Abstract
Intercellular transfer of organelles via tunneling nanotubes (TNTs) is a novel means of cell-to-cell communication. Here we demonstrate the existence of TNTs between co-cultured RT4 and T24 bladder cancer cells using light microscopy, fluorescence imaging, and scanning electron microscopy (SEM). Spontaneous unidirectional transfer of mitochondria from T24 to RT4 cells was detected using fluorescence imaging and flow cytometry. The distribution of mitochondria migrated from T24 cells was in good agreement with the original mitochondria in RT4 cells, which may imply mitochondrial fusion. We detected cytoskeleton reconstruction in RT4-Mito-T24 cells by observing F-actin redistribution. Akt, mTOR, and their downstream mediators were activated and increased. The resultant increase in the invasiveness of bladder cancer cells was detected in vitro and in vivo. These data indicate that TNTs promote intercellular mitochondrial transfer between heterogeneous cells, followed by an increase in the invasiveness of bladder cancer cells.
Highlights
Intercellular communication promotes the maintenance and development of multicellular organisms, especially in cancer cell proliferation and invasion [1,2,3,4]
Open ending filopodia-like cell protrusions were connected between T24 and RT4 cells (Figure 2A), while blindly ending filopodia-like cell protrusions were extended from T24 cells (Figure 2B)
This implied an involvement of these tubes in intercellular cytoplasmic component transportation, and that the membranous-based structures were originally formed by T24 cells, but not RT4 cells
Summary
Intercellular communication promotes the maintenance and development of multicellular organisms, especially in cancer cell proliferation and invasion [1,2,3,4]. A novel nanotubular structure, referred to as tunneling nanotubes (TNTs), has been found to facilitate intercellular communication [5,6,7]. TNTs are long-distance cytoplasmic extensions that are F-actin based, do not adhere to the substrate, and are small in diameter. Bladder cancer cells are heterogeneous in both clinical and pathological behaviors. Large scale sequencing analysis has shown intra-tumor histological heterogeneity in urothelial carcinoma at nucleotide resolution [16]. Intra-tumor heterogeneity influences bladder cancer cell topography in the bladder wall, which demonstrates the correlation between intra-tumor heterogeneity and cancer cell invasive ability [17, 18]
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