Abstract
Matrix metalloproteinases (MMPs) may play a critical role in metastatic cancers, yet multiple human clinical trials targeting MMPs have surprisingly failed. Cancer cell density changes dramatically during the early growth of a primary tumor and during the early seeding steps of secondary tumors and has been implicated in playing an important role in regulating metastasis and drug resistance. This study reveals that the expression of MMPs is tightly regulated by local tumor cell density through the synergistic signaling mechanism of Interleukin 6 (IL-6) and Interleukin 8 (IL-8) via the JAK2/STAT3 complex. Local tumor cell density also plays a role in the responsiveness of cells to matrix metalloproteinases inhibitors (MMPI), such as Batimastat, Marimastat, Bryostatin I, and Cipemastat, where different migratory phenotypes are observed in low and high cell density conditions. Cell density-dependent MMP regulation can be directly targeted by the simultaneous inhibition of IL-6 and IL-8 receptors via Tocilizumab and Reparixin to significantly decrease the expression of MMPs in mouse xenograft models and decrease effective metastasis. This study reveals a new strategy to decrease MMP expression through pharmacological intervention of the cognate receptors of IL-6 and IL-8 to decrease metastatic capacity of tumor cells.
Highlights
Matrix metalloproteinases (MMPs) form a family of metzincin proteases that contribute to the degradation of extracellular-matrix proteins and remodeling of the basement membrane [1,2,3]
ShRNA-mediated knockdowns of particular MMPs induces different migratory phenotypes at low and high cell densities. These different migratory phenotypes can be observed when fibrosacroma and carcinoma cells are treated with matrix metalloproteinases inhibitors (MMPI), including Batimastat, Marimastat, Bryostatin-1, and Cipemastat
Considering the role that MMPs play in regulating cell migration, and that cell density regulates MMP production through the synergistic signaling of Interleukin 6 (IL-6) and Interleukin 8 (IL-8), we speculated that treatment of cells with Tocilizumab and Reparixin (T+R) would down-regulate MMP production
Summary
Matrix metalloproteinases (MMPs) form a family of metzincin proteases that contribute to the degradation of extracellular-matrix proteins and remodeling of the basement membrane [1,2,3]. Overexpression and activation of MMPs leads to the degradation of the basement membrane facilitating tumor cell invasion. Following many successful preclinical studies using matrix metalloproteinases inhibitors (MMPIs) as anti-cancer agents, these inhibitors were tested in multiple human clinical trials [5]. These clinical trials of over 50 MMPIs failed. While the failure of these clinical trials may be attributed to poor design, limited specificity, inadequate clinical end points, and poor pharmacokinetics (poor oral bioavailability and dose-limiting toxicities), a limited fundamental understanding of the specific regulators of MMPs could be an important underlying cause [6]
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