Publication Summaries

Expression of Components of the Renin-Angiotensin System by the Embryonic Stem Cell-Like Population within Keloid Lesions

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.

Characterization of Cancer Stem Cells in Renal Clear Cell Carcinoma

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.

Therapeutic Targeting of Cancer Stem-Like Cells – The Current State of the Art

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

Expression of Components of the Renin-Angiotensin System in Pyogenic Granuloma

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.

Expression of Cathepsins B, D and G in WHO Grade I Meningioma

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.

Expression of Embryonic Stem Cell Markers in Microcystic Lymphatic Malformation

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.

Cancer Stem Cells in Liver Metastasis from Colon Adenocarcinoma Express Components of the Renin-Angiotensin System

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.

Embryonic Stem Cell-like Population Within Venous Malformation Expresses the Renin-Angiotensin System

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.

Chalkley Counting in Oral Tongue Squamous Cell Carcinoma: Does It Have a Prognostic Value?

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. 

Expression of Embryonic Stem Cell Markers on the Microvessels of WHO Grade I Meningioma

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.

Expression of Cancer Stem Cell Markers in Metastatic Melanoma to the Brain

Authors: Agadha C. Wickremesekera, Helen D. Brasch, Valerie M. Lee, Paul F. Davis, Kelvin Woon, Reuben Johnson, Swee T. Tan and Tinte Itinteang.

Journal of Clinical Neuroscience (2019) Volume 60. Pp112 – 116. https://doi.org/10.1016/j.jocn.2018.10.068

Published research undertaken by the team at the GMRI in collaboration with the Neurosurgery Department of Wellington Hospital has shown that cancer stem cells are present in brain tumours that have developed from the spread of melanomas.

Melanoma tumours spreading to the brain occur in up to 30% of melanoma patients and account for up to 8% of all brain tumours.

Cancer stem cells have been shown to be the drivers of the growth of many cancers, including melanoma. Our research has shown that cancer stem cells are present in these metastatic melanomas. In fact, there appear to be three different subpopulations of cancer stem cells, which may be due to a hierarchy of development and/or to heterogeneity of the tumour.

As the GMRI and collaborators have demonstrated for a number of other cancers, the presence of cancer stem cells may be the basis of the growth of this type of brain tumour. Further characterisation of the properties of the cancer stem cells may provide an opportunity to develop an alternative treatment of this type of cancer.

Expression and Localization of Cathepsins B, D and G in Cancer Stem cells in Liver Metastasis from Colon Adenocarcinoma

Authors: Shreeja Mehrotra, Susrutha K. Wickremesekera, Helen D. Brasch, Bede Van Schaijik, Reginald W. Marsh, Swee T. Tan and Tinte Itinteang

Frontiers in Surgery April 2018. Volume 5, doi.org/10.3389/fsurg.2018.00031 https://doi.org/10.3389/fsurg.2018.00040

Colorectal cancer is the third most common cancer worldwide with an approximately 50% mortality rate. It metastasises with the liver being the most common secondary site. Up to 70% of the deaths associated with colorectal cancer manifest liver metastasis. Although surgery of the liver has the best outcome for these patients, a procedure following diagnosis is possible in only about 20% of cases.

Three sub-populations of cancer stem cells have been characterised in liver metastasis. These stem cells are thought to be responsible for generating the tumour, tumour differentiation, maintenance, spread and relapse. Components of the renin-angiotensin system are expressed in cancer stem cells. The cathepsin enzymes (B, D and G) digest proteins and so can facilitate the invasion and metastasis of colorectal cancer to the liver. The paper reports the detection of these three enzymes in the stem cells found in liver cancer.

Phosphorylated Forms of STAT1, STAT3 and STAT5 Are Expressed in Proliferating But Not Involuted Infantile Hemangioma

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

Frontiers in Surgery April 2018. Volume 5, doi.org/10.3389/fsurg.2018.00031 https://doi.org/10.3389/fsurg.2018.00031

The research team has established the presence of stem cells in strawberry birthmarks (haemangiomas) that are proliferating. This has been determined by confirming the presence of proteins characteristic of these cells. However there is a family of three proteins called STATs that are associated with stem cells which are also known to have a role in the development of red blood cells – an activity known to occur in strawberry birthmarks. These STATs can be modified by the binding of phosphate groups. These phosphorylated proteins can promote the expansion and regulate the development of stem cells.

