Tissue Inhibitor of Metalloproteinases-1 Promotes Liver Metastasis by Induction of Hepatocyte Growth Factor Signaling

Abstract

Balanced expression of proteases and their inhibitors is one prerequisite of tissue homeostasis. Metastatic spread of tumor cells through the organism depends on proteolytic activity and is the death determinant for cancer patients. Paradoxically, increased expression of tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural inhibitor of several endometalloproteinases, including matrix metalloproteinases and a disintegrin and metalloproteinase-10 (ADAM-10), in cancer patients is negatively correlated with their survival, although TIMP-1 itself inhibits invasion of some tumor cells. Here, we show that elevated stromal expression of TIMP-1 promotes liver metastasis in two independent tumor models by inducing the hepatocyte growth factor (HGF) signaling pathway and expression of several metastasis-associated genes, including HGF and HGF-activating proteases, in the liver. We also found in an in vitro assay that suppression of ADAM-10 is in principle able to prevent shedding of cMet, which may be one explanation for the increase of cell-associated HGF receptor cMet in livers with elevated TIMP-1. Similar TIMP-1-associated changes in gene expression were detected in livers of patients with metastatic colorectal cancer. The newly identified role of TIMP-1 to create a prometastatic niche may also explain the TIMP-1 paradoxon. [Cancer Res 2007;67(18):8615-23]

Anti-inflammatory cytokines hepatocyte growth factor and interleukin-11 are over-expressed in Polycythemia vera and contribute to the growth of clonal erythroblasts independently of JAK2V617F

“…Our study demonstrates that anti-inflammatory cytokines HGF and IL-11, as well as gp130, the signalling receptor chain common to IL-11 and IL-6, are upregulated in PV independently of JAK2V617F. In addition, TIMP-1, a molecule that controls HGF activity and has been reported to be over-expressed in primary myelofibrosis, was also found to be elevated in PV (Ho et al, 2007;Kopitz et al, 2007). HGF, IL-11 and IL-6 are produced by JAK2WT BMMSCs and JAK2V617F-mutated erythroid progenitors; they act in cascade, activate the STAT3 pathway and stimulate myeloid hematopoiesis.…”

Implication of Metastasis Suppressor NM23-H1 in Maintaining Adherens Junctions and Limiting the Invasive Potential of Human Cancer Cells

“…Interestingly, invasive NM23-H1-silenced cells expressed high levels of TIMP-1 (data not shown). Enhanced expression of this endogenous MMP inhibitor has been linked to poor prognosis in human cancer types and was shown to promote hepatocyte growth factor/scatter factor signaling and downstream expression of MMP-2 and MMP-9 in the liver (37).…”

Migratory neighbors and distant invaders: tumor-associated niche cells

“…HGF can then bind to c-Met expressed in many cancer cells and can increase their invasive and migratory capacity (Nakamura et al 1997). The MMP inhibitor TIMP-1 may also act as a key regulator of HGF/c-Met signaling through suppression of metalloproteinase-10 (ADAM-10) (Kopitz et al 2007). Other paracrine signals involving TGF-␤, EGF, and insulin growth factor (IGF), as well as Wnt1, likely mediate mutually supportive cross-talk between the stromal cells and tumor cells (Bhowmick et al 2004).…”