Retinoblastoma: childhood eye cancer and future stem cell treatments

by Wideacademy - 08 January, 2018

  • Childhood cancer
  • Stem Cell Transplant
  • Eye cancer
  • Induced pluripotent stem cells (iPS cells)
  • Allogeneic
  • Autologous
  • Chemotherapy

What is Retinoblastoma?

Retinoblastoma is a rare form of eye cancer, usually affecting children under five. In Britain, approximately one child is diagnosed with the condition every week.

It is a cancer of the retina, the light-sensitive lining at the back of the eye, and develops when immature nerve cells, called retinoblasts, grow out of control and form a tumour.

Retinoblastoma has a very good survival rate if it is diagnosed early. In the UK, around 98 per cent of children will survive following treatment.

In most cases, the child is treated before the cancer spreads from the eye to the rest of the body. However, sometimes it can spread to the brain, lymphatic system or elsewhere.

The condition is caused by a mutation in the RB1 gene — which is either inherited from a child’s parents (meaning the mutation exists in all the child’s cells) or happens at random in just one cell.

Symptoms may include:

  • a white reflection in the child’s pupil that is evident in photos
  • a squint
  • a red, inflamed eye without pain
  • poor vision
  • a change to the colour in the iris
  • lazy-eye
  • a larger than normal eyeball

Tumours can appear on just one eye (when the RB1 mutation is random) or both eyes when it is inherited.

How can stem cells help?

Stem cell treatment is not a primary treatment for retinoblastoma.

However, stem cells are an option when the cancer has spread outside the child’s eye and the cancer is unlikely to be cured by surgery, chemo or radiotherapy.

Having a stem cell transplant allows doctors to give the child higher doses of chemotherapy than could be given safely otherwise. This process is called a stem cell rescue, because it allows the bone marrow to rebuild itself again.

There are serious side effects to stem cell rescue and improving the success rate (in terms of patient survival) is an on-going area of study. A phase III trial by the Children’s Oncology Group, which is expected to run until 2018, is looking into the side effects of chemotherapy combined with autologous (from the child’s own body) stem cell transplant for patients with retinoblastoma.

How stem cells may help in future

Looking at the role stem cells play in the origin of retinoblastoma can reveal much about the disease and therefore potential ways to treat it.

The faulty gene RB1 is a tumour suppressor gene which controls the process of cells multiplying and specialising into a particular form or function, and the survival of cells.

Research indicates that the absence of RB1 in stem cells or progenitor cells can cause tumours to start growing. Progenitor cells are similar to stem cells but are not immortal and are more specific in their function.

A current study by St Jude Children’s Research Hospital in Memphis is using human induced pluripotent stem cells to do this. The researchers will take skin and blood samples from children with the genetic form of retinoblastoma and use them to make induced pluripotent stem cells that are each deficient in the RB1 gene.

The aim is to see if these human RB1-deficient, induced pluripotent stem cells can create retinoblastoma in the laboratory. This will provide an opportunity to study the beginnings of retinoblastoma and how tumours begin to develop.

Research into exactly how RB1 controls stem cells to divide, self-renew or differentiate, could help scientists learn how to control these processes, and potentially prevent cancer development.

Another study by the St Jude Children’s Research Hospital in collaboration with the Pediatric Cancer Genome Project, mapped the whole developmental process of retinoblastoma cells as they turn cancerous. It analysed how and why the gene was expressed (the process by which information from a gene is used in the synthesis of a functional gene) to see the effect gene expressions have to play in initiating retinoblastoma tumours.

The findings have narrowed down the window during which normal cells turn into tumour cells. This paves the way for further, more focused research into exactly how changes or malfunctions in epigenetics (inherited changes in gene function) cause cancer.

Once scientists crack the epigenetic code, i.e the specific changes in the organisation of the genes that guide each type of cell to differentiate, they will be closer to understanding how to treat the disease effectively.

A study funded by the Childhood Eye Cancer Trust, focused on the precise genetic markers of retinoblastoma. Researchers compared the gene expression in invasive tumours against those in non-invasive tumours, in children with retinoblastoma. By comparing the two they could better understand the steps after the mutation of RB1, that lead to the formation of tumours.

They looked at the DNA sequence of every active gene in the retinoblastoma cell lines they established and compared them to the sequence in normal genes, to identify which ones had mutated.

They identified 50 genes that are more expressed in the invasive form of tumours. These results will help us to assess risk for the spread of retinoblastoma and also help to identify new therapeutic targets.

Cancer Stem Cells

Cancer stem cells are a fascinating subset of stem cell biology that hold exciting promise for highly targeted treatment of cancer in the future. Cancer stem cells are rare, immortal cells within a tumour that self-renew and give rise to many cell types that make up a tumour. In this way, they act like stem cells and share other properties such as quiescence (when the cell is not dividing), proliferation and drug-resistance.

Understanding how cancer stem cells work and how they can be disabled makes them useful subjects for cancer research. If they behave in the same way as normal stem cells, it follows that scientists can harness what they know about normal stem cells, to identify and attack cancer stem cells and the malignant cells they produce.

If cancer stem cells are the primary force for cancer growth and metastasis (spread of cancer), then effective cancer treatments must attack them. If the cancer stem cell cannot be disabled, such as is often the case with chemotherapy, then the cancer can relapse. By targeting cancer stem cells only – and specifically – treatments will have fewer side effects, as the other normal cells will remain untouched.

Another study published in “Biochemical and Biophysical Research Communications” in 2017 transformed malignant retinoblastoma cancer cells back into cancer stem cells through reprogramming technology. This new method provides the opportunity to study the beginnings of cancer and the epigenetics of cancer, as well as the area where the mechanisms of cancer and stem cell behaviour collide.