The role of these modified STAT proteins in strawberry birthmark development has been investigated. All three phosphorylated STATs studied were demonstrated in proliferating strawberry birthmarks but their expressions were reduced in the involuting (shrinking) haemangiomas. The STAT3 variant was the most abundant form. These reductions as the strawberry birthmark involutes reflect a depletion of the stem cells.

Expression and Localization of Cathepsin B, D, and G in Dupuytren’s Disease

Authors: Kirin Tan, Helen D. Brasch, Bede van Schaijik, James R. Armstrong, Reginald W. Marsh, Paul F. Davis, Swee T. Tan and Tinte Itinteang

 

Plastic Reconstructive Surgery Global Open 2018. Volume 6,

doi:10.1097/GOX.0000000000001686

https://journals.lww.com/prsgo/Fulltext/2018/02000/Expression_and_Localization_of_Cathepsins_B,_D,.9.aspx

 

Dupuytren’s disease is a slowly developing condition involving the palm of the hand. Knots of tissue (nodules) form, which eventually grow into cords that pull one or more fingers into a bent position. These affected fingers cannot be straightened, restricting a person performing a number of activities.

 

The current management of the disease involves either injections of steroids or collagenase or surgery but, nonetheless, recurrence is up to 70%.  While the cause of the condition is uncertain, we have identified embryo stem cell-like cells in it. These cells have been shown to express constituents of the renin-angiotensin system. Our findings suggest that these stem cells might give rise to the condition and that regulating the renin-angiotensin system may have a role in its treatment.

 

The production of the angiotensin II component of the renin-angiotensin system may be promoted by the proteases cathepsins B, D and G. This paper establishes the presence of these three proteases in Dupuytren’s disease tissues and demonstrates that the B and D forms are localised to the stem cells which are known to express the renin-angiotensin system.

 

Characterization of Cancer Stem Cells in Colon Adenocarcinoma Metastasis to the Liver

Authors: Hugo N. Humphries, Susrutha K. Wickremesekera, Reginald W. Marsh, Helen D. Brasch, Shreeja Mehrotra, Swee T. Tan and Tinte Itinteang

Frontiers in Surgery 2018. Volume 4

doi:10.3389 /fsurg.2017.00076

https://www.frontiersin.org/articles/10.3389/fsurg.2017.00076

Worldwide, colon cancer is the third most common cause of cancer deaths. In New Zealand it is ranked second. A range of environmental, lifestyle and genetic factors has been attributed to its progression. Approximately 50% of patients with colon cancer develop secondary tumours in the liver and this accounts for two-thirds of the disease-related deaths.

Cancer stem cell populations have now been identified and characterised in liver tumours. This paper confirms that the concept of the presence and function of stem cells established by the GMRI in a number of other cancers is also present in this tumour.

Subcellular Localization of the Stem Cell Markers OCT4, SOX2, NANOG, KLF4 and c-MYC in Cancer: A Review

Authors: Bede van Schaijik, Paul F. Davis, Agadha C. Wickremesekera, Swee T. Tan and Tinte Itinteang

Journal of Clinical Pathology 2018. Volume 71, 88-91
doi:10.1136/j.jclinpath-2017-204815
http://jcp.bmj.com/content/71/1/88

The cancer stem cell (CSC) concept of cancer proposes that not all cancer cells participate in tumour formation and that the development and progression of cancer is driven by CSCs, a small sub-population of cells. A number of molecules specific to stem cells have been identified.

This review summarises the current understanding of the localisation and function of these molecules in relation to the role of cancer stem cells for a number of types of cancer. These findings give clues relating to their roles in cancer development and growth. They are found both inside and outside the nuclei of cells, which suggest that their movement in the cells may determine their functional activities with regards to tumour proliferation.

