Trading in your spindles for blebs: the amoeboid tumor cell phenotype in prostate cancer

Abstract

Prostate cancer (PCa) remains a principal cause of mortality in developed countries. Because no clinical interventions overcome resistance to androgen ablation therapy, management of castration resistance and metastatic disease remains largely untreatable. Metastasis is a multistep process in which tumor cells lose cell-cell contacts, egress from the primary tumor, intravasate, survive shear stress within the vasculature and extravasate into tissues to colonize ectopic sites. Tumor cells reestablish migratory behaviors employed during nonneoplastic processes such as embryonic development, leukocyte trafficking and wound healing. While mesenchymal motility is an established paradigm of dissemination, an alternate, ‘amoeboid’ phenotype is increasingly appreciated as relevant to human cancer. Here we discuss characteristics and pathways underlying the phenotype, and highlight our findings that the cytoskeletal regulator DIAPH3 governs the mesenchymal-amoeboid transition. We also describe our identification of a new class of tumor-derived microvesicles, large oncosomes, produced by amoeboid cells and with potential clinical utility in prostate and other cancers.

Figure 1

(a) Mesenchymal (top) and amoeboid (bottom) subpopulations occur naturally within DU145 PCa cells. Cells were stained with antitubulin (green) and phalloidin (red) to demonstrate differences in tubulin and actin cytoskeletal organization. The cell nucleus is blue (DAPI). Note the difference in size between mesenchymal and amoeboid cells. (b) Mesenchymal (top)-amoeboid (bottom) transition in HMEC-HRasV12-transformed HMECs upon DIAPH3 silencing. DAPI: 4’,6-diamidino-2-phenylindole; HMEC: human mammary epithelial cells; PCa: prostate cancer.

Figure 2

Signal transduction mechanisms and cell processes that regulate or are associated with the amoeboid phenotype. CSF-1: Colony stimulating factor 1; EGFR: epidermal growth factor receptor; EPC: endothelial progenitor cell; EV: extracellular vesicle; GAP: GTPase-activating protein; GEF: guanine nucleotide exchange factor; IL-6: interleukin-6; MAT: mesenchymal-to-amoeboid transition; PAI: plasminogen activator inhibitor type-1; TGFβ1: transforming growth factor beta 1; TNC: Tenascin C.