Mutations in Bone Marrow-Derived Stromal Stem Cells Unmask Latent Malignancy
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 a...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Mary Ann Liebert
2011
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| Online Access: | http://hdl.handle.net/1721.1/62305 |
| _version_ | 1826193889629831168 |
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| author | Houghton, JeanMarie Li, Hanchen Fan, Xueli Liu, Yingwang Liu, Jian Hua Rao, Varada P. Poutahidis, Theofilos Taylor, Christie L. Jackson, Erin A. Hewes, Christine M. Lyle, Stephen Cerny, Anna Bowen, Glennice Cerny, Jan Moore, Nathan Kurt-Jones, Evelyn A. Erdman, Susan E. |
| author2 | Massachusetts Institute of Technology. Division of Comparative Medicine |
| author_facet | Massachusetts Institute of Technology. Division of Comparative Medicine Houghton, JeanMarie Li, Hanchen Fan, Xueli Liu, Yingwang Liu, Jian Hua Rao, Varada P. Poutahidis, Theofilos Taylor, Christie L. Jackson, Erin A. Hewes, Christine M. Lyle, Stephen Cerny, Anna Bowen, Glennice Cerny, Jan Moore, Nathan Kurt-Jones, Evelyn A. Erdman, Susan E. |
| author_sort | Houghton, JeanMarie |
| collection | MIT |
| description | 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, ApcMin/+ [superscript Min /+] and ApcMin/+ [superscript 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 ApcMin/+ [superscript Min /+] mutation, p53MSC homed to mammary tissue and significantly increased the incidence of mammary carcinoma. Tumor necrosis factor (TNF)-α-dependent [(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-α [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. |
| first_indexed | 2024-09-23T09:46:55Z |
| format | Article |
| id | mit-1721.1/62305 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:46:55Z |
| publishDate | 2011 |
| publisher | Mary Ann Liebert |
| record_format | dspace |
| spelling | mit-1721.1/623052022-09-26T13:41:54Z Mutations in Bone Marrow-Derived Stromal Stem Cells Unmask Latent Malignancy Houghton, JeanMarie Li, Hanchen Fan, Xueli Liu, Yingwang Liu, Jian Hua Rao, Varada P. Poutahidis, Theofilos Taylor, Christie L. Jackson, Erin A. Hewes, Christine M. Lyle, Stephen Cerny, Anna Bowen, Glennice Cerny, Jan Moore, Nathan Kurt-Jones, Evelyn A. Erdman, Susan E. Massachusetts Institute of Technology. Division of Comparative Medicine Erdman, Susan E. Rao, Varada P. Poutahidis, Theofilos Jackson, Erin A. Hewes, Christine M. Erdman, Susan E. 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, ApcMin/+ [superscript Min /+] and ApcMin/+ [superscript 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 ApcMin/+ [superscript Min /+] mutation, p53MSC homed to mammary tissue and significantly increased the incidence of mammary carcinoma. Tumor necrosis factor (TNF)-α-dependent [(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-α [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. National Institutes of Health (U.S.) (Grant RO1CA119061) (Grant R01 AI51405) (Grant RO1CA108854) United States. Dept. of Defense ( Contract W81XWH-05-01-0460) Pythagoras II Grant (80860) 2011-04-22T20:40:40Z 2011-04-22T20:40:40Z 2010-07 2010-03 Article http://purl.org/eprint/type/JournalArticle 1547-3287 http://hdl.handle.net/1721.1/62305 Houghton, Jeanmarie et al. “Mutations in Bone Marrow-Derived Stromal Stem Cells Unmask Latent Malignancy.” Stem Cells and Development 19.8 (2010) : 1153-1166. Copyright © 2010, Mary Ann Liebert, Inc. en_US http://dx.doi.org/10.1089/scd.2009.0439 Stem Cells and Development Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Mary Ann Liebert IEEE |
| spellingShingle | Houghton, JeanMarie Li, Hanchen Fan, Xueli Liu, Yingwang Liu, Jian Hua Rao, Varada P. Poutahidis, Theofilos Taylor, Christie L. Jackson, Erin A. Hewes, Christine M. Lyle, Stephen Cerny, Anna Bowen, Glennice Cerny, Jan Moore, Nathan Kurt-Jones, Evelyn A. Erdman, Susan E. Mutations in Bone Marrow-Derived Stromal Stem Cells Unmask Latent Malignancy |
| title | Mutations in Bone Marrow-Derived Stromal Stem Cells Unmask Latent Malignancy |
| title_full | Mutations in Bone Marrow-Derived Stromal Stem Cells Unmask Latent Malignancy |
| title_fullStr | Mutations in Bone Marrow-Derived Stromal Stem Cells Unmask Latent Malignancy |
| title_full_unstemmed | Mutations in Bone Marrow-Derived Stromal Stem Cells Unmask Latent Malignancy |
| title_short | Mutations in Bone Marrow-Derived Stromal Stem Cells Unmask Latent Malignancy |
| title_sort | mutations in bone marrow derived stromal stem cells unmask latent malignancy |
| url | http://hdl.handle.net/1721.1/62305 |
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