On Saturday – April 9th, the Conor Foley Neuroblastoma Cancer Research Foundation had their annual fundraising Dinner. This year the theme of the Dinner was Jungle Jazz in memory of the favourite movie of Conor – Madagascar at Trim Castle Hotel.
So many people came to support this fantastic family. The family, who lost their beloved son to neuroblastoma, but has found unacceptable to stop their fight against neuroblastoma. They do know that a cure won’t be found tomorrow. Instead, it may take time, money and efforts to crack the code of this disease so other kids can do better. Thier deal with the situation is priceless and infectious – none can stand still around.
There is no short answer. Research is a slow, meticulous process of testing theories and finding out which ones work.It is exactly the same for both curiosity- and disease- driven questions. Long years of ground research full of ups and downs are critical for any breakthrough or progress. Very often with more downs than ups. Importantly, all researchers build on the work of their predecessors. This is the nature of science.
To understand the world around us, we have to do be curious and do “blue sky or curiosity-driven” research. It is a long shot, but this type of research can lead to practical applications down the road. One of the most recent examples is a drug Vismodegib (Erivedse) to treat basal cell carcinoma (the most common type of skin cancer) approved by the FDA in 2012. This drug targets genes of a hedgehog-associated signalling pathway. Defects in this pathway were found to drive many cases of skin cancer. But, how this relationship was found? Blue sky research!
Researchers studied hedgehog signalling in fruit flies and mice. One of the researchers had a strong interest in a fruit fly gene called hedgehog. If this gene is defective, then fly embryos look stubby and hairy aka a hedgehog. Further research brought more interesting facts and relationships leading to the identification of a drug that can stop the function of this faulty gene. Decades later with the advancement of genome sequencing, the defect in hedgehog signalling pathway genes was identified in patients with locally advanced and metastatic basal cell carcinoma.
What would happen if there were no research in fruit flies and mice? There would have been no rationale to create a drug like Vismodegib!
The best discovery research is unrestricted. It is driven by intellectual curiosity and conceptual advancement. More such curiosity- driven research is needed. For every medical breakthrough, for every Vismodegib, there were hundreds of blind alleys and failed ideas.
The research is a long-term investment. This contradicts to the short-term life of the politicians and governments who give the money. They do not take the risks. So, the discovery research becomes critically underfunded.
Fundraising creates opportunities for blue sky research and developing cancer treatments.
Thank you all who support cancer research charities!
Today, we are celebrating International Childhood Cancer Day to raise awareness and to express support for children and adolescents with cancer, survivors and their families.
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.
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.
Every 100th patient diagnosed with cancer is a child.
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 when compared to 50% of children with cancer survived in 1970s-80s.
Childhood cancer is the second most common cause of death among children between the ages of 1 and 14 years after accidents.
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). Children with a rare brain cancer – diffuse intrinsic pontine glioma survive less than 1 year from diagnosis. Children with soft tissue tumours have 5-year survival rates ranging from 64% (rhabdomyosarcoma) to 72% (Ewing sarcoma).
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.
It is always interesting to see what kids think about science and scientists. How their vision is affected by environment. A 7 year old boy drew a scientist in a funny but positive way. The scientist’s heart has a form of chemical flask.
Three years later, the same boy participated in the RDS Primary Science Fair which runs side by side with the BT Young Scientist and Technology Exhibition. The idea of this exhibition is very simple. It is a non-competitive event, showcasing STEM research projects (science, technology, engineering and maths) carried out by primary school classes across Ireland. The research projects encourage children’s native curiosity to explore the science behind the everyday.
His class presented a research project ‘Are We Living in the Dark Ages?’ The bunch of 4th class students were exploring the importance of sun light and electricity in our every day life.A colleague of mine was ‘Head Judge’ at this Fair and pointed out the overall enthusiasm and positivity coming from these young children about the research undertaken. I personally was stopped by every school team. Children wanted to share their findings. The project and its presentation were very important for them.
Children are natural explorers and when their ability can be encouraged by the events like the RDS Primary Science Fair, then we, adults, can feel reassured that research can make dreams come true. Dreams about new effective therapies, spaceflights to new stars and planets and many more.
