Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 25, Pages 9786-9791Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1121160109
Keywords
mechanobiology; desmoplasia; angiogenesis; tissue engineering
Categories
Funding
- NIH/NCI [RC1 CA146065, R21 CA161532, R01 CA96823]
- Cornell Center on the Microenvironment and Metastasis [NCI U54 CA143876]
- NSF [CMMI-1031068]
- Graduate Research Fellowship
- Div Of Civil, Mechanical, & Manufact Inn
- Directorate For Engineering [1031068] Funding Source: National Science Foundation
- Div Of Civil, Mechanical, & Manufact Inn
- Directorate For Engineering [1031139] Funding Source: National Science Foundation
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Multipotent adipose-derived stem cells (ASCs) are increasingly used for regenerative purposes such as soft tissue reconstruction following mastectomy; however, the ability of tumors to commandeer ASC functions to advance tumor progression is not well understood. Through the integration of physical sciences and oncology approaches we investigated the capability of tumor-derived chemical and mechanical cues to enhance ASC-mediated contributions to tumor stroma formation. Our results indicate that soluble factors from breast cancer cells inhibit adipogenic differentiation while increasing proliferation, proangiogenic factor secretion, and myofibroblastic differentiation of ASCs. This altered ASC phenotype led to varied extracellular matrix (ECM) deposition and contraction thereby enhancing tissue stiffness, a characteristic feature of breast tumors. Increased stiffness, in turn, facilitated changes in ASC behavior similar to those observed with tumor-derived chemical cues. Orthotopic mouse studies further confirmed the pathological relevance of ASCs in tumor progression and stiffness in vivo. In summary, altered ASC behavior can promote tumorigenesis and, thus, their implementation for regenerative therapy should be carefully considered in patients previously treated for cancer.
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