Oral squamous cell carcinoma (OSCC), which is the most common malignancy of the oral cavity, is often associated with local and regional invasion. Increased expression of matrix metalloproteinase-9 (MMP-9) is correlated with invasive behavior of OSCC. Because transforming growth factor B1 (TGF-B1) is up-regulated in OSCC tumors, we examined the relationship between TGF-B1 signaling and MMP-9 in human OSCC specimens. Evaluation of human specimens showed that tumors with enhanced TGF-B1 signaling also showed increased MMP-9 expression.

thesis. Further, p38 MAPK inhibition promoted ERK1/2 phosphorylation, providing additional evidence for cross-talk between MAPK pathways. These observations demonstrate the complex reciprocal effects of ERK1/2 and p38 MAPK in the regulation of MMP activity, which could complicate the use of MAPK-specific inhibitors as therapeutic agents to down-regulate the biologic effects of TGF-␤1 on pericellular collagen degradation and tumor invasion.

Pancreatic ductal adenocarcinoma (PDAC) is associated with an intense fibrotic reaction around the tumor known as desmoplastic reaction. This tissue is composed of interstitial matrix, predominantly type I collagen, together with proliferating fibroblastic cells. Despite the recognized importance of tumor-stromal interactions, very little is known about the interactions among pancreatic cells, myofibroblasts, and the interstitial matrix. The current study was undertaken to test the hypothesis that the desmoplastic reaction alters PDAC gene expression and cellular behavior. Evaluation of human pancreatic specimens showed increased fibrosis and enhanced membrane type 1-matrix metalloproteinase (MT1-MMP) expression in tumor specimens compared with normal pancreas. Using an in vitro model of tumor cell-stromal interactions, type I collagen and the extracellular matrix deposited by pancreatic fibroblasts and PDAC cells regulated motility of human papillomavirus-immortalized human pancreatic ductal epithelial (HPDE) cells. These ''stromal'' matrices also regulated MT1-MMP expression by HPDE cells, without affecting the expression of tissue inhibitor of metalloproteinase 2. Treatment with transforming growth factor-B1 (TGF-B1) type I receptor kinase inhibitors and functionblocking anti-TGF-B1 antibody abrogated matrix-mediated MT1-MMP induction. TGF-B1 also promoted MT1-MMPdependent migration by HPDE cells. Moreover, compared with normal tissue, there was increased TGF-B1 signaling in grade 3 tumor specimens as shown by increased phosphoSmad2 staining. These data show that the crosstalk between cancer cells and stromal elements mediated by TGF-B1 influences cell surface-and pericellular matrix-degrading potential in vitro and may contribute to pancreatic cancer progression in vivo.

promoter activity exclusively in oral keratinocytes but not in OSCC cells. The effect of EGF on TGFβ1-mediated Smad-driven promoter activity and N-cadherin expression was reversed when activation of ERK1/2 was blocked. Although EGF and TGFβ1 independently promoted migration of both oral keratinocytes and OSCC cells, EGF decreased TGFβ1-mediated migration of oral keratinocytes but enhanced migration of OSCC cells. Together, these data support a model wherein EGF signaling has an important negative regulatory role on TGFβ1-mediated N-cadherin expression and motility in normal oral keratinocytes, and in which loss of this regulatory mechanism accompanies malignant transformation of the oral epithelium.

Supplementary Figure S from Extracellular Matrix–Mediated Membrane-Type 1 Matrix Metalloproteinase Expression in Pancreatic Ductal Cells Is Regulated by Transforming Growth Factor-β1