Abstract
Neoplastic epithelia may remain dormant and clinically unapparent in human patients for decades. Multiple risk factors including mutations in tumor cells or the stromal cells may affect the switch from dormancy to malignancy. Gene mutations, including p53 mutations, within the stroma of tumors are associated with a worse clinical prognosis; however, it is not known if these stromal mutations can promote tumors in genetically at-risk tissue. To address this question, Apc(Min/+) and Apc(Min/+) Rag2(-/-) mice, which have a predilection to mammary carcinoma (as well as wild-type (wt) mice), received mesenchymal stem cells (MSC) with mutant p53 (p53MSC) transferred via tail vein injection. In the wt mouse, p53MSC circulated in the periphery and homed to the marrow cavity where they could be recovered up to a year later without apparent effect on the health of the mouse. No mammary tumors were found. However, in mice carrying the Apc(Min/+) mutation, p53MSC homed to mammary tissue and significantly increased the incidence of mammary carcinoma. Tumor necrosis factor (TNF)-alpha-dependent factors elaborated from mesenchymal cells converted quiescent epithelia into clinically apparent disease. The increased cancer phenotype was completely preventable with neutralization of TNF-alpha or by transfer of CD4(+) regulatory T cells from immune competent donors, demonstrating that immune competency to regulate inflammation was sufficient to maintain neoplastic dormancy even in the presence of oncogenic epithelial and stromal mutations. The significant synergy between host immunity and mesenchymal cells identified here may restructure treatments to restore an anticancer microenvironment.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Animals
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Antigens, CD / metabolism
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Bone Marrow
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Bone Marrow Cells / metabolism
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Bone Marrow Cells / pathology*
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Breast Neoplasms / etiology
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Carcinoma, Ductal, Breast / etiology
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Carcinoma, Ductal, Breast / metabolism
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Carcinoma, Ductal, Breast / pathology
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Movement / genetics
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Cell Proliferation / drug effects
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Culture Media, Conditioned / metabolism
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Culture Media, Conditioned / pharmacology
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DNA-Binding Proteins / genetics
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Epithelium / pathology
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Female
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Genes, APC
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Humans
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Mammary Glands, Animal / pathology
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Mammary Neoplasms, Animal / etiology*
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Mammary Neoplasms, Animal / genetics
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Mammary Neoplasms, Animal / immunology
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Mammary Neoplasms, Animal / metabolism
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Mammary Neoplasms, Animal / pathology
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Mesenchymal Stem Cell Transplantation
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Mesenchymal Stem Cells / metabolism
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Mesenchymal Stem Cells / pathology*
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Mice
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, Knockout
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Mice, Mutant Strains
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Mice, SCID
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Middle Aged
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Mutation / genetics*
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Mutation, Missense / genetics
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Neoplasm Transplantation / pathology
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Stromal Cells / metabolism
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Stromal Cells / pathology
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / transplantation
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Transplantation, Heterologous / pathology
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
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Tumor Suppressor Protein p53 / genetics*
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antigens, CD
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Culture Media, Conditioned
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DNA-Binding Proteins
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Rag2 protein, mouse
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Protein p53