reparixin and Sarcoma

Following uncontrolled proliferation, a subset of primary tumour cells acquires additional traits/mutations to trigger phenotypic changes that enhance migration and are hypothesized to be the initiators of metastasis. This study reveals an adaptive mechanism that harnesses synergistic paracrine signalling via IL-6/8, which is amplified by cell proliferation and cell density, to directly promote cell migration. This effect occurs in metastatic human sarcoma and carcinoma cells- but not in normal or non-metastatic cancer cells-, and likely involves the downstream signalling of WASF3 and Arp2/3. The transcriptional phenotype of high-density cells that emerges due to proliferation resembles that of low-density cells treated with a combination of IL-6/8. Simultaneous inhibition of IL-6/8 receptors decreases the expression of WASF3 and Arp2/3 in a mouse xenograft model and reduces metastasis. This study reveals a potential mechanism that promotes tumour cell migration and infers a strategy to decrease metastatic capacity of tumour cells.

Topics: Actin-Related Protein 2-3 Complex; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Cell Movement; Cell Proliferation; Humans; Interleukin-6; Interleukin-8; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Neoplasm Invasiveness; Paracrine Communication; Receptors, Interleukin-6; Receptors, Interleukin-8A; RNA, Small Interfering; Sarcoma; Signal Transduction; Sulfonamides; Wiskott-Aldrich Syndrome Protein Family; Xenograft Model Antitumor Assays