Tumor cell density regulates matrix metalloproteinases for enhanced migration

Abstract

// Hasini Jayatilaka 1, 2, 3 , Fatima G. Umanzor 1, 2, * , Vishwesh Shah 1, * , Tomer Meirson 7 , Gabriella Russo 1 , Bartholomew Starich 1 , Pranay Tyle 1 , Jerry S.H. Lee 1, 4, 5, 6 , Shyam Khatau 1 , Hava Gil-Henn 7 and Denis Wirtz 1, 2, 8 1 Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA 2 Johns Hopkins Physical Sciences-Oncology Center, The Johns Hopkins University, Baltimore, MD, USA 3 Department of Pediatrics, Bass Center for Childhood Cancer, Stanford University, Stanford, CA, USA 4 Center for Strategic Scientific Initiatives, National Cancer Institute, Bethesda, MD, USA 5 Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, USA 6 Department of Medicine/Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 7 The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel 8 Department of Oncology and Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA * These authors contributed equally to this work Correspondence to: Denis Wirtz, email: wirtz@jhu.edu Hasini Jayatilaka, email: hasinij@stanford.edu Keywords: cell migration; matrix metalloproteinases; interleukin 6; interleukin 8 Received: February 08, 2018      Accepted: July 18, 2018      Published: August 24, 2018 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.