Thursday, 31 January 2013

A subset of T cells provide new insight into the mechanism of Graft Versus Host Disease

The term leukemia covers a range of haematological malignancies (cancers of blood cell origin). Patients can be treated by radiation or multi-drug chemotherapy. Recent research has focused on single agent therapeutics for use alone, or in combination with established treatments. Even difficult to treat leukemias such as chronic lymphocytic leukemia (CLL) have seen advances

However, the treatment of haematological malignancies usually involves high doses of chemo- and radio-therapy, which kills cancerous blood cells but also affects the body's ability to repopulate the blood with healthy white blood cells. To combat this, cancer treatment can be followed up with a replacement of the bone marrow or blood stem cells by transplantation from a donor. One very unfortunate side effect of this transplantation is the response of the transplanted (graft) cells to the host cells, this is known as Graft Versus Host Disease (GVHD). To treat GVHD, patients are given drugs to suppress the graft cell immune response, however these drugs can have severe side effects.

A very interesting research article published in the journal PLoS One, by van der Waart et al from The Netherlands, addresses one mechanism by which GVHD develops in patients treated for haematological malignancies by stem cell transplantation.

A recently discovered subtype of white blood cells, T cells called Th17 cells which produce a small signalling protein called IL-17, have been implicated in GVHD. This present study assessed the white blood cell content of patients with a range of haematological malignancies treated in the manner described above. They found that a subpopulation of Th17 cells which had high levels of the protein CD161 on their surface were resistant to the  effects of immuno suppressive drug treatment. These cells are protected by expression of a transporter on their surface (ABCB1) that removes the drug which would normally prevent their growth.

An interesting observation was that in patients with GVHD the number of CD161 expressing cells in the blood was decreased. The study goes on to show that in fact these cell relocate from the blood to tissue sites where GVHD is visible. These cells are able to respond to a small signalling protein, a chemokine called CCL20, which is enriched in tissue from patients with GVHD and  potentially pulls these cells from the blood into the tissue. An elegant use of an imaging technique known as immuno fluorescence, showed that the cells found in GVHD tissue indeed contains cells which are T cells expressing high levels of CD161 on their surface as well, as the protein which recognises CCL20.

This study provides two observations that could be potentially beneficial for the management of GVHD: a decrease in the number of CD161 expressing white blood cells in the blood of patients following reconstitution by stem cell transplantation may act as a marker for patients likely to develop GVHD. Additionally, further understanding of the role of this subset of T cells in GVHD may give rise to novel treatments for the management of GVHD.

Mentioned Articles

van der Waart AB, van der Velden WJ, van Halteren AG, Leenders MJ, Feuth T, Blijlevens NM, van der Voort R, Dolstra H. (2012)
Decreased levels of circulating IL17-producing CD161+CCR6+ T cells are associated with graft-versus-host disease after allogeneic stem cell transplantation.
PLoS One. 2012;7(12):e50896. doi: 10.1371/journal.pone.0050896. Epub 2012 Dec 4. (2009) About graft versus host disease (GVHD) : Cancer Research UK : CancerHelp UK. [online] Available at: [Accessed: 31 Jan 2013].

Breast cancer cells TWIST macrophages to aid blood vessel growth

Epithelial to mesenchymal transition (EMT) is a process where epithelial cells, those that form tissues of our major organs such as the lungs, gut, skin and breast can transform into mesenchymal cells. This transition causes the cells to take on a more motile and flexible pattern of behaviour. EMT is a crucial process in the initial development of the human body and also helps to repair damaged tissue following wounds. However, cancer cells are also able to exploit the process of EMT to help them to help them leave the mass of epithelial cells forming the primary tumour and move to distant secondary sites.

The processes that regulate EMT during development are highly regulated, this is achieved in part by small proteins called transcription factors. Transcription factors interact with DNA and recruit machinery that controls when genes are made into the proteins, which ultimately bring about changes within the cell. Three transcription factors particularly important in EMT during development are: Slug, Snail and Twist; recently these proteins have begun to be investigated in the context of cancer. They are often up-regulated in cancer and their presence in tumours may indicate a poor survival rate for patients. They promote cancer mainly through their effects on proteins involved in EMT, and much research is being currently undertaken with this aspect in mind.

However, a study published this month in the journal Cancer Research by Low-Marchelli and colleagues describes a novel function for Twist in the way in which cancer cells recruit blood vessels. This process, termed angiogenesis, is required to give a tumour sufficient blood to continue to grow. Normal breast epithelial cells do not express detectable levels of Twist, but when Twist is artificially added to these cells they are better at encouraging blood vessel growth.

While looking for the mechanism by which Twist increases angiogenesis, the group found that Twist expressing breast cells released more of one particular signalling protein, CCL2, than normal breast cells. This CCL2 was shown to be required for the promotion of blood vessel growth by Twist; interestingly this was independent of Twist’s role in EMT. CCL2 belongs to a group of proteins called chemokines which act to attract other cells to move towards their source, in this case the breast cancer cells. The cells which are attracted to this CCL2 are an immune cell called macrophages, cells which are normally required for the removal of damaged, infected or even cancerous cells. However, the signalling molecules released by macrophages can also promote tumour growth directly as well as promoting stages of blood vessel development.

In conclusion, this study has elegantly revealed a mechanism where Twist in breast cancer cells can cause increased CCL2 levels to attract macrophages and promote blood vessel growth. This is an interesting new facet to Twist biology, adding further complexity to its role in cancer.

Mentioned Articles

Low-Marchelli JM, Ardi VC, Vizcarra EA, van Rooijen N, Quigley JP, Yang J. (2013)
Twist1 Induces CCL2 and Recruits Macrophages to Promote Angiogenesis
Cancer Res. 2013 Jan 15;73(2):662-71. doi: 10.1158/0008-5472.CAN-12-0653.

Shioiri M, Shida T, Koda K, Oda K, Seike K, Nishimura M, Takano S, Miyazaki M. (2006)
Br J Cancer. 2006 Jun 19;94(12):1816-22. doi:10.1038/sj.bjc.6603193

J Exp Clin Cancer Res. 2010 Sep 1;29:119. doi: 10.1186/1756-9966-29-119.

Loss of Fam38 gets SCLC moving

Small cell lung cancer (SCLC) is a very aggressive form of lung cancer; response of patients to the initial chemotherapy is good, however in most cases the cancer reoccurs and progresses. A key step in progression of advanced cancer is the breaking away of a number of cells from the original tumour which move through the body and act as a seed for new tumours in areas such as the lymph nodes. This process, termed metastasis requires cells of the original tumour to take up a more invasive pattern of cell movement. The way in which cells move is a complicated and highly regulated process, cancers hijack this processes to their own end: metastasis. 

The majority of solid tumours rely on a combination of proteins called integrins, which regulate how well one cell sticks to other cells at it moves across them, and a group of enzymes which break up and remodel the environment surrounding the tumour. However, a recent study by McHugh et al. from Edinburgh MRC and Kings College London has shown that SCLC can adopt a vastly different method of cell movement.
Normal lung cells express high levels of a protein called Fam38, this protein is involved in integrin regulation for cellular movement. A key initial observation by the group was that SCLC cells, in contrast, have very low levels of Fam38. In normal lung cells McHugh and colleagues artificially reduced Fam38 levels to a similar degree as seen in SCLC cells and looked to see what changes Fam38 loss caused. These cells showed a remarkable loss of dependence on integrins for their movement and consequently were less able to stick to other cells. 

Cells lacking Fam38 adopted a different method of movement which allowed them to move faster over a two-dimensional area and further through a three-dimensional tissue-like substance. This increased invasiveness following Fam38 loss may explain why, in part, SCLC is so aggressive and difficult to treat.
Drug discovery for treatment of the most common form of lung cancer, non-small cell lung cancer (NSCLC), has advanced quicker than for SCLC. With the discovery of the role of Fam38 in SCLC a potential new therapeutic target has been found. Further research is required, but watch this space!

Mentioned Articles:

McHugh BJ, Murdoch A, Haslett C, Sethi T (2012) Loss of the Integrin-Activating Transmembrane Protein Fam38A (Piezo1) Promotes a Switch to a Reduced Integrin-Dependent Mode of Cell Migration. PLoS ONE 7(7): e40346. doi:10.1371/journal.pone.0040346