SIOP is the International Society of Paediatric Oncology. It is a global multidisciplinary society representing doctors, nurses, other health care professionals, scientists and patients or their relatives. The Society’s motto is ‘no child should die of cancer’. The meeting 2017 is being held in Dublin, the city where I live and work.
Indeed, it was appealing to attend the key meeting in childhood oncology field. As any participant, I had an opportunity to submit an abstract about my research. To no surprise at all, I received email notifying me on my work being selected for e-Poster presentation. Common stuff. The email also said that it would be displayed at designated stations, like big screens throughout the meeting. Very unusual format, but we are living in the digital technology era; things are changing all the time. So, I would not need to stay by the poster this time. Great – more time for networking and talks.
Then I received another email informing about a Poster Discussion session, which I assumed to be a standard procedure when a group of selected piers stand by your poster and ask Qs. None comes in majority cases. A participant stands and waits and waits till the session is over. So, of course I took it easy.
A day before the meeting, I downloaded the meeting app and started to browse along the content and features. Out of curiosity, I checked details of the Poster Discussion session. This was the moment of mental breakdown – I discovered being selected for an oral poster presentation! My chances were 1 in 1475 (the number of submitted abstracts). I should probably also buy a lottery ticket tonight. Could lucky things come together?
I will reflect on the new e-poster presentation experience later today…
We do not hear much on neuroblastoma or childhood cancer in our everyday life unless we know a child affected by the disease. How much information can we get from newspapers? How do newspapers report it? What is their focus – a child, his/her family or social circles? In the next posts I will try to get insights from the content of newspaper’s stories.
To start with, I needed to select those newspaper articles that cover a story of a child with cancer over a period of time. To do that I selected a recent period from January 1, 2010 to December 31, 2015 because two major events happened during this time.
The first was the 2011 Pulitzer Prize book written by Siddhartha Mukherjee ‘The Emperor of All Maladies: A Biography of Cancer’ which describing the history of both adult and childhood cancer treatment development and research (Mukherjee 2010). Importantly, this book inspired to produce a documentary film of three episodes of two hours each and released in 2015 (Goodman 2015). Researchers in social sciences agree that the publication of a prominent popular science book can lead to increased media interest in the issues raised in the book (e.g. (Nisbet & Fahy 2013).
Another most recent milestone was a breakthrough in childhood cancer management – the FDA approval of a novel drug Unituxin (dinutuximab) for neuroblastoma, the most common solid tumour in children (U.S. Food and Drug Administration 2015).
next step is actual paper selection. There is an archive of all newspapers and magazines called Nexis®UK database. This database stores copies of all printed papers and magazines worldwide as well as online versions.
Then an a search for articles carried out looking for key words:‘child’, ‘children’, ‘childhood’, ‘kid(s)’, ‘cancer (s)’, ‘tumour (s)’, ‘treatment’, ‘chemotherapy’, ‘radiation’ and their combinations. Only articles published by the UK national newspapers and included key words in either the headline or text were selected. The search returned 255 articles. Of 255 articles, 84 contained a story about a child with cancer. The rest were standardised obituaries in the ‘announcements’ or ‘deaths’ sections, horoscopes containing the word ‘cancer’, fundraising and charity activities not involving an identified child, funding initiatives related to pure cancer research and service, reports on scientific achievements or challenges were excluded.
The selected 84 articles were published by the broad range of local and national papers that are daily on sale through news outlets to a general public in the UK.
The Q1: What has been the level of media attention to childhood cancer?
In the last three years, in average 20 articles per year across 9 UK newspapers were published telling us a story about a child with cancer. In other terms it is less than 2 stories per month. It is not enough to raise awareness, educate the public and form their opinion. Tabloid editorial was more interested in this type of stories than broadsheet. This observation is likely due to the nature of tabloid paper interests looking for people personal stories, entertainment, sports and scandal.
Unfortunately, no change in media coverage of childhood cancer was observed around these two milestones (in 2011 and 2015). All together it suggests that neither of them had a strong influence on journalists or editorials regarding childhood cancer coverage.
Interestingly, the growing trend in media coverage of children with cancer occurred by the increase in neuroblastoma coverage. Neuroblastoma had a nearly two fold boost in 2013 vs 2012 and then slightly declined in 2014 and 2015. Nevertheless, the FDA approval did not trigger attention to this cancer.