This post is dedicated to parents of children with neuroblastoma. Some parents asked about DFMO – a re-purposing drug. In this post, I tried to collect and summarize information available from academic sources.
Q1: What is DFMO?
Difluoromethylornithine (DFMO, Eflornithine) is an anti-protozoan drug. It was originally developed and FDA approved for the treatment of Trypanosoma brucei gambiense encephalitis (“African sleeping sickness”). DFMO permanently binds to ornithine decarboxylase (ODC), an important enzyme in polyamine metabolism, and prevents the natural substrate ornithine from entering the active site.
By inhibiting ODC, DFMO reduces cellular polyamines and inhibits cell growth and proliferation of actively dividing cells, thus making DFMO an attractive candidate for cancer therapy. In neuroblastoma, a positive regulation of all aspects of polyamine metabolism by MYCN was reported (revived by Bassiri 2015, Gamble 2012). So, it is believed that MYCN amplified neuroblastomas would most benefit of the drug.
Q2: How intense is basic science behind DFMO in neuroblastoma?
Figure 1. Breakdown of papers covering DFMO in neuroblastoma
To find out the intensity of basic science on DFMO in neuroblastoma search for ‘difluoromethylornithine/DFMO/Eflornithine’ and ‘neuroblastoma’ was run in PubMed, a web-based resource with 26 million citations for biomedical literature from MEDLINE, life science journals, and online books. The search returned 23 papers including 3 reviews and 20 primary research reports published from 1980 to present.
In comparison, I did another search for a novel drug Unituxin (dinutuximab) approved by FDA in 2015. It is monoclonal antibody against the glycolipid disialoganglioside GD2, a biomarker specific for neuroblastoma. Search for ‘anti-GD2 antibody’ and ‘neuroblastoma’ returned 181 papers including 25 reviews and 156 primary articles for the same period.
Q3: Is DFMO in cancer clinical trials?
“ClinicalTrials.gov is a Web-based resource that provides patients, their family members, health care professionals, researchers, and the public with easy access to information on publicly and privately supported clinical studies on a wide range of diseases and conditions. The Web site is maintained by the National Library of Medicine (NLM) at the National Institutes of Health (NIH).
Figure 2. Clinical trials of DFMO in various health conditions.
Search for ‘difluoromethylornithine/DFMO/Eflornithine’ in ClinicalTrials.gov returned 36 registered trials across different health conditions.Two of these were withdrawn, the breakdown for the rest 34 is as follows: Adenomatous Polyp (1), Anaplastic Astrocytoma/Recurrent Anaplastic Astrocytoma (1), Bladder Cancer (1), Cervical Cancer/Precancerous Condition (1), Colorectal Cancer (3), Esophageal Cancer (1), Familial Adenomatous Polyposis (1), Gastric Cancer/Gastric Intestinal Metaplasia (1), Hirsutism (2), Human African Trypanosomiasis (5), Neuroblastoma (7), Non-melanomatous Skin Cancer/Precancerous/Nonmalignant Condition (4), Post-solid Organ Transplant/Skin Neoplasms (1), Precancerous Condition (1), Prostate Cancer (2), Pseudofolliculitis Barbae (1), Type 1 Diabetes (1) (Fig. 2). To see full details of 34 trials please click at this Table.
Figure 3. DFMO clinical trials from ClinicalTrials.gov
All of them have various statuses (Fig. 3) as well as study design. Importantly, 30 out of 34 studies are focused on safety and efficacy of this drug. Vast majority of studies of DFMO in adult cancers/benign conditions are randomized (16/18 or 89%). Randomization in assignment of patients in studied groups (control and new drug/combination) helps minimize researcher’s bias when comparing effect of the new treatment vs current/no treatment. All trials of DFMO in neuroblastoma are not randomized. Instead, studies use a single group assignment.
Three trails have been either completed/terminated and published results are available at ClinicalTrials.gov (NCT01059071, NCT00033371. NCT00118365).
Q4: What about clinical trials of DFMO in neuroblastoma?