Tumour Stem Cells in Meningioma: A Review

Authors: Ganeshwaran Shivapathasundram, Agadha C. Wickremesekera, Swee T. Tan and Tinte Itinteang

Journal of Clinical Neuroscience 2018. Volume 47, 66-71 doi:10.1016/j.jocn.2017.10.059

https://www.researchgate.net/publication/320859474_Tumour_stem_cells_in_meningioma_A_review

Meningiomas are cancers that occur in the brain and spinal cord. They comprise about 25% of all neurological cancers. Their incidence is around 6 per 100,000 with a slightly higher preponderance in females. While the majority of these cancers are benign, they have a high rate of recurrence especially when the location is at the base of the skull.

The presence of stem cells in meningioma was first reported in 2009 in an aggressive malignant form. This review discusses the identification of a number of stem cell marker proteins in this tumour so as to establish a possible hierarchy of them. However it is apparent that there is relatively little known at this stage about the properties and functions of these cells in meningiomas and that further studies are needed.

Embryonic Stem Cell-Like Population in Venous Malformation

Authors: Elysia M.S. Tan, Sam D. Siljee, Helen D. Brasch, Susana Enriquez, Swee T. Tan and Tinte Itinteang

Frontiers in Medicine (Dermatology). October 2017. Doi:10.3389/fmed.2017.00162

https://www.frontiersin.org/articles/10.3389/fmed.2017.00162/full

Vascular malformations alter arteries, veins, capillaries and lymphatic vessels. The most common of these is venous malformation, which affects about 1% of the population. These malformations are composed of anomalous veins with thin walls and are present at birth but only become apparent later in life.

The cause of this condition is not well understood although a number of possibilities have been proposed. We have identified and characterised stem cells in this condition. The paper reports that there are two populations of these cells, one being part of the lining of the blood vessels, the other outside the lining.

The further characterisation of these primitive cells is the subject of ongoing research in the hope of identifying properties that might provide the opportunity of regulating and controlling them and the consequent development of these malformations.

Embryonic Stem Cell–Like Population in Dupuytren’s Disease Expresses Components of the Renin-Angiotensin System

Authors: Nicholas On, Sabrina P. Koh, Helen D. Brasch, Jonathan C. Dunne, James R. Armstrong, Swee T. Tan and Tinte Itinteang

Plastic Reconstructive Surgery Global Open. July 2017 Vol. 5, e1422; doi:10.1097/GOX.0000000000001422     

http://journals.lww.com/prsgo/Fulltext/2017/07000
/Embryonic_Stem_Cell_Like_Population_in_Dupuytren_s.12.aspx

Dupuytren’s disease is a chronic fibrotic condition that causes the fingers to bend over. It occurs throughout the world but is particularly prevalent in Northern Europe. Surgery is the most common form of treatment but almost 40% of the cases relapse within five years.

Previously the GMRI identified and characterised embryonic stem cells in Dupuytren’s disease and it was suggested that dysregulation of these cells led to the progression of the disease. This paper has identified the presence of four components of the renin-angiotensin system in Dupuytren’s disease tissue and has located them in the stem cells associated with the microvessels in the tissue. These findings suggest that the stem cells in Dupuytren’s disease could provide a novel method for treatment through modulation of the renin-angiotensin system.

Expression and Localisation of Cathepsins B, D, and G in Two Cancer Stem Cell Subpopulations in Moderately Differentiated Oral Tongue Squamous Cell Carcinoma

Authors: Therese Featherston, Reginald Marsh, Bede van Schaijik, Helen D. Brasch, Swee T. Tan and Tinte Itinteang

Frontiers in Medicine. July 2017. Volume 4, Article 100  doi: 10.3389/fmed.2017.00100

http://journal.frontiersin.org/article/10.3389/fmed.2017.00100/full

 

The GMRI has previously demonstrated the putative presence of two cancer stem cell (CSC) subpopulations within moderately differentiated oral tongue squamous cell carcinoma (MDOTSCC), which express components of the renin–angiotensin system (RAS).

In this study we investigated the expression and localisation of the proteases cathepsins B, D, and G in relation to these CSC subpopulations within MDOTSCC.

We identified the presence of cathepsins B and D in the CSCs and cathepsin G on what are phenotypically mast cells. The identification of these suggests the presence of bypass loops for the RAS. Consistent with our other findings with respect to the control of the RAS, this represents an additional area of regulation as part of a novel therapeutic target for MDOTSCC.