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Angiogenesis - Research
Tumour Angiogenesis
Tumour growth and metastasis is dependent on formation of new tumour
vasculature, a process known as tumour angiogenesis (Folkman, 1971; Folkman,
1990). The initiation of the ‘angiogenic switch’ may occur
at different stages of tumour progression depending on tumour type and
environment, and is regulated by the balance of pro- and anti-angiogenic
factors in the tumour microenvironment (Bergers & Benjamin, 2003).
Our research interests include:
- Expression and regulation of angiogenic factors in human cancers
- Vascular Endothelial Growth Factor (VEGF) family
- Angiopoietin/Tie2 pathway
- Effects of the tumour microenvironment on tumour angiogenesis
- Hypoxia, HIF regulation and control of hypoxic response
- Other cellular components of the tumour
- Targeting tumour endothelium
- Early molecular mechanisms of vascular targeting agents (CA-4-P,
DMXAA)
- Gene Directed Enzyme Prodrug Therapy (GDEPT)
- Links between cancer, inflammation, and thrombosis
- Ethnicity and cancer biology
- Metabolism, insulin resistance and chronic low-grade inflammation
in cancer biology.
- Skin cancers in immune-suppressed renal transplant recipients.
Funded research projects 2007/2008
- Does insulin resistance fuel tumour angiogenesis and colon cancer
progression?
Research Staff: Dr Margaret Currie, Dr Gabi Dachs, Dr Jinny Willis, Assoc
Prof Bridget Robinson.
Obesity and diabetes increase the risk of developing and dying from colon
cancer. Prevalence of all three diseases is high in New Zealand, and
increases with age. Based on related studies and early data, we propose
that factors in blood from obese diabetic patients stimulate formation
of new blood vessels that support aggressive tumour growth and spread,
and promote resistance to therapy.
Stored blood and tumour samples from 400 colon cancer patients will be
used to investigate links between metabolic factors in blood, tumour
blood vessel growth, and patient survival. Cell culture models will be
used to study biological pathways, and test the ability of anti-diabetes
drugs to prevent tumour blood vessel growth.
Findings from this study will inform clinical decisions and may improve
survival of colon cancer patients with obesity-related diabetes.
Funding Bodies: NZ Cancer Society, Lottery Health, University of
Otago.
- Markers of thromboembolism in patients with cancer.
Research Staff: Dr Sarah Gunningham, Dr Lutz Beckert, Assoc Prof
Bridget Robinson
People with cancer have a significantly increased risk of developing
clotting problems above those of the general population. These clots
can lodge in major organs and blood vessels posing significant risk
to their health, and increasing the risk of death. In a recent
report from
the European Union, deaths from disordered clotting problems in cancer
patients (163,036), exceeded those directly caused by breast cancer
(86,831) and prostate cancer (63,636) combined.
Because of the importance of coagulation, platelet adhesion and angiogenesis
in both blood clotting and cancer, we will examine the levels of
proteins involved in these processes to find a marker or combination
of markers
predictive of DVT/PE in patients with or without cancer. A simple
blood test could determine whether cancer patients have a predisposition
to
blood clots, would enhance the speed, accuracy of diagnosis of DVT/PE
enable more rapid treatment and increase the possibility of prophylactic
treatment. Conversely the same markers might also show a pattern
predictive of occult cancer.
Funding Bodies: Division of Health Sciences Post Doctoral Fellowship,
University of Otago; University of Otago; CDHB; Lottery Health.
- The Role of Neuropilin-1, a Novel Vascular Endothelial Growth
Factor Receptor, in Cancer.
Research Staff: