Help a neighbor

Cancer cells have transferred drug resistance to each other

Daria Spasskaya, N+1

Researchers from University of California at San Diego (USA) has discovered the phenomenon of intercellular signaling in cancer cells, which allows cell-to-cell transmission of resistance to nutrient deficiencies and medications. The development of resistance occurs due to the launch of a cellular response to a specific type of stress caused by the accumulation of damaged proteins, which cells have learned to stimulate from each other. This mechanism allows the tumor to grow faster, despite the unfavorable environment. The work was published in the journal Science Signaling (Rodvold et al., Intercellular transmission of the unfolded protein response promotes survival and drug resistance in cancer cells).

Cancer cells living inside the tumor are constantly experiencing a lack of oxygen and nutrients. Poor living conditions lead to the development of various types of stress reactions inside the cell, which normally can trigger the process of apoptosis, that is, cellular suicide. However, there are mechanisms to counteract intracellular stress.

One of the characteristic phenomena for tumor cells is endoplasmic stress, which develops as a result of the accumulation of damaged or incorrectly folded proteins in the endoplasmic reticulum (the cellular organelle where protein synthesis is concentrated). In response to endoplasmic stress, a response signaling cascade (UPR – unfolded protein response) develops, the purpose of which is to reduce protein synthesis and repair damaged molecules with the help of special assistants–chaperones.

Scientists have found that cancer cells, with the development of the corresponding signaling cascade (UPR), secrete soluble molecules that initiate the launch of the same mechanism in the surrounding cells. Previously, it was shown that in this way malignant cells can manipulate immune cells, suppressing the body's protective reaction. In the new work, the researchers focused on the interaction between tumor cells. 

In the culture of human prostate cancer cells, scientists artificially induced endoplasmic stress, and then the nutrient medium in which the stressed cells were sitting was added to experimental cells, both of cancer origin and normal. Signaling molecules from the medium caused an increase in the expression of molecular markers of the anti-stress response in the treated cells. Such cells felt good in a poor environment with a low glucose content, and the synthesis of factors causing apoptosis in them was suppressed. In addition to improving survival, cells with induced endoplasmic stress were resistant to drugs, including those unrelated to protein synthesis and degradation, such as paclitaxel.

Activation of the anti-stress chaperone GRP78 in cells treated with a medium with signaling molecules (right). Antibodies against chaperone are labeled with a green fluorescent dye. Here and below are the drawings from the article in Science Signaling.

At the final stage of the experiment, cells with activated resistance were inoculated in mice to find out how the tumor would develop from them. Compared with control mice injected with unstressed cells, tumors in experimental mice developed faster and were significantly larger. 

Tumors that developed in mice a month after the introduction of control cells (upper row) and cells with induced endoplasmic stress (lower row).

The authors of the work were not interested in what kind of signaling molecules cells secrete to activate the signaling cascade in their neighbors, but they established the molecular mechanism of resistance development. This is already enough to try to suppress the development of sustainability. A similar signaling cascade was observed in the primitive worm Caenorhabditis elegans, which, in response to endoplasmic stress, allows it to starve for a long time, so the mechanism seems to be evolutionarily conservative.

Portal "Eternal youth" http://vechnayamolodost.ru  08.06.2017