MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis.
The matrix metalloproteinase MMP-9/gelatinase B is upregulated in angiogenic dysplasias and invasive cancers of the epidermis in a mouse model of multi-stage 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.
Coussens
L M
LM
Cancer Research Institute, University of California, San Francisco 94143, USA. coussens@cc.ucsf.edu
Tinkle
C L
CL
Hanahan
D
D
Werb
Z
Z
D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology*; D016026:Bone Marrow Transplantation; D002294:Carcinoma, Squamous Cell / Q000145:classification / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007249:Inflammation / Q000201:enzymology / Q000473:pathology; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D027383:Papillomaviridae / Q000502:physiology; D019899:Paracrine Communication; D010641:Phenotype; D012878:Skin Neoplasms / Q000145:classification / Q000378:metabolism / Q000473:pathology*; D017154:Stromal Cells / Q000201:enzymology / Q000637:transplantation; D015854:Up-Regulation; D014965:X-Rays
D020780:Matrix Metalloproteinase 9