The very first human cancer cell line was developed from a patient with an aggressive cervical cancer in 1951. This cell line was called HeLa after the patient name – Henrietta Lacks. This is the most popular and robust cancer cell line in biomedical research. Since then, other cancer cell lines were developed including neuroblastoma.
The first successful neuroblastoma ‘cell lines’ were cell populations from tumours that were adapted to grow for a short period in the lab environment in 1947. These tumour cell populations were used as a tool for diagnosis. This success inspired other researchers to develop long-term or immortal neuroblastoma cell lines. To date different neuroblastoma cell lines exist.
Cancer cell lines are sensitive and delicate in handling. They can only grow in the safe environment. Researchers have to protect them against bacteria, low temperatures, and too acidic/alkaline conditions. We protect cancer cells from bacteria contamination by handling them in cabinets where all plastic and media are sterile.
Cancer cells like to grow in conditions similar to conditions in human body. They like temperature of 36.6 – 37C. To achieve it special ‘green cell houses’ – CO2 incubators are built, which maintain the constant temperature, humidity and CO2 concentration.
The cell growth and well being are checked regularly using microscopes. Healthy cells are to have similar shape, even distribution and grow attached to the plastic surface. Most microscopes have a camera attached to the top and linked to a computer. It helps to take picture of growing cells and record changes in cell behaviour.
Children with neuroblastoma undergo several cycles of intensive chemotherapy to stop disease progression with the final aim to eliminate the tumour. Chemotherapy includes carboplatin or cisplatin in various combinations with drugs such as cyclophosphamide, ifosfamide, doxorubicin, etoposide, topotecan and vincristine (1). Nevertheless, in average 1 in 5 children with stage 4 disease do not respond to therapy. Up to 50% of children that do respond experience disease recurrence with tumour resistant to multiple drugs and more aggressive behaviour that all too frequently results in death.
The development of drug resistance is the major obstacle in treatment of neuroblastoma. To tackle this problem, researchers need to study different models of disease using cell lines, 3D tumour cell models, mice models and have access to clinical samples.
The first stage in testing drugs is to understand their killing ability of cancer cells. At this stage, researchers test drugs using cell lines. Cell lines are derived from tumours which were surgically removed from children with neuroblastoma. Researchers usually take a small piece of tumour straight after surgery and bring it into the laboratory. Here, they place this piece into special solution that has enzymes to separate cells from each other. Then the suspension of all kind of tumour cells is placed into plastic dishes or flasks in a highly nutrient media to let cells grow. Cells that can adapt to these conditions start to grow, divide and produce a new generation of cancer cells. Researchers look after their growth, inspect their shape and behaviour; and test them on the presence of tumour markers. Once identity of these cells is confirmed they become a cell line and obtain a name. These cells keep majority of characteristics of the parental tumour and represent very useful tools in cancer research.
In our lab we use such cell lines to study neuroblastoma resistance to drugs. To understand changes in neuroblastoma biology during the development of drug resistance, we created drug resistant neuroblastoma cell lines (2). We treated three neuroblastoma cell lines CHP212, SK-N-AS and Kelly with cisplatin – a common drug in anticancer therapy. SK-N-AS and Kelly cells are sensitive to this drug, while CHP212 cells responded to this drug at much higher levels that the other two. Cells were grown in media containing cisplatin for several weeks. During this period most of the cells responded to cisplatin and died. Then we let cell survivors to recover in media without drug. This cycle was repeated several times until we got a population of cell survivors that can stand doses of cisplatin that can kill 50% of parental cells. It took us more than 6 months to generate cisplatin resistant neuroblastoma cell lines CHP212Cis100, SK-N-ASCis24 and KellyCis83.
At the next step, we studied differences between these cell lines. We first compared their behaviour and cell shapes. Two resistant cell lines KellyCis83 and CHP212Cis100 started to grow faster, but SK-N-ASCis24 – slower than their parental cell lines. Interestingly, these cells also became more resistant to other drugs such as doxorubicin, etoposide, temozolomide, irinotecan and carmustin. These results are very important as they demonstrate that one drug can activate the cell defense systems that allow to escape toxicity of other drugs. These cell lines can be used to test new drugs and find those that can overcome developed resistance.
Cisplatin resistant cells also changed their appearance. Most dramatic changes occurred in SK-N-ASCis24 cells (see Figure 1).
