Migratory cells including invasive tumor cells frequently express CD44, a major receptor for hyaluronan and membrane-type 1 matrix metalloproteinase (MT1-MMP) that degrades extracellular matrix at the pericellular region. In this study, we demonstrate that MT1-MMP acts as a processing enzyme for CD44H, releasing it into the medium as a soluble 70-kD fragment. Furthermore, this processing event stimulates cell motility; however, expression of either CD44H or MT1-MMP alone did not stimulate cell motility. Coexpression of MT1-MMP and mutant CD44H lacking the MT1-MMP–processing site did not result in shedding and did not promote cell migration, suggesting that the processing of CD44H by MT1-MMP is critical in the migratory stimulation. Moreover, expression of the mutant CD44H inhibited the cell migration promoted by CD44H and MT1-MMP in a dominant-negative manner. The pancreatic tumor cell line, MIA PaCa-2, was found to shed the 70-kD CD44H fragment in a MT1-MMP–dependent manner. Expression of the mutant CD44H in the cells as well as MMP inhibitor treatment effectively inhibited the migration, suggesting that MIA PaCa-2 cells indeed use the CD44H and MT1-MMP as migratory devices. These findings revealed a novel interaction of the two molecules that have each been implicated in tumor cell migration and invasion.
Therapeutic
nanoreactors are of increasing interest in precise
cancer therapy, which have been explored to in situ produce therapeutic compounds from inert prodrugs or intrinsic molecules
at the target sites. However, engineering a nanoreactor with tumor
activable cascade reactions for efficient cooperative cancer therapy
remains a great challenge. Herein, we demonstrate a polymersome nanoreactor
with tumor acidity-responsive membrane permeability to activate cascade
reactions for orchestrated cooperative cancer treatment. The nanoreactors
are constructed from responsive polyprodrug polymersomes incorporating
ultrasmall iron oxide nanoparticles and glucose oxidase in the membranes
and inner aqueous cavities, respectively. The cascade reactions including
glucose consumption to generate H2O2, accelerated
iron ion release, Fenton reaction between H2O2 and iron ion to produce hydroxyl radicals (•OH), and •OH-triggered
rapid release of parent drugs can be specifically activated by the
tumor acidity-responsive membrane permeability. During this process,
the orchestrated cooperative cancer therapy including starving therapy,
chemodynamic therapy, and chemotherapy is realized for high-efficiency
tumor suppression by the in situ consumed and produced
compounds. The nanoreactor design with tumor-activable cascade reactions
represents an insightful paradigm for precise cooperative cancer therapy.
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