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Cited by 1,361

The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.

Collagen density promotes mammary tumor initiation and progression

Open access
Provenzano, Paolo P, Inman, David R, Eliceiri, Kevin W, Knittel, Justin G, Yan, Long, Rueden, Curtis T, White, John G, Keely, Patricia J·2008·BMC Medicine
DOI 10.1186/1741-7015-6-11
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Abstract

BACKGROUND: Mammographically dense breast tissue is one of the greatest risk factors for developing breast carcinoma. Despite the strong clinical correlation, breast density has not been causally linked to tumorigenesis, largely because no animal model has existed for studying breast tissue density. Importantly, regions of high breast density are associated with increased stromal collagen. Thus, the influence of the extracellular matrix on breast carcinoma development and the underlying molecular mechanisms are not understood. METHODS: To study the effects of collagen density on mammary tumor formation and progression, we utilized a bi-transgenic tumor model with increased stromal collagen in mouse mammary tissue. Imaging of the tumors and tumor-stromal interface in live tumor tissue was performed with multiphoton laser-scanning microscopy to generate multiphoton excitation and spectrally resolved fluorescent lifetimes of endogenous fluorophores. Second harmonic generation was utilized to image stromal collagen. RESULTS: Herein we demonstrate that increased stromal collagen in mouse mammary tissue significantly increases tumor formation approximately three-fold (p < 0.00001) and results in a significantly more invasive phenotype with approximately three times more lung metastasis (p < 0.05). Furthermore, the increased invasive phenotype of tumor cells that arose within collagen-dense mammary tissues remains after tumor explants are cultured within reconstituted three-dimensional collagen gels. To better understand this behavior we imaged live tumors using nonlinear optical imaging approaches to demonstrate that local invasion is facilitated by stromal collagen re-organization and that this behavior is significantly increased in collagen-dense tissues. In addition, using multiphoton fluorescence and spectral lifetime imaging we identify a metabolic signature for flavin adenine dinucleotide, with increased fluorescent intensity and lifetime, in invading metastatic cells. CONCLUSION: This study provides the first data causally linking increased stromal collagen to mammary tumor formation and metastasis, and demonstrates that fundamental differences arise and persist in epithelial tumor cells that progressed within collagen-dense microenvironments. Furthermore, the imaging techniques and signature identified in this work may provide useful diagnostic tools to rapidly assess fresh tissue biopsies.

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Metadata

Authors
Provenzano, P. P., Inman, D. R., Eliceiri, K. W., Knittel, J. G., Yan, L., Rueden, C. T., White, J. G., & Keely, P. J.
Venue
BMC Medicine
Publisher
Springer Science and Business Media LLC
Published
2008-04-28
Volume
6
Issue
1
Pages
11-11
ISSN
1741-7015 (ISSN-L)
DOI
10.1186/1741-7015-6-11
OpenAlex
W2136737404
Cited by
1,361
References
7
FWCI
13.53
Type
journal article
Language
en
Open access
gold

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