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. (in press 2018). /j.jocn.2018.10.068

Up to 30% of melanoma tumours metastasise to the brain and between 5%-8% of all brain tumours have originated from melanomas. For many years the median survival period of patients with metastatic melanoma to the brain has remained at 6-9 months following conventional treatments. The short period of remission has been attributed to the initiation, propagation and differentiation of cancer stem cells that possess the ability to undergo uncontrolled growth and propagation.

The cancer stem cell concept proposes that a small population of cancer stem cells are the driving force of cancer growth. The presence of cancer stem cells has been demonstrated in a number of cancers, including melanomas. In collaboration with the Department of Neurosurgery at the Wellington Regional Hospital, the GMRI team has discovered three cancer stem cell subpopulations in metastatic melanoma to the brain, suggesting the presence of a hierarchy amongst the cancer stem cells, similar to what we have found in glioblastoma. The characterisation of these cells raises the possibility of providing a therapeutic target for these metastatic tumours.

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,

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,

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,



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

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

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

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

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

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


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.