The trial NCT01059071 was a Phase 1 clinical trial. A phase I clinical trial tries to find out whether a new treatment/drug is safe, what its side effects are, the best dose of the new treatment, if the treatment shrinks the cancer.
Twenty one patients were enrolled and eligible for treatment with DFMO and DFMO + etoposide. These patients were assigned into 4 groups of different DFMO doses (Fig. 4). The treatment was in cycles of 21 days. Cycle 1 – DFMO only followed by cycle 2 – combined treatment of DFMO+etoposide (14 days) and DFMO only (the last 7 days).
Figure 4. Table was adopted from results section of the clinical trial NCT01059071
According to results of the trial: 14 patients did not complete the treatment due to different reasons. It was not clear what stage/cycle they left the trial.
As mentioned earlier this study used a single group assignment and a design called ‘3+3’. This design is straightforward and safe. Briefly, it means that for a dose (X) of the drug, 6 patients are selected. Of these, 3 receive the dose X and are monitored for a period of time. If no adverse effects are registered in these 3, then another new 3 patients start the same treatment. The effect of the drug is evaluated on the patent’s health condition before-, during – the treatment and after its completion. This approach is often used in vaccine tests and dose escalation methods in Phase I cancer clinical trials. This type of study can answer mainly two questions: 1) whether the tested drug is safe to use and 2) what doses are safe? The main drawbacks of this design are
Many patients treated at doses below therapeutic effect
Slow dose increase
Uncertainty about the recommended phase II dose (RP2D)
Only the result from the current dose is used for determining the dose of next cohort of patients. Information on other doses is ignored
Figure 5 is adopted from Sholler GL et al, PLoS One. 2015 May 27;10(5):e0127246.
Q6: What are main findings of the clinical trial NCT01059071?
The overflow of the study is presented in Fig 5 providing additional information on those who did not complete the trial. Out of 14 participants, disease has progressed in 11 patients – it is 52% of the enrolled participants. Authors highlighted that this phase I study was not designed to evaluateanti-tumour efficacy of DFMO. But tumour response and clinical response were monitored during the study.
According to the paper, 21 patients received at least one dose of DFMO only (Cycle 1, 21 days). During this cycle, 3 patients were withdrawn. All of them were assessed for safety of DFMO.
Eighteen of them completed cycle 1 and continued treatment with DFMO+etoposide for another 4 cycles followed with DFMO only therapy for a number of cycles. Their clinical response data were examined for efficacy of DFMO alone.
Three out of 21 participating patients in this clinical trial remain alive and disease free between 2–4.5 years after starting DFMO.
Authors concluded that
DFMO doses of 500-1500mg/m2/day are safe and well tolerated in children with relapsed NB
Research and review papers covering DFMO in neuroblastoma:
Evageliou NF, Haber M, Vu A, Laetsch TW, Murray J, Gamble LD, Cheng NC, Liu K, Reese M, Corrigan KA, Ziegler DS, Webber H, Hayes CS, Pawel B, Marshall GM, Zhao H, Gilmour SK, Norris MD, Hogarty MD. Polyamine Antagonist Therapies Inhibit Neuroblastoma Initiation and Progression. Clin Cancer Res. 2016 Sep 1;22(17):4391-404. doi: 10.1158/1078-0432.CCR-15-2539.
Bassiri H, Benavides A, Haber M, Gilmour SK, Norris MD, Hogarty MD. Translational development of difluoromethylornithine (DFMO) for the treatment of neuroblastoma. Transl Pediatr. 2015 Jul;4(3):226-38. doi: 10.3978/j.issn.2224-4336.2015.04.06. Review.
Saulnier Sholler GL, Gerner EW, Bergendahl G, MacArthur RB, VanderWerff A, Ashikaga T, Bond JP, Ferguson W, Roberts W, Wada RK, Eslin D, Kraveka JM, Kaplan J, Mitchell D, Parikh NS, Neville K, Sender L, Higgins T, Kawakita M, Hiramatsu K, Moriya SS, Bachmann AS. A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma. PLoS One. 2015 May 27;10(5):e0127246. doi: 10.1371/journal.pone.0127246.
Lozier AM, Rich ME, Grawe AP, Peck AS, Zhao P, Chang AT, Bond JP, Sholler GS Targeting ornithine decarboxylase reverses the LIN28/Let-7 axis and inhibits glycolytic metabolism in neuroblastoma. Oncotarget. 2015 Jan 1;6(1):196-206.
Samal K, Zhao P, Kendzicky A, Yco LP, McClung H, Gerner E, Burns M, Bachmann AS, Sholler G. AMXT-1501, a novel polyamine transport inhibitor, synergizes with DFMO in inhibiting neuroblastoma cell proliferation by targeting both ornithine decarboxylase and polyamine transport. Int J Cancer. 2013 Sep 15;133(6):1323-33. doi: 10.1002/ijc.28139.
Koomoa DL, Geerts D, Lange I, Koster J, Pegg AE, Feith DJ, Bachmann AS. DFMO/eflornithine inhibits migration and invasion downstream of MYCN and involves p27Kip1 activity in neuroblastoma. Int J Oncol. 2013 Apr;42(4):1219-28. doi: 10.3892/ijo.2013.1835.
Gamble LD, Hogarty MD, Liu X, Ziegler DS, Marshall G, Norris MD, Haber M. Polyamine pathway inhibition as a novel therapeutic approach to treating neuroblastoma. Front Oncol. 2012 Nov 16;2:162. doi: 10.3389/fonc.2012.00162. Review
Passariello CL, Gottardi D, Cetrullo S, Zini M, Campana G, Tantini B, Pignatti C, Flamigni F, Guarnieri C, Caldarera CM, Stefanelli C. Evidence that AMP-activated protein kinase can negatively modulate ornithine decarboxylase activity in cardiac myoblasts. Biochim Biophys Acta. 2012 Apr;1823(4):800-7. doi: 10.1016/j.bbamcr.2011.12.013.
Rounbehler RJ, Li W, Hall MA, Yang C, Fallahi M, Cleveland JL. Targeting ornithine decarboxylase impairs development of MYCN-amplified neuroblastoma. Cancer Res. 2009 Jan 15;69(2):547-53. doi: 10.1158/0008-5472.CAN-08-2968.
Koomoa DL, Yco LP, Borsics T, Wallick CJ, Bachmann AS. Ornithine decarboxylase inhibition by alpha-difluoromethylornithine activates opposing signaling pathways via phosphorylation of both Akt/protein kinase B and p27Kip1 in neuroblastoma. Cancer Res. 2008 Dec 1;68(23):9825-31. doi: 10.1158/0008-5472.CAN-08-1865.
Hogarty MD, Norris MD, Davis K, Liu X, Evageliou NF, Hayes CS, Pawel B, Guo R, Zhao H, Sekyere E, Keating J, Thomas W, Cheng NC, Murray J, Smith J, Sutton R, Venn N, London WB, Buxton A, Gilmour SK, Marshall GM, Haber M. ODC1 is a critical determinant of MYCN oncogenesis and a therapeutic target in neuroblastoma. Cancer Res. 2008 Dec 1;68(23):9735-45. doi: 10.1158/0008-5472.CAN-07-6866.
Wallick CJ, Gamper I, Thorne M, Feith DJ, Takasaki KY, Wilson SM, Seki JA, Pegg AE, Byus CV, Bachmann AS. Key role for p27Kip1, retinoblastoma protein Rb, and MYCN in polyamine inhibitor-induced G1 cell cycle arrest in MYCN-amplified human neuroblastoma cells. Oncogene. 2005 Aug 25;24(36):5606-18.
Bachmann AS. The role of polyamines in human cancer: prospects for drug combination therapies. Hawaii Med J. 2004 Dec;63(12):371-4. Review
Chen ZP, Chen KY. Differentiation of a mouse neuroblastoma variant cell line whose ornithine decarboxylase gene has been amplified. Biochim Biophys Acta. 1991 Dec 3;1133(1):1-8.
