Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion.
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.
Liu
Dan
D
Department of Physiology and Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas, USA.
Hornsby
Peter J
PJ
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004151:Dipeptides / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D051381:Rats; D014183:Transplantation, Heterologous
D004273:DNA, Neoplasm; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D001761:Bleomycin; D020782:Matrix Metalloproteinases