When growth becomes a weakness for cancer cells

Cells in which only division is suppressed (left) continue to grow and lose their ability to divide, unlike cells in which both growth and division are suppressed. Credit: Sandhya Manohar / ETH Zurich

ETH Zurich researchers shed light on what can happen when cells grow beyond their normal size and become senescent. The new findings could help optimize cancer therapies.

Growth is a fundamental biological process and a prerequisite for the development and reproduction of living organisms. The processes of cell growth (i.e. the production of new biomass) and cell division must be coordinated with each other.

In multicellular organisms such as humans, cell growth must also be coordinated with their environment so that cells are present in sufficient numbers and sizes to form functional tissues or organs. Cell growth is therefore strictly regulated and only takes place when certain growth signals are present.

But cancer cells are different. They grow unchecked, divide over and over, and don’t respond to stop signals from their environment.

An advantage can be a disadvantage

Now, several studies published in the journal Molecular cell show that uncontrolled growth is not only an advantage for cancer cells but also a weakness.

One of these studies was led by Professor Gabriel Neurohr from the Institute of Biochemistry at ETH Zurich. For several years, he and his group have been studying how cell growth influences cell function. They also study what happens when cells grow beyond their normal size and enter a state that researchers call senescence. In this state, cells are supernaturally large and lose their ability to divide. However, they remain active and can influence their environment, for example by releasing messenger substances.

Senescent cells are found in normal tissues and play an important role in the aging process. But senescence can also be induced by chemicals, and because it leads to a loss of the ability to divide, it is the goal of some cancer treatments.

A breakdown in DNA repair

Neurohr colleague Sandhya Manohar has now investigated whether excess size affects the cellular functions of senescent cells. In her research, she treated a non-cancer cell line and a breast cancer cell line with substances that inhibit growth and division.

When she used only division-suppressing substances in her cell cultures, the cells were indeed no longer able to divide, but they continued to grow and entered senescence. As a result, they permanently lost their ability to divide. This effect persisted even after Manohar stopped the division inhibitors.

An important reason for the loss of the ability to divide is that enlarged cells can no longer repair damage to their genetic material, such as DNA double-strand breaks. Such breaks always occur spontaneously when a cell duplicates its genetic material before cell division.

Additionally, these cells cannot properly activate a key signaling pathway (p53–p21), essential for a coordinated response to DNA breaks. As a result, the damage is not repaired effectively enough. This means for hypertrophied cells that many irreparable DNA breaks accumulate during division, to the point that division is no longer possible.

Is combination therapy counterproductive?

Yet when the researchers simultaneously treated the cells with substances that inhibit division and growth, the cells were able to divide and multiply normally again after stopping both substances. “In cancer treatment, this is precisely what we don’t want,” says Neurohr.

Growth and division inhibiting agents are already used in the treatment of cancer. “Based on our observations in cell cultures, we would expect an increased relapse rate when simultaneously treating a tumor with division inhibitors and growth inhibitors. It would make more sense to use first a division inhibitor, then a drug that further damages the cell. The DNA in the cells makes division completely impossible,” Neurohr explains.

Clinical tests are needed to confirm the results

So far, the ETH researchers have tested their new findings only on cell cultures. Since growth and division are highly dependent on the cellular environment, the team cannot transfer these results directly to the clinical setting. Trials with organoids or on tissue samples are therefore necessary first to better test the potential treatment. Clinical studies of various combinations of division inhibitors and other drugs are also underway.

The idea put forward by ETH and Neurohr researchers is supported by studies carried out by three other international research teams, also published in the same issue of Molecular cell.

These studies show that hyperactively growing cancer cells are sensitive to treatment with division inhibitors. As these substances are already used to treat certain types of breast cancer, the new findings could have a long-term impact on cancer treatment.

More information:
Sandhya Manohar et al, Genome homeostasis defects lead to hypertrophied cells toward senescence, Molecular cell (2023). DOI: 10.1016/j.molcel.2023.10.018

Quote: When growth becomes weakness for cancer cells (November 17, 2023) retrieved November 17, 2023 from https://phys.org/news/2023-11-growth-weakness-cancer-cells.html

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