Abstract B56: Transfer of senescent signals in a hypoxic tumor microenvironment: A mechanism of tumor cell survival mediated by exosomes

The objective of this study was to establish if exosomes released from the TNBC cell line MDA-MB-231 (MSL) grown in a hypoxic environment, can mediate the transfer of viable cellular fate signatures (senescent and autophagic) to non-hypoxic cells rendering them non-apoptotic and chemoresistant. Experimentally, MDA-MB-231 (MSL) TNBC cells were cultured in hypoxia (1%) for 0-96 hours. Senescent, autophagic and cell cycle markers (LC3, p21, HDAC6, TSG101 and MAD2) were analysed by Western Blot. Nanoparticle Tracking Analysis (NTA), performed on the Nanosight LM10 microscope, allowed the enumeration and characterisation of harvested exosomes, while Dil labelled fluorescent imaging confirmed exosomal uptake in vitro. Hypoxic exposure (1%) of the MDA-MB-231 (MSL) confirmed by an increase in HIF1a, demonstrated that cellular senescence (p21), autophagy (LC3II), HDAC6 and the tumor susceptibility gene 101 (TSG101) markers increased in prolonged hypoxic exposure. Prolonged hypoxic exposure was also shown to result in an increase in the number of exosomes released from MDA-MB-231 (MSL) cells. siRNA knockdown of TSG101, a component of the ESCRT pathway involved in exosome release, resulted in a decrease in the amount of exosomes released from MDA-MB-231 (MSL) cells. In summary, it is well established in the literature that TNBCs are more hypoxic and chemoresistant than non-TNBC histological subtypes. The fact that both senescence and autophagy are induced in this environment underlies t...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Cell Interactions in the Tumor Microenvironment Source Type: research