Piacentini M, Fesus L, Farrace MG, Ghibelli L, Piredda L, Melino G. The expression of “tissue” transglutaminase in two human cancer cell lines is related with the programmed cell death (apoptosis). Eur J Cell Biol. 1991 Apr;54(2):246-54.
Melino G, Piacentini M, Patel K, Annicchiarico-Petruzzelli M, Piredda L, Kemshead JT. Retinoic acid and alpha-difluoromethylornithine induce different expression of neural-specific cell adhesion molecules in differentiating neuroblastoma cells. Prog Clin Biol Res. 1991;366:283-91.
Stephanou A, Knight RA, De Laurenzi V, Melino G, Lightman SL.Expression of pre-opiomelanocortin (POMC) mRNA in undifferentiated and in vitro differentiated human neuroblastoma cell lines. Prog Clin Biol Res. 1991;366:173-80.
Melino G, Farrace MG, Ceru’ MP, Piacentini M. Correlation between transglutaminase activity and polyamine levels in human neuroblastoma cells. Effect of retinoic acid and alpha-difluoromethylornithine. Exp Cell Res. 1988 Dec;179(2):429-45.
Chen KY, Dou QP. NAD+ stimulated the spermidine-dependent hypusine formation on the 18 kDa protein in cytosolic lysates derived from NB-15 mouse neuroblastoma cells. FEBS Lett. 1988 Mar 14;229(2):325-8.
Karvonen E, Andersson LC, Pösö H. A human neuroblastoma cell line with a stable ornithine decarboxylase in vivo and in vitro. Biochem Biophys Res Commun. 1985 Jan 16;126(1):96-102.
Pösö H, Karvonen E, Suomalainen H, Andersson LC. A human neuroblastoma cell line with an altered ornithine decarboxylase. J Biol Chem. 1984 Oct 25;259(20):12307-10.
Chen KY, Nau D, Liu AY. Effects of inhibitors of ornithine decarboxylase on the differentiation of mouse neuroblastoma cells. Cancer Res. 1983 Jun;43(6):2812-8.
Chapman SK. Antitumor effects of vitamin A and inhibitors of ornithine decarboxylase in cultured neuroblastoma and glioma cells. Life Sci. 1980 Apr 21;26(16):1359-66. No abstract available.
I continue to share the meaning of research for non-science students. Zaki was a summer medical student in 2015.
“I am a final year Malaysian medical student studying at RCSI. I had the opportunity to join RCSI Research Summer School (RSS) by assisting in research with Cancer Genetics, Molecular and Cellular Therapeutics Department of RCSI. My mentor was Dr Olga Piskareva. My research project investigated the role of chromogranin A as a biomarker in drug-resistant neuroblastoma by analysing its expression in different neuroblastoma samples of murine models.
Frankly speaking, I had zero experience in clinical research (apart from basic science project I did at high school) before the placement started. The reading materials that Dr Piskareva handed to me felt like an alien language that had to be deciphered, let alone doing experiment with western blotting and ELISA. I remembered my first day at the lab, staring enthusiastically at every apparatus and machines but not knowing how to run them.
Fortunately, Dr Piskareva and other lab buddies were very experienced and helpful enough with my insufficiency. Their perseverance and willingness to share knowledge and tip built my confidence and understanding to finish my research project. I never had any difficulty to discuss and ask for help any time I needed it from them in the lab. They were also very warm and friendly not just inside the lab but also outside of the lab.
My poster presentation at ICHAMS 2016
I felt like we were one big multinational family in one small lab. Imagine researchers coming from Russia, Ireland, Italy, Netherlands and myself from Malaysia working hand-in-hand, together. Over time, we bonded very close especially with our weekly breakfast getaway at Gerry’s and my friend Mei Rin and I even prepared our Malaysian cuisine for everyone in the lab in our last days. Even though most of my friends went home for the summer break, never did I felt lonely during my time in the lab. I am very grateful to have them in the lab and to call them my ‘keluarga’ (means family in Malay language).
