Tumor cell density regulates matrix metalloproteinases for enhanced migration
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Hasini Jayatilaka1,2,3, Fatima G. Umanzor1,2,*, Vishwesh Shah1,*, Tomer Meirson7, Gabriella Russo1, Bartholomew Starich1, Pranay Tyle1, Jerry S.H. Lee1,4,5,6, Shyam Khatau1, Hava Gil-Henn7 and Denis Wirtz1,2,8
1Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA
2Johns Hopkins Physical Sciences-Oncology Center, The Johns Hopkins University, Baltimore, MD, USA
3Department of Pediatrics, Bass Center for Childhood Cancer, Stanford University, Stanford, CA, USA
4Center for Strategic Scientific Initiatives, National Cancer Institute, Bethesda, MD, USA
5Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, USA
6Department of Medicine/Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
7The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
8Department of Oncology and Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
*These authors contributed equally to this work
Denis Wirtz, email: [email protected]
Hasini Jayatilaka, email: [email protected]
Keywords: cell migration; matrix metalloproteinases; interleukin 6; interleukin 8
Received: February 08, 2018 Accepted: July 18, 2018 Published: August 24, 2018
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.
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