TY - JOUR
T1 - MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis
AU - Coussens, Lisa M.
AU - Tinkle, Christopher L.
AU - Hanahan, Douglas
AU - Werb, Zena
N1 - Funding Information:
We wish to thank Ole Behrendtsen, Alexis Scherl, C. Alex Hartman, Lidiya Korets, and Helen Capili for technical assistance; Dylan Daniels and Nicole Meyer-Morse for assistance with bone marrow transplantation; Alex McMillan for statistical advice; and Gabriele Bergers and Yves DeClerck for critical discussions and insightful comments on the manuscript. This work was supported by grants from the National Cancer Institute (CA72006 to Z. W. and CA 47632 and R37-CA37395 to D. H.) and the American Cancer Society (IRG-9715001 to L. C.); L. C. gratefully acknowledges startup support provided by the UCSF Comprehensive Cancer Center.
PY - 2000/10/27
Y1 - 2000/10/27
N2 - The matrix metalloproteinase MMP-9/gelatinase B is upregulated in angiogenic dysplasias and invasive cancers of the epidermis in a mouse model of multistage tumorigenesis elicited by HPV16 oncogenes. Transgenic mice lacking MMP-9 show reduced keratinocyte hyperproliferation at all neoplastic stages and a decreased incidence of invasive tumors. Yet those carcinomas that do arise in the absence of MMP-9 exhibit a greater loss of keratinocyte differentiation, indicative of a more aggressive and higher grade tumor. Notably, MMP-9 is predominantly expressed in neutrophils, macrophages, and mast cells, rather than in oncogene-positive neoplastic cells. Chimeric mice expressing MMP-9 only in cells of hematopoietic origin, produced by bone marrow transplantation, reconstitute the MMP-9-dependent contributions to squamous carcinogenesis. Thus, inflammatory cells can be coconspirators in carcinogenesis.
AB - The matrix metalloproteinase MMP-9/gelatinase B is upregulated in angiogenic dysplasias and invasive cancers of the epidermis in a mouse model of multistage tumorigenesis elicited by HPV16 oncogenes. Transgenic mice lacking MMP-9 show reduced keratinocyte hyperproliferation at all neoplastic stages and a decreased incidence of invasive tumors. Yet those carcinomas that do arise in the absence of MMP-9 exhibit a greater loss of keratinocyte differentiation, indicative of a more aggressive and higher grade tumor. Notably, MMP-9 is predominantly expressed in neutrophils, macrophages, and mast cells, rather than in oncogene-positive neoplastic cells. Chimeric mice expressing MMP-9 only in cells of hematopoietic origin, produced by bone marrow transplantation, reconstitute the MMP-9-dependent contributions to squamous carcinogenesis. Thus, inflammatory cells can be coconspirators in carcinogenesis.
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U2 - 10.1016/S0092-8674(00)00139-2
DO - 10.1016/S0092-8674(00)00139-2
M3 - Article
C2 - 11081634
AN - SCOPUS:0034721666
SN - 0092-8674
VL - 103
SP - 481
EP - 490
JO - Cell
JF - Cell
IS - 3
ER -