Leaving Italy

What is the neuroblastoma?

Unfortunately, my Erasmus time in Lyon only lasted four months and I did not have the chance to spend more time there and get to master properly the new techniques I had the chance to learn. However, even though it was such a short experience, it was quite sweet, in the way that I had the opportunity to change completely my area of research by having the chance to work with patients and learn a more “human” side of the medical research area. Not to mention the amazing group I had the chance to join and that this time I spent in France was my very first time living and working abroad. This sweet and short experience gave me the push to actually continuing staying abroad and get the chance to look for more.

Indeed, while I was looking for where to go and what to do next, I found an Italian scholarship to study for a year at the University of York in the United Kingdom and I applied for it. I managed to win it and I decided to spend it doing a Master of Science by Research (MRes). This kind of Master gives you the opportunity to work on a project for a year and, again, I decided to use this time to learn something new: I joined the group of Gareth Evans and he offered me a project on a protein complex possibly involved in neuroblastoma differentiation.

What I always tried to do with my studies was to research on a medical problem, in order to be able to contribute with my work to improve humankind wellness and to fight diseases. This project gave me the opportunity to get to study neuroblastoma and, even though I was coming back to what I might define “basic research”, I was actually working with neuroblastoma cells and I was seeing how the protein complex I was researching on was actually influencing the differentiation of this cancerous cells.

Since I mentioned that the medical problem behind my project was the neuroblastoma, today for the SRF I would like to briefly talk about it by presenting a paragraph of MRes thesis.

“Science Related Fact” (SRF):

The onset of cancer is a multi-step process that induces genomic instability and life- threatening cellular phenotypes. However, the evidence that a minority of cancer cells possess embryonal features or the plasticity to revert to embryonal features during postnatal life has led to the cancer stem cell hypothesis, which describes the heterogeneity that is evident in tumours. In some childhood cancers such as neuroblastoma, the precursor hyperplasia of embryonal cells has a tendency to undergo spontaneous regression and cell death. It is known that during embryogenesis many more cells are produced than are required for organogenesis but mechanisms such as trophic factor withdrawal remove cells that are in excess after organogenesis is complete. Unfortunately, in some cases embryonal cells can resist cell death signals, and later acquire additional alterations, which can lead to postnatal malignant transformation.

Neuroblastoma is the most common extracranial solid tumour in childhood and nearly half of neuroblastoma cases occur in children less than two years of age. This tumour arises from the sympathoadrenal lineage of the neural crest, and therefore tumours can develop anywhere in the sympathetic nervous system (have a look below for the clinical presentations of neuroblastoma).

Clinical presentations of neuroblastoma. From Maris et al., New England Journal of Medicine, 2010.

There have been several staging systems for neuroblastoma, but currently the most widely used is the International Neuroblastoma Staging System (INSS), which combines clinical and surgical staging. The system comprises 5 different stages of neuroblastoma, relating to risk: the low- risk group is composed of patients with Stage 1, 2A and 2B neuroblastoma, who all have localized tumours; the intermediate group comprises Stage 3 patients, who have an unresectable unilateral tumour; and finally the high-risk group, which includes Stage 3 patients with an unresectable tumour, and Stage 4 patients, who have a primary tumour with dissemination to distant lymph nodes, bone marrow, liver and other organs. The INSS also identifies Stage 4S, which represents a specific subset of patients younger than 1 year old, with tumours that tend to spontaneously remit.

Many clinical and experimental features link neuroblastoma to altered embryogenesis. As I have already mentioned above, a significant percentage of stage 4S patients with neuroblastoma in early childhood have spontaneous regression without therapy. Moreover, the autopsies of sympathoadrenal tissues from children whose cause of death was not cancer show an incidence of neuroblast pre-cancer cells that is higher than the incidence of clinical neuroblastoma. Patients’ biopsies show that the tumour cells are arrested at various stages of neuronal differentiation and the grade of differentiation correlates with clinical course.

Since clinical heterogeneity is a hallmark of neuroblastoma, current treatments involve a risk- based approach based on combinations of clinical and biological prognostic markers. For patients with low- or intermediate-risk neuroblastoma, who have excellent outcomes, surgery alone or a reduced treatment of chemotherapy and resection of the tumour are curative. However, patients with high-risk tumours undergo cycles of chemotherapy, plus surgery and radiotherapy for residual local and metastatic disease. Unfortunately, these approaches have resulted in improved outcomes, although survival for high-risk patients remains poor, emphasising the need for more effective treatments.

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