Figure 1. Microscopic images sensitive and drug resistant neuroblastoma cells (adapted from (2))
Two drug resistant cell lines SK-N-ASCis24 and CHP212Cis100 cells developed additional mobility skills – they became more invasive than their parental counterparts.
Then we asked a question: what type of changes allowed cells to adapt to cytotoxic environment? We examined changes in their genomic DNA first. We found that some genes increased their copy number, other went missing.
We identified changes in protein expression. More intriguingly, some proteins with the increased presence in the cells did not increase their presence in genomic DNA. We sorted these proteins on their role in cell processes such as migration, growth, cell cycle, etc. We found that each cisplatin resistant cell line developed a unique set of features that help them to escape cytotoxic stress (2). The similar patterns are found in clinic. Each patient responds to treatment differently.
What did we learn from this study?
One drug, in our study cisplatin, can activate the cell defense systems that allow to escape toxicity of other drugs.
The development of drug resistance gives cells new advantages and changes their behaviour and appearance, e.g. mobility skills, different cell shape, response to drugs, etc.
Each cisplatin resistant cell line developed a unique set of features that help them to escape cytotoxic stress.
These cell lines can be used to test new drugs and find those that can overcome developed resistance.
Tumour cells send different types of messages from one cell to another aka people post letters, postcards, and parcels to their families, friends, colleagues or business. Cells can direct their messages using free moving proteins – postcards. They can wrap it in microvesicles with different cargo. Big microvesicles can take up big messages – parcels, small microvesicles or exosomes contain a limited number of texts – letters.
Tumour cells change their behaviour quickly adapting to anticancer therapies, so the messages they are sending. These messages can easily join blood stream and be read by researchers to understand how treatment is working and tumour cells are feeling. Reading these messages from blood is more favourable as blood tests are done on the regular bases during and after the treatment.
In our lab we investigate how neuroblasts communicate with each other and the entire body through exosomes. We are interested to see what they write in their letters – exosomes. Do drug resistant and sensitive neuroblasts write different texts? What is the difference and how we can use this difference to predict child response to anticancer therapy?
In one set of experiments, we found that exosomes from drug resistant neuroblasts stimulate growth of sensitive cells. The more resistant neuroblasts send more powerful messages pushing cells to grow faster.
In the other set of experiments, we partially cracked the message showing that their texts are different. This finding explains why more resistant neuroblasts send more growth stimulating messages.
Schematic of exosome biogenesis and secretion. Cells produce exosomes through different pathways. This process is tightly regulated and controlled by numerous molecules. It can be triggered by many factors including extracellular stimuli (e.g., microbial attack, UV, drugs) and other stresses. The exosomes wrap up biologically active components such as proteins, RNA and miRNA. Exosomes can interact with recipient cells using four mechanisms: ligand/receptor interaction, protein transfer, membrane fusion or internalisation. Once exosomes entered the recipient cell, they release their content and re-programme the cell functions.
Johnsen KB, Gudbergsson JM, Skov MN, Pilgaard L, Moos T, Duroux M. A comprehensive overview of exosomes as drug delivery vehicles – Endogenous nanocarriers for targeted cancer therapy. Biochim Biophys Acta – Rev Cancer. 2014;1846(1):75–87.
El Andaloussi S, Mäger I, Breakefield XO, Wood MJ a, Andaloussi S EL, Mäger I, et al. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov. 2013;12(5):347–57.
Childhood cancer is 1% of all newly diagnosed cancers globally (1,2).
It is the second most common cause of death among children under age of 19 after accidents.
Childhood cancer is an umbrella term for a great variety of malignancies which vary by site of disease origin, tissue type, race, sex, and age.
Cancer in children is not the same as cancer in adults (3–5).
The cause of childhood cancers is believed to be due to faulty genes in embryonic cells that happen before birth and develop later. In contrast to many adult’s cancers, there is no evidence that links lifestyle or environmental risk factors to the development of childhood cancer.
The most common types of childhood cancer are (1,2):
Leukaemia and lymphoma (blood cancers)
Brain and other central nervous system tumours
Muscle cancer (rhabdomyosarcoma)
Kidney cancer (Wilms tumour)
Neuroblastoma (tumour of the non-central nervous system)
Bone cancer (osteosarcoma)
Testicular and ovarian tumours (gonadal germ cell tumours)
In the last 40 years the survival of children with most types of cancer has radically improved owing to the advances in diagnosis, treatment, and supportive care. Now, more than 80% of children with cancer in the same age gap survive at least 5 years (1,6) when compared to 50% of children with cancer survived in 1970s-80s (7).
