International Business Department           Liu Bojia           August 13, 2024

  In 2017, Dr Humsa Venkatesh, a neuroscientist at Harvard Medical School, was looking at a sample of human gliomas on a computer screen when she accidentally discovered that the cells produced some intense electrical activity, and that the tumour cells not only 'communicated' with each other, but also synchronised their electrical signals with the healthy neurons around them. Dr Venkatesh and colleagues presented some of these results two years later in Nature, where they found that the tumours appeared to be very good at manipulating neurons to aid self-growth.

  Another Nature paper from the same time period supported this conclusion, that gliomas possess active electrical activity and can also participate in the surrounding neural circuits. They can draw on nerve cells to grow blood vessels, suppress the immune system and prepare for subsequent metastasis.

  Metastasis is the most dangerous condition for cancer patients, seriously affecting their prognosis and leading to death. The prevailing view is that once cancer cells are shed from the original tumour tissue, they travel through the bloodstream or lymphatic system to reach a suitable place for growth and then form a new tumour.

  But in recent years, similar to Dr Venkatesh's findings, there has been growing evidence linking cancer metastasis to the nervous system, such as the fact that gliomas can promote synapse formation and that the autonomic nervous system is involved in the development of gastric and prostate cancers.

  In the latest issue of Nature, Sohail Tavazoie's team from The Rockefeller University has further discovered that the sensory nerves in our bodies can also be hijacked by cancer cells to help them spread, a process that does not promote an immune response, and therefore can also allow tumours to grow more safely.

  Professor Tavazoie screened for genes that promote tumour spread in earlier studies, and they found that a number of the targeted genes turned out to be associated with neurological function; for example, SLIT2 is a class of molecules that directs axonogenesis but it is also highly expressed in metastatic tumour tissues, and in particular there is a high level of SLIT2 in the endothelium of metastatic breast tumours, whereas, under healthy conditions, breast tissue is itself rich in sensory nerves, which also led Prof Tavazoie to wonder whether these nerves support the development of cancer metastasis.

  In their experiments, they attempted to knock down SLIT2 in cells from different parts of the breast tumour and showed that the tumour only lost innervation if the tumour endothelium was deprived of SLIT2, which also suggests that SLIT2 originates in the endothelium-rich tumour vasculature and helps to drive innervation to occur.

  Also, the study examined breast tumour tissues with different levels of invasiveness and they found that often those tumours that were more invasive had more nerves. If some sensory neurons are added to breast cancer cells in a petri dish, the cancer cells not only grow faster, but also stimulate the neurons to produce a special class of molecules, substance P. This molecule is originally a neuropeptide that can act as a neurotransmitter involved in processes such as pain transmission.

  However, in the cancer cell environment, substance P is no longer involved in nociceptive regulation, but instead binds to the tachykinin receptor TACR1, which then activates genes related to cancer growth and metastasis, a process of innervation that is also responsible for the greater tendency of cancers to metastasise. According to the results of the analysis of human breast cancer samples, the more substance P there is in the tumour tissue, the higher the probability of metastasis in the lymph nodes.

  Thankfully, in the face of this metastatic strategy of cancer cells, humans may already have a way to deal with it. A drug commonly used to combat vomiting, aprepitant, is a TACR1 antagonist, and researchers have found that aprepitant not only slows down the growth of tumours in mice, but also significantly reduces their invasiveness in cell culture, even when sensory neurons are co-existing. The authors note that cancer patients may be able to receive aprepitant for a longer period of time in clinical trials compared to the dose used to stop vomiting, which exemplifies the potential for repurposing many drugs.