MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis

The matrix metalloproteinase MMP-9/gelatinase B is upregulated in angiogeni c dysplasias and invasive cancers of the epidermis in a mouse model of mult istage tumorigenesis elicited by HPV16 oncogenes. Transgenic mice lacking M MP-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 differ entiation, indicative of a more aggressive and higher grade tumor. Notably, MMP-9 is predominantly expressed in neutrophils, macrophages, and mast cel ls, rather than in oncogene-positive neoplastic cells. Chimeric mice expres sing MMP-9 only in cells of hematopoietic origin, produced by bone marrow t ransplantation, reconstitute the MMP-9-dependent contributions to squamous carcinogenesis. Thus, inflammatory cells can be coconspirators in carcinoge nesis.