A revised treatment protocol was introduced in the 1970s leading to dramatic improvements in outcome for some of the most common blood cancers such as non-Hodgkin lymphoma and acute lymphoblastic leukaemia. The 5-year survival rate for non-Hodgkin lymphoma is 85% in 2003-2009. It was just less than 50% in the late 1970s. The 5-year survival rate for acute lymphoblastic leukaemia is about 90% in 2003-2009 and just 10% – in the 1960s (1,6).Children with some types of brain cancers survive from 70% (medulloblastoma) to 85% (astrocytoma) within 5 years (2).
Unfortunately, no progress has been made in survival of children with tumours that have the worst prognosis (brain tumours, neuroblastoma and sarcomas, cancers developing in certain age groups and/or located within certain sites in the body), along with acute myeloid leukaemia (blood cancer) (1,2). Children with a rare brain cancer – diffuse intrinsic pontine glioma survive less than 1 year from diagnosis (8). Children with soft tissue tumours have 5-year survival rates ranging from 64% (rhabdomyosarcoma) to 72% (Ewing sarcoma) (2).
For majority of children who do survive cancer, the battle is never over. Over 60% of long‐term childhood cancer survivors have a chronic illness as a consequence of the treatment; over 25% have a severe or life‐ threatening illness (9).
Gatta G, Botta L, Rossi S, Aareleid T, Bielska-Lasota M, Clavel J, et al. Childhood cancer survival in Europe 1999-2007: Results of EUROCARE-5-a population-based study. Lancet Oncol. 2014;15(1):35–47.
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Ries L a. G, Smith M a., Gurney JG, Linet M, Tamra T, Young JL, et al. Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. NIH Pub No 99-4649. 1999;179 pp
Warren KE. Diffuse intrinsic pontine glioma: poised for progress. Front Oncol [Internet]. 2012;2(December):205.
Lackner H, Benesch M, Schagerl S, Kerbl R, Schwinger W, Urban C. Prospective evaluation of late effects after childhood cancer therapy with a follow-up over 9 years. Eur J Pediatr. 2000;159(10):750–8.
A very nice piece of journalist’s story about neuroblastoma through a mother’s view. I met the mother personally at the 4th Neuroblastoma Research Symposium in Newcastle-upon-Tyne, UK in November 2015. Susan Hay and other same minded parents of children with neuroblastoma joint their efforts to raise money not only for current kids battling this nasty cancer, but more importantly for research in the cancer biology, diagnostics and new therapies which are to give a better deal for children with neuroblastoma.
Neuroblastoma is a childhood cancer caused by the abnormal growth and development of non-mature nerve cells, called neuroblasts . The disease commonly affects children age 5 years or younger. Approximately 50% of children have tumours that have spread at diagnosis . The main challenge in treating neuroblastoma is to stop tumour spread and resistance to multiple drugs. Despite major advances in available therapies, children with drug resistant and/or recurrent neuroblastoma have a dismal outlook with 5 year survival rates of less than 20% [2-4]. Therefore, this cancer needs more research and funding as well as people awareness of these needs.
Davidoff, A. M. Neuroblastoma. Semin. Pediatr. Surg.21, 2–14 (2012).
Gatta, G. et al. Childhood cancer survival in Europe 1999-2007: Results of EUROCARE-5-a population-based study. Lancet Oncol.15, 35–47 (2014)
Peinemann, F., Tushabe, D. A., van Dalen, E. C. & Berthold, F. Rapid COJEC versus standard induction therapies for high-risk neuroblastoma. The Cochrane database of systematic reviews5, CD010774 (2015).
Peinemann, F., van Dalen, E. C., Tushabe, D. A. & Berthold, F. Retinoic acid post consolidation therapy for high-risk neuroblastoma patients treated with autologous hematopoietic stem cell transplantation. Cochrane database Syst. Rev.1, CD010685 (2015)
This blog is about neuroblastoma biology, its research challenges, and people and media perception of this disease. I am researcher and active supporter of science communication. I hope you will find interesting to read my blog and ask questions. Your questions would help me to cover topics which I have not heard of or may not plan to cover yet.