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 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.
Houghton
JeanMarie
J
Department of Medicine, Division of Gastroenterology, University of Massachusetts Medical School, Worcester, Massachusetts 01635, USA. jeanmarie.houghton@umassmed.edu
Li
Hanchen
H
Fan
Xueli
X
Liu
Yingwang
Y
Liu
Jian Hua
JH
Rao
Varada P
VP
Poutahidis
Theofilos
T
Taylor
Christie L
CL
Jackson
Erin A
EA
Hewes
Christine
C
Lyle
Stephen
S
Cerny
Anna
A
Bowen
Glennice
G
Cerny
Jan
J
Moore
Nathan
N
Kurt-Jones
Evelyn A
EA
Erdman
Susan E
SE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001853:Bone Marrow; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics; D004848:Epithelium / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D017491:Genes, APC; D006801:Humans; D008321:Mammary Glands, Animal / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D016513:Mice, SCID; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009368:Neoplasm Transplantation / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000637:transplantation; D014183:Transplantation, Heterologous / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D015703:Antigens, CD; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53