Authors: Hugo Humphries, Helen D. Brasch, Bede van Schaijik, Swee T. Tan, Tinte Itinteang

Plastic and Reconstructive Surgery (2019). Volume 144(2)  pp 372 – 384. Doi:10.1097/PRS.0000000000005867.

https://journals.lww.com/plasreconsurg/Abstract/2019/08000/Expression_of_Components_of_the_Renin_Angiotensin.22.aspx

Keloid disorders are characterised by abundant scar tissue resulting from excessive collagen deposition in the skin, being 15 times more common in dark-skinned people. They appear to be genetically inherited and are associated with wound repair but, unlike hypertrophic scars, which are confined to the area around the wound, keloid lesions extend beyond it.

The Gillies McIndoe Research Institute has now demonstrated that the renin-angiotensin system is present in keloid lesions and in the stem cells of the lesion. This raises the possibility of inhibitors of the renin-angiotensin system, classically associated with cardiovascular homeostasis and electrolyte balance, being potential treatments.

These results provides support and a possible mechanism for the recent observation that enalapril, an ACE inhibitor, and so connected to the renin-angiotensin system, is efficacious in treating keloid disorder.

Authors: Reuben Cane, Andrew Kennedy-Smith, Helen D. Brasch, Stephanie Savage, Reginald W. Marsh, Tinte Itinteang, Swee T. Tan 

Journal of Stem Cell and Regenerative Biology (2019) Volume 5, pp6 – 17. https://www.ommegaonline.org/articles/publishimages/16710-JSRB-19-RA-2462.pdf

Renal cell carcinoma is the ninth most common cancer, with renal clear cell carcinoma comprising up to 85% of renal cell carcinomas. Obesity, smoking and high blood pressure are well-established risk factors for these cancers.

Surgery is the conventional treatment although there is still a 40% recurrence rate. 30% eventually develop metastases. Advanced disease can be treated with drugs. The five-year survival rate is only 10%.

The GMRI and collaborators have proposed that tumour development and proliferation is driven by cancer stem cells that possess self-renewal and pluripotent properties and are responsible for metastasis and recurrence. Our research has demonstrated that many types of cancer express cancer stem cells.

This study concludes that there are at least two types of cancer stem cells in renal clear cell carcinoma, each expressing several common constituents with some constituents that are unique to a specific population. There is evidence that one of these populations is more mature than the other.

Therefore it has now been demonstrated that this most common type of kidney cancer has cancer stem cells similarly to many other cancers. The implication is that the GMRI’s novel cancer treatment approach may be efficacious.

The GMRI has just published a review article in Frontiers in Oncology following an invitation to submit an article to the special issue on ‘Therapeutic Targeting of Cancer Stem-Like Cells – The Current State of the Art

https://www.frontiersin.org/research-topics/8187

The article describes the links between cancer stem cells and the renin-angiotensin system, which controls blood pressure and fluid balance, and outlines the evidence that suggests targeting this system might target cancer stem cells.

Lead author Dr Imogen Roth explains in the article, titled ‘Therapeutic Targeting of Cancer Stem Cells via Modulation of the Renin-Angiotensin System’, how the renin-angiotensin system also appears to have a role in stem cell differentiation, and suggests that the renin-angiotensin system might also have a role in cancer stem cell maintenance.

To support this, Dr Roth outlines numerous studies which have shown that the renin-angiotensin system is elevated in cancer, and how common anti-hypertensive medications which target the renin-angiotensin system have been shown to prevent or reduce the development of cancer.

As such, it appears that the roles of the renin-angiotensin system in both stem cell maintenance and tumour development may converge on cancer stem cells, making targeting the renin-angiotensin system a potential cancer therapy.

