Research ArticleCancer

Intercellular transmission of the unfolded protein response promotes survival and drug resistance in cancer cells

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Science Signaling  06 Jun 2017:
Vol. 10, Issue 482, eaah7177
DOI: 10.1126/scisignal.aah7177

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Stress signals improve tumor fitness

Mechanisms that promote the survival of healthy cells are often exploited by tumor cells. Tumors experience increased cellular stress, and targeting the endoplasmic reticulum (ER) stress response, an adaptive response to increased protein translation, has been proposed as an anticancer therapy. Rodvold et al. found that prostate cancer cells undergoing an ER stress response transmit some signal to cocultured, naïve cancer cells that then also launch an ER stress response. This phenomenon, which the authors call “transmissible ER stress” (TERS), promoted faster tumor growth and resistance to common anticancer drugs in xenograft mouse models. The findings show that tumor cells leverage this intrinsically adaptive stress response to enhance the fitness of the overall tumor. Inhibiting this signal (once identified) or the pathways induced in the recipient cells might avert drug resistance in prostate cancer patients.


Increased protein translation in cells and various factors in the tumor microenvironment can induce endoplasmic reticulum (ER) stress, which initiates the unfolded protein response (UPR). We have previously reported that factors released from cancer cells mounting a UPR induce a de novo UPR in bone marrow–derived myeloid cells, macrophages, and dendritic cells that facilitates protumorigenic characteristics in culture and tumor growth in vivo. We investigated whether this intercellular signaling, which we have termed transmissible ER stress (TERS), also operates between cancer cells and what its functional consequences were within the tumor. We found that TERS signaling induced a UPR in recipient human prostate cancer cells that included the cell surface expression of the chaperone GRP78. TERS also activated Wnt signaling in recipient cancer cells and enhanced resistance to nutrient starvation and common chemotherapies such as the proteasome inhibitor bortezomib and the microtubule inhibitor paclitaxel. TERS-induced activation of Wnt signaling required the UPR kinase and endonuclease IRE1. However, TERS-induced enhancement of cell survival was predominantly mediated by the UPR kinase PERK and a reduction in the abundance of the transcription factor ATF4, which prevented the activation of the transcription factor CHOP and, consequently, the induction of apoptosis. When implanted in mice, TERS-primed cancer cells gave rise to faster growing tumors than did vehicle-primed cancer cells. Collectively, our data demonstrate that TERS is a mechanism of intercellular communication through which tumor cells can adapt to stressful environments.

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