MECHANISTIC COUPLING OF CANCER CELL PROLIFERATION AND MIGRATION
MetadataShow full item record
Following uncontrolled proliferation, a subset of primary tumor cells exhibit phenotypic changes that enhance migration and are hypothesized to be the initiators of the metastatic cascade. Tumor cell proliferation and migration have been previously shown to occur either concurrently or divergently of each other. This study reveals a direct coupling between proliferation and migration, through cell density, in metastatic human sarcoma and carcinoma cells - but not in normal or non-metastatic cancer cells-, through a novel synergistic paracrine signaling mechanism via Interleukin 6 (IL-6) and Interleukin 8 (IL-8) with WASF3 and Arp2/3 as key intermediates. Transcriptome sequencing reveals that the functional phenotype of high-density cells that emerges due to proliferation resembles that of low-density cells simultaneously treated with of IL-6 and IL-8 where cell movement is the most enriched gene ontology category. Simultaneous inhibition of IL-6 and IL-8 receptors using Tocilizumab and Reparixin significantly decreases the expression of Arpc2, an important subunit of the Arp2/3 complex, in a mouse xenograft model and consequently reduces metastasis While therapeutic intervention with Tocilizumab and Reparixin represses cell-density-dependent migration and accordingly decreases the metastatic burden of tumor cells, the combination of the drugs does not affect cell proliferation and thus tumor growth. Epidermal growth factor (EGF) and its family of receptors have been implicated in regulating uncontrolled proliferation in tumor cells. To simultaneously target cell proliferation and migration, receptors of IL-6, IL-8, and EGF were inhibited using Tocilizumab, Reparixin, and Cetuximab. The combination of these therapeutics significantly decreases tumor cell migration and proliferation. This study infers a new strategy to decrease tumor growth and metastatic capacity of tumor cells and thus and improve patient outcomes.