The article can be viewed at https://doi.org/10.3389/fonc.2019.00745

Authors: Jessica C. Papali’i-Curtin, Helen D. Brasch, Bede van Schaijik, Jennifer de Jongh, Reginald W. Marsh, Swee T. Tan and Tinte Itinteang

Frontiers in Surgery (2019). doi:10.3389/fsurg.2019.00013 
https://www.frontiersin.org/articles/10.3389/fsurg.2019.00013/full

Pyogenic granuloma is a relatively common benign vascular tumour affecting the skin. Most commonly it occurs as a small red nodule, primarily in the head and neck region, and bleeds repeatedly. Current treatments include surgery, prescription drugs and in some circumstances laser therapy.

Although the pathogenesis of pyogenic granuloma is uncertain, the small blood vessels are immature. We have previously shown that two sub-populations of embryonic stem cell markers are expressed in them.

We have now demonstrated that the renin-angiotensin system is present in these stem cells. This system, which has long been associated with the regulation of blood pressure and fluid balance, can be modulated and controlled with a range of drugs.

The consequence of these findings is that it may be possible to treat pyogenic granuloma by inhibiting the renin-angiotensin system at the origin of the condition.

Authors: Rosanna M. A. Rahman, Bede van Schaijik, Helen D. Brasch, Reginald W. Marsh, Agadha C. Wickremesekera, Reuben Johnson, Kelvin Woon, Swee T. Tan and Tinte Itinteang

Frontiers in Surgery (2019). doi:10.3389/fsurg.2019.00006 https://www.frontiersin.org/articles/10.3389/fsurg.2019.00006/full

One of the most common primary tumours of the central nervous system is meningioma. While surgery is the standard approach for treatment, it is not achievable in 50% of the cases. A better method of management is therefore required.

The Gillies McIndoe Research Institute and collaborators have characterised stem cells in meningioma and demonstrated the renin-angiotensin system (RAS)  within these cells. This system is known to promote tumour growth as well as regulate blood pressure.

The RAS can be activated by classical methods involving renin and the prorenin receptor or by an alternative process involving a group of protease enzymes called cathepsins. This paper establishes that two of these cathepsins (cathepsins B and D) are localised to the stem cells in meningioma while cathepsin G is present in cells in the matrix.

We conclude that, if the RAS is to be the basis of a therapy for meningioma, inhibition of these enzymes will need to be part of the treatment.

Authors: Elizabeth K. Eady, Helen D. Brasch, Jennifer de Jongh, Reginald W. Marsh, Swee T. Tan and Tinte Itinteang
Lymphatic Research and Biology (2019) Doi: 10.1089/lrb.2018.0046
https://www.liebertpub.com/doi/10.1089/lrb.2018.0046

Malformations of the lymph vessels occurs in about 1 in 5,000 infants. It is characterised by slowly increased swelling, frequently in the head and neck area. They are classified as either macrocystic (involving larger lymph vessels) or microcystic (small vessels). These vessels are thin and so prone to leakage. Treatment of the microcystic form is unsatisfactory while sclerotherapy is the preferred treatment for the macrocystic ones.

Some have suggested that these malformations may originate from gene mutations. Others have described progenitor-like cells in them and, as embryonic stem cells have been described in venous malformations, GMRI researchers have proposed that similar stem cells may be present in lymphatic malformations.

Using several techniques, the GMRI team has confirmed the presence of progenitor cells and identified a small population of stem cells in microcystic lymphatic malformations. The implication of this finding is that the possible origin of the condition has been identified and consequently a novel potential approach to treating the condition identified.

Authors: Ananatha Narayanan, Susurutha K. Wickremesekera, Bede van Schaijik, Reginald W. Marsh, Helen D. Brasch, Swee T. Tan and Tinte Itinteang

Journal of Cancer Metastasis and Treatment (2019).5: 36 – 46. Doi:10.20517/2394-4722.2018.77

https://jcmtjournal.com/article/view/3054

Colorectal (colon) cancer accounts for about 10% of all cancers. It is the second most common cause of cancer death in New Zealand.

Colorectal cancer may spread in the body. The liver is the most common site for secondary tumours, with up to 50% of patients developing consequent liver tumours.

