| Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. | |
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MedLine Citation:
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PMID: 17409418 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Although cellular senescence is believed to have a tumor suppressor function, senescent cells have been shown to increase the potential for growth of adjacent cancer cells in animal models. Replicatively senescent human fibroblasts increase the growth of cotransplanted cancer cells in vivo, but the role of cells that have undergone damage-mediated stress-induced premature senescence (SIPS) has not been studied in mouse transplant models. Here, we show that human fibroblasts that have undergone SIPS by exposure to the DNA-damaging agent bleomycin increase the growth of cotransplanted cancer cells (MDA-MB-231) in immunodeficient mice. Xenografts containing SIPS fibroblasts (SIPSF) exhibited early tissue damage as evidenced by fluid accumulation (edema). Cancer cells adjacent to the fluid showed increased DNA synthesis. Fluid accumulation, increased xenograft size, and increased cell proliferation were all reduced by the matrix metalloproteinase (MMP) inhibitor GM6001. MMPs and other genes characteristic of inflammation/tissue injury were overexpressed in SIPSF. Inhibition of MMP activity did not affect SIPSF stimulation of cancer cell proliferation in culture. However, another overexpressed product (hepatocyte growth factor) did have a direct mitogenic action on cancer cells. Based on the present results, we propose that senescent cells may promote cancer growth both by a direct mitogenic effect and by an indirect effect via tissue damage. Senescent stromal cells may cause an MMP-mediated increase in permeability of adjacent capillaries, thereby exposing incipient cancer cells to increased levels of mitogens, cytokines, and other plasma products. This exposure may increase cancer cell proliferation and result in promotion of preneoplastic cells. |
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Authors:
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Dan Liu; Peter J Hornsby |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Cancer research Volume: 67 ISSN: 0008-5472 ISO Abbreviation: Cancer Res. Publication Date: 2007 Apr |
Date Detail:
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Created Date: 2007-04-05 Completed Date: 2007-05-09 Revised Date: 2007-12-03 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 3117-26 Citation Subset: IM |
Affiliation:
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Department of Physiology and Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bleomycin / pharmacology Breast Neoplasms / enzymology*, genetics, pathology* Cell Aging / drug effects, physiology Cell Growth Processes / drug effects, physiology Cell Line, Tumor Coculture Techniques DNA, Neoplasm / biosynthesis Dipeptides / pharmacology Fibroblasts / cytology*, drug effects, enzymology*, secretion Humans Matrix Metalloproteinases / antagonists & inhibitors, genetics, metabolism, secretion* Mice Mice, Inbred ICR Mice, SCID Neoplasm Transplantation Rats Transplantation, Heterologous |
| Grant Support | |
ID/Acronym/Agency:
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AG12287/AG/NIA NIH HHS; AG20752/AG/NIA NIH HHS; P30 CA54174/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DNA, Neoplasm; 0/Dipeptides; 0/GM 6001; 11056-06-7/Bleomycin; EC 3.4.24.-/Matrix Metalloproteinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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