Profile of MMP and TIMP Expression in Human Pancreatic Stellate Cells: Regulation by IL-1α and TGFβ and Implications for Migration of Pancreatic Cancer Cells

Abstract

Pancreatic ductal adenocarcinoma is characterized by a prominent fibroinflammatory stroma with both tumor-promoting and tumor-suppressive functions. The pancreatic stellate cell (PSC) is the major cellular stromal component and the main producer of extracellular matrix proteins, including collagens, which are degraded by metalloproteinases (MMPs). PSCs interact with cancer cells through various factors, including transforming growth factor (TGF)β and interleukin (IL)-1α. The role of TGFβ in the dual nature of tumor stroma, i.e., protumorigenic or tumor suppressive, is not clear. We aimed to investigate the roles of TGFβ and IL-1α in the regulation of MMP profiles in PSCs and the subsequent effects on cancer cell migration. Human PSCs isolated from surgically resected specimens were cultured in the presence of pancreatic cancer cell lines, as well as IL-1α or TGFβ. MMP production and activities in PSCs were quantified by gene array transcripts, mRNA measurements, fluorescence resonance energy transfer–based activity assay, and zymography. PSC-conditioned media and pancreatic cancer cells were included in a collagen matrix cell migration model. We found that production of IL-1α by pancreatic cancer cells induced alterations in MMP and tissue inhibitors of matrix metalloproteinase (TIMP) profiles and activities in PSCs, upregulated expression and activation of MMP1 and MMP3, and enhanced migration of pancreatic cancer cells in the collagen matrix model. TGFβ counteracted the effects of IL-1α on PSCs, reestablished PSC MMP and TIMP profiles and activities, and inhibited migration of cancer cells. This suggests that tumor TGFβ has a role as a suppressor of stromal promotion of tumor progression through alterations in PSC MMP profiles with subsequent inhibition of pancreatic cancer cell migration.

Functional heterogeneity in tumor-derived human pancreatic stellate cells: Differential expression of HGF and implications for mitogenic signaling and migration in pancreatic cancer cells

“…Furthermore, the SC41 cells revealed interesting additional details about the regulation and functional role of HGF in the cellular interactions studied here. Thus, while we have previously shown that IL-1α is abundantly present in the malignant cells in PDAC and regulates PSC production of various ECM components [ 30 ], and enhances the ability of PSCs to stimulate pancreatic cancer cells [ 20 ], the present results indicated that IL-1α also increased the HGF production in SC41 cells up to a level that permitted stimulation of BxPC-3 cell migration. This did not occur in the SC42 cells, adding to the evidence of heterogeneity.…”

Targeting the tumour stroma to improve cancer therapy

“…These proteins are endogenous negative regulators of MMP activity; many cancers have aberrant expression of TIMPs and/or MMPs 95 . Loss or reduction of expression TIMPs causes an increase in MMP function and enables activation of the stroma and subsequent tumour progression 96,97 . Overexpression of TIMPs, on the other hand, reduces tumorigenesis, growth, angiogenesis, and metastasis in cancer models, such as those of the pancreas 98 .…”

Pancreatic Cancer Chemoresistance to Gemcitabine

“…In PDAC, PSCs are activated through multiple activation pathways including platelet-derived growth factor (PDGF), transforming growth factor (TGF)-β, tumor necrosis factor (TNF)-α and interleukins (IL)-1, -6 and -10 [ 17 , 32 ]. Activated PSCs play decisive roles in the desmoplastic reaction and ECM remodeling in PDAC, via secretion of factors such as collagen-type I, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) [ 33 , 34 ]. In addition, the multiple CAF stimulated signals in cancer cells are often redundant to specific target(s) of a selected chemotherapy; hence, effective therapy must typically overcome several obstacles at different levels [ 35 , 36 ].…”