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Cancer Cells Plot Together To Resist Chemotherapy

Cancer cells will plot together to resist chemotherapy, and to survive, suggests new research. The findings are published in the journal Science Signaling.

A group of malignant cells (red) in a human breast tumour that have become resistant to chemotherapy. Photo credits: NCI.

Cancer cells are loyal to each other: they will send signals to others of their kind to protect their ‘life’, says the new study conducted by a team of researchers from University of California San Diego School of Medicine. The communication that is established between the cancer cells is meant to turn on an internal cell mechanism that supports tumour survival, and builds resistance to chemotherapies.

The internal mechanism, called unfolded protein response (UPR), is normally used by mammalian cells when they are under stress. It is activated as a response to the accumulation of unfolded or misfolded proteins in a cell organelle called the endoplasmic reticulum (ER); the UPR will, then, decide whether the cell will survive or if it should die. It has been suspected from before that cancer cells might be exploiting this very mechanism to interact with bone-marrow-derived immune cells to give them pro-tumorigenic characteristics. The study lead author, Maurizio Zanetti, had conducted a research 6 years ago based on this hypothesis.

Now, in the new paper, Zanetti and his colleagues show that cancer cells might affect more than just bone marrow cells through this system: they appear to be using transmissible ER stress (TERS) to activate a cellular signalling pathway linked to the initiation of cancer (a process called carcinogenesis) in recipient cancer cells.

When the researchers implanted cancer cells subject to TERS into mice, they found that tumours would grow faster. Tumour cells otherwise live under adverse conditions—deprivation of both nutrients and oxygen—that should have limited their growth, explains Zanetti. However, through stress transmission, the tumour cells help each other to resist the negative environmental factors such that they eventually survive, having acquired growth advantages.

Stress signals, thus, allow the cells to sustain themselves better when starved from nutrients or even when treated with common chemotherapies than cells which did not experience the stress, explains first author Jeffrey J. Rodvold.

“In each instance, receiving stress signals caused cells to survive better. Understanding how cellular fitness is gained within the tumor microenvironment is key to understand cooperativity among cancer cells as a way to collective resilience to nutrient starvation and therapies,” says Rodvold.

This study might help explain previous ones that suggest some cancer cells acquire better fitness and survival than others thereby making cancer treatment more challenging. Zanetti advises other researchers to take these dynamic cellular changes into consideration when developing new treatment techniques.


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