After the research, I had the opportunity to do poster presentation at RCSI Research Day 2016 and International Conference for Healthcare and Medical Students (ICHAMS) 2016 at RCSI. These were great platforms for me to share my findings with other researchers. Above all, these were made possible with the help of Dr Piskareva and my lab buddies in preparing the poster and full report of the research. Additionally, the findings also provided me with extra information about neuroblastoma in line with my medicine study in paediatrics.
I would cherish every moment in the lab and indeed it was a very priceless experience. I would very much do it all over again in the lab if I had the chance because of the craving for knowledge and warmth of the lab buddies.
Continue research into 3D neuroblastoma models, we imaged cells growing on collagen based scaffolds using confocal microscopy. This technique is very popular in cell biology providing depth in cell imaging.
Here you can see cells growing on scaffolds: white dots – cells, irregular fibers – collagen containing scaffold.
The results are fascinating! Cell nucleus is in blue (DAPI), cell actin is in red (phalloidin). You will be able also to see how two cells ‘having a handshake’. It is happening just in the middle.
I am a medical student at Penang Medical College under a twinning programme with the Royal College of Surgeons in Ireland. I studied my pre-clinical years at RCSI Dublin. In the summer of 2015, I had the opportunity to join the RCSI Research Summer School (RSS) Programme. I was mentored by Dr Olga Piskareva, from Cancer Genetics, Molecular and Cellular Therapeutics (MCT) Department, RCSI. Being in this lab was simply one of the greatest experiences I have in my life; it was really rewarding.
My RSS project investigated the role of VDAC-1 protein on chemotherapy resistance in neuroblastoma. The only research focus of this lab is to find key players in neuroblastoma pathogenesis and to advance anti-cancer therapy.
Neuroblastoma cell line SK-N-AS. The cell line in my experiments.
I was entrusted with the task of splitting cells. I would plate them onto 96-well plates, add cisplatin drug and measure their viability afterwards. It may sound simple here, but the whole process required passion and hard-work.
Prior to this, I did not have any experience in the medical research field. During my first two weeks, everything seemed so tough; however, they became easier as the weeks flew by. My mentor, Olga, and the other staff and PhD students (Garret, John and Ross) were helpful and always guided me to explore my potentials. This programme taught me various new things which I would not have acquired on a normal day-to-day basis in school.
Introduction to Malaysian cuisine.
The people at Cancer Genetics were warm and wonderful. The hospitality, love and guidance cannot be quantified and words cannot express my immense gratitude towards them. It has been fascinating and I cherish every moment I spent there. We bonded over our weekly breakfast and tea sessions so well, and I am indeed grateful for being a part of this big family. It is my sincere wish that this positive spirit of togetherness will be preserved and will grow stronger in the future. This is something special, and I think ours is the best lab at RCSI!
I returned to Penang Medical College to further my studies in my clinical years. I took part in the PMC Research Day 2016 in which I was awarded the First Prize in Oral Presentation. I would like to dedicate this success to Olga and everyone who has been with me throughout my time at Cancer Genetics. Without all the guidance, I would not have made it this far.
I strongly urge students to take part in the research opportunities, because you gain invaluable experiences that you do not get elsewhere. May whatever we do at the lab today make a difference in another person’s life someday in the future.
For children who do survive cancer, the battle is rarely over. Over 60% of long‐term childhood cancer survivors have a chronic illness as a consequence of the treatment they received; over 25% have a severe or life‐ threatening illness. How much do we know about quality of life of childhood cancer survivors?
Researchers in health- and illness-related social sciences understand that the there is a life after the treatment completed. The life is full if diverse levels and issues from health related to social adaptation in different shapes and forms. Children and teenagers may experience fear when returning to school due to temporary or permanent changes to their physical appearance (1,2). They worry about their ability to socialise with their friends due to lengthy absences (3–5). Treatment can result in the development of learning disabilities in children and thus marking school as a major source of frustration (1,2). These learning difficulties can affect a child’s confidence and self-esteem, if left without attention and care (1,3). All studies come to the same conclusion. Challenges in education of children with cancer are complex, however most can be tackled efficiently through planning and good communication (1–5).
It is important not only to recognise the problems but to start changing the situation. Apparently much more could be done more efficiently if patients are involved in setting up future research agenda.
Reading
Gurney JG, Krull KR, Kadan-Lottick N, Nicholson HS, Nathan PC, Zebrack B, et al. Social outcomes in the childhood cancer survivor study cohort. J Clin Oncol. 2009;27(14):2390–5.
McDougall J, Tsonis M. Quality of life in survivors of childhood cancer: A systematic review of the literature (2001-2008). Supportive Care in Cancer. 2009. p. 1231–46.
Barrera M, Shaw AK, Speechley KN, Maunsell E, Pogany L. Educational and social late effects of childhood cancer and related clinical, personal and familial characteristics. Cancer. 2005;104(8):1751–60.
Langeveld NE, Stam H, Grootenhuis MA, Last BF. Quality of life in young adult survivors of childhood cancer. Support Care Cancer. 2002;10(8):579–600.
Klassen AF, Anthony SJ, Khan A, Sung L, Klaassen R. Identifying determinants of quality of life of children with cancer and childhood cancer survivors: A systematic review. Support Care Cancer. 2011;19(9):1275–87.
Yeh JM, Hanmer J, Ward ZJ, Leisenring WM, Armstrong GT, Hudson MM, et al. Chronic Conditions and Utility-Based Health-Related Quality of Life in Adult Childhood Cancer Survivors. J Natl Cancer Inst [Internet]. 2016;108(9):4–7.
Armstrong GT, Chen Y, Yasui Y, Leisenring W, Gibson TM, Mertens AC, et al. Reduction in Late Mortality among 5-Year Survivors of Childhood Cancer. N Engl J Med. 2016;374(9):833–42.
The conference on models and tumour microenvironment has brought together International experts in this field. Two keynote speakers (Peter Friedl, Radboud UMC/MD Anderson and Andrew Ewald, John Hopkins University) presented exhaustive experimental data on plasticity and microenvironmental control of cancer invasion and metastasis.
Their research teams independently found that
Tumour cells migrate collectively as a team from a piece of tumour like a group of people who changed their minds and decided to travel by bus when the majority stayed camping. However, Andrew Ewald acknowledged that they are not pioneers in this discovery. In 1976 Liotta observed migration of tumour cells in a group of 6-10 cells.
A migration group of cells has their leaders who crave the path through surroundings to the new locations.
Leader cells depend on cancer types. It can be any tumour cell in some cancer types or a specialised one.
Migrating cells take shape and follow the pattern of tissues to be invaded.
The experiments by Ewald’s research team on collective cell migration. In short, they co-implanted two lung tumour cell populations labelled differently into mice. One cell population had a green protein tag, another had red. After 6-8 weeks, researchers examined metastases and found that they had a mixed population of green and red tumour cells.
Multicellular seeding is a frequent mechanism for distant metastasis. (A) Schema of multicolor lineage tracing assay. ROSAmT/mG;MMTV-PyMT tumor organoids were treated with adenoviral Cre to induce recombination from membrane tdTomato (mTomato) to membrane eGFP (mGFP). Mosaic tumor organoids were then transplanted into nonfluorescent NSG host mice. After 6–8 wk, lungs of these mice were harvested. If metastases arise exclusively from single-cell seeding, there should be only single color metastases. In contrast, multicellular seeding should produce metastases with both colors. (B) Representative micrographs of polyclonal lung metastases of different sizes. n = 355 polyclonal metastases, across 16 mice and 4 independent experiments. (C) Representative micrograph of a mosaic tumor organoid treated with adeno-Cre and grown in 3D Matrigel with intermixing of red and green tumor cell clones. (D and E) Representative micrographs of primary tumors arising from mosaic tumor organoids transplanted into NSG host mice. Primary tumors varied in their local mixing of red and green tumor cell clones (local mixing %). These differences correlated with the percentage of multicolored metastases detected in the lung (% multicolored). n = 12 mice, 4 independent experiments, 4,072 metastases. Correlation determined by Spearman rank test for samples with more than five lung metastases per mouse. (Scale bars, 20 μm in B and C, and 2 mm in D.)
