Mutations in Bone Marrow-Derived Stromal Stem Cells Unmask Latent Malignancy

Department of Medicine, Division of Gastroenterology, University of Massachusetts Medical School, Worcester, Massachusetts 01635, USA.
Stem cells and development (Impact Factor: 4.2). 03/2010; 19(8):1153-66. DOI: 10.1089/scd.2009.0439
Source: PubMed

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.

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Available from: Jan Cerny, Aug 12, 2015
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    • "Recent work with stMSCs using a mouse model of breast cancer has defined the importance of aberrant immune responses in the in vivo transformation and maintenance of these cells (Houghton et al., 2010). The local tissue environment may be considered carcinogenic, whereby with the ablation of tumor necrosis factor α (TNFα), the progression of neoplasia stimulated by recruited MSCs within epithelia can be halted (Houghton et al., 2010). A study using human MSCs transduced to express TNF-related apoptosis-inducing ligand (TRAIL), are recruited to the site of tumor formation where they produce significant cancer cell apoptosis in a model of squamous and lung cancer cells, enhancing the effects of chemotherapeutic agents (Loebinger et al., 2010). "
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