The concept of cancer stem cells, the focus of much of the GMRI’s research,  proposes that there is a sub-population of cells within a cancer that have properties similar to embryonic stem cells which are the driving force of the development of the cancer. The paper identifies three sub-populations of these cells, through their distinctive markers, which are shown to be present in liver metastases arising from colon adenocarcinoma.

The GMRI and collaborators have shown that the renin-angiotensin system, which is well-known as a regulator of blood pressure and fluid balance, is associated with stem cells in a range of cancers. There are a number of modulators of this system which are prescribed when it is malfunctioning. The paper demonstrates that this hormonal system is present within the stem cells of metastatic liver cancer.

Our findings suggest that these properties could be used as a novel therapeutic target for treating these liver cancers.

Authors: Elysia M.S. Tan, Helen D. Brasch, Paul F. Davis, Tinte Itinteang and Swee T. Tan

PRS Global Open (2019).10.1097/GOX.0000000000002170. https://journals.lww.com/prsgo/Abstract/latest/Embryonic_Stem_Cell_like_Population_within_Venous.98030.aspx

Venous (vein) malformation is the most common type of vascular abnormality. These defective veins affect about 1% of the population and, although present a birth, may not be noticed until later. They frequently involve the skin and occasionally muscle. About 40% occur in the head and neck, with another 40% found in the extremities and 20% on the trunk.

Generally management of venous malformations is unsatisfactory. The basis of them is poorly understood but mutations of several different genes have been proposed.

GMRI researchers have recently demonstrated the activity of the renin-angiotensin system in these lesions. This system is well-known as a regulator of blood pressure. As a result of this finding there is the prospect of being able to control the development of this condition by means of inhibition of the renin-angiotensin system. This paper establishes that this system is located in the stem cells of the venous malformations. The finding provides a basis for proposing that the use of renin-angiotensin inhibitors may be beneficial for the treatment of venous malformations.

Authors: Paul Campbell, Reuben Bennet, Louise Joyce Lim, Helen D. Brasch, Reginald Marsh, Tinte Itinteang and Swee T. Tan

Journal of Biotechnology and Biomedical Science (2019). doi:10.14302/issn.2576-6694.jbbs-19-2625 https://openaccesspub.org/jbbs/article/1014

Oral cavity squamous cell carcinoma is the 15th most common cancer worldwide with substantial geographical differences and greater incidence in developing countries. It affects males most commonly, in their fifth and sixth decades of life, although the incidence is increasing in women and those under the age of 45. Risk factors include alcohol abuse, tobacco smoking and betel quid chewing.

The prognosis depends on several factors, including the development of new blood vessels. Quantification of this development has led to its use for determining tumour-related prognosis. One method is Chalkley counting, which has been shown to be appropriate for predicting the survival of patients with gastrointestinal tumours. However its applicability for quantifying blood vessel development in breast cancer has been questioned.

The GMRI team and collaborators have investigated the effectiveness of Chalkley counting for quantifying blood vessel development in oral tongue squamous cell carcinoma and its relation to cancer progression and metastasis. Only one of the four markers for the vessel development showed any correlation with the prognosis. We conclude that Chalkley counting is not a reliable prognostic method for oral tongue squamous cell carcinoma. 

Authors: Ganeshwaran Shivapathasundram, Agadha C. Wickremesekera, Helen D. Brasch, Reginald Marsh, Swee T. Tan and Tinte Itinteang

Frontiers in Surgery. (2018). doi:10.3389/fsurg.2018.00065
https://www.frontiersin.org/articles/10.3389/fsurg.2018.00065/full

Research by the GMRI and others proposes that tumour stem cells are the cellular origin of several benign conditions such as Dupuytren’s disease, infantile haemangioma and meningioma. 25-30% of cranial and spinal tumours are meningiomas.

A collaborative research project involving the GMRI and the Neurosurgery Department of Wellington Hospital has investigated the presence and possible role of these stem cells in the origin and development of meningiomas. Using four independent procedures, five biomarkers of stem cells were identified in 11 different meningiomas. These stem cells were localised to the micro blood vessels in the tumour. The presence of these putative stem cells suggests that they may give rise to the meningiomas.