancer reversion, and that its inductive capability resides at least in part in the ECM protein biglycan that it produces.
Author List
Bischof AG, Yüksel D, Mammoto T, Mammoto A, Krause S, Ingber DEAuthors
Akiko Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of WisconsinTadanori Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBiglycan
Breast Neoplasms
Cell Culture Techniques
Cell Differentiation
Cell Proliferation
Coculture Techniques
Culture Media, Conditioned
Epithelium
Estrogen Receptor alpha
Extracellular Matrix
Female
Fibroblasts
Humans
Immunohistochemistry
Mammary Glands, Animal
Mammary Neoplasms, Animal
Mesoderm
Mice
Proteomics
RNA, Small Interfering
Tenascin
Time Factors
Tissue Engineering