International Business Department           Liu Bojia           January 02, 2023

  Cancer cells are perceived as selfish and competitive, abusing everything around them for the energy they need to survive in order to proliferate indefinitely. Now, a disruptive discovery has revealed the hidden side of cancer cells. Like many other groups in nature, some cancer cells exhibit altruistic behaviour: they will even sacrifice themselves in order to help other cancer cells around them grow. This selfless co-operation may lead future researchers to clues for developing more effective cancer therapies.

  Tumour recurrence after treatment is an important factor contributing to a poor prognosis for patients. In breast cancer, for example, patients with early-stage breast cancer have a 7 to 11 per cent chance of having a recurrence within five years of receiving treatment; for patients with intermediate to advanced stages, the rate is even higher. A collaborative team led by Professor Leong Sai Mun of the National University of Singapore (NUS) has been conducting research for more than 10 years to unravel the reasons why some cancer cells continue to survive during breast cancer treatment. Their findings were recently published in the journal Molecular Cancer.

  In this study, the team collected blood samples from breast cancer patients at different stages of the disease and analysed the circulating tumour cells in the blood for miRNAs.

  Among other things, a pair of seemingly contradictory processes emerged in a class of cancer cells that highly expressed miR-125b, a small non-coding RNA: on the one hand, when exposed to chemotherapeutic drugs, these cancer cells released two proteins - IGFBP2 and CCL28 - that prompted neighbouring cancer cells to become more chemo tolerance, thus helping the cancer cells to survive the treatment; but on the other hand, these cancer cells simultaneously experience a self-sacrificing inhibitory process that hinders their own proliferation by bringing the cell cycle to a standstill.

  Both of these processes, which have a pro-cancer and an inhibitory effect, respectively, are regulated by miR-125b by engaging different parts of the nuclear factor-κB (NF-κB) signalling pathway. Together, these processes form the basis of altruism: inhibiting one's own growth while enhancing the ability of neighbouring cells to enhance resistance to chemotherapy. Notably, it was also found that miR-125b in altruistic cancer cells directly inhibits the expression of the GAB1 protein, thus preventing itself from benefiting from the secreted product, so these cells can be considered truly self-sacrificing.

  Professor Leong Sai Mun, who led the study, said, "Our research has identified these cooperative behaviours between cancer cells, and treatments for these cancer cells must be targeted to destroy them more effectively. Such treatments must take into account the mechanisms by which surrounding cancer cells respond to, and benefit from, 'self-sacrificing' cells."

  The question arises, according to Darwinian evolution, these self-sacrificing cancer cells should have been eliminated by the process of natural selection, but why is this not actually the case? The team found that these altruistic cancer cells, after self-sacrificing, can also regenerate from other non-altruistic cancer cells - albeit less frequently, but still able to remain in the tumour tissue - through a KLF2/PCAF-mediated epigenetic mechanism.

  Such findings also serve as a wake-up call for future cancer treatment strategies: while removing altruistic cancer cells can certainly be a potential therapeutic strategy, scientists must take into account the persistence of these cells.

  The study also suggests that certain pathways that inhibit or promote cancer development by other mechanisms can act as concurrent events with altruistic cancer cells, working together to regulate the balance of cooperative social behaviours within the tumour.

  The authors of the paper note that this study provides important insights into the intricate biological mechanisms of breast cancer, as well as promising avenues for better understanding its behavioural aspects, prognosis and potential therapeutic targets. And beyond cancer treatment, the mechanisms of such altruistic behaviour have broader implications for understanding the interactions between social organisms in other diseases, such as those driven by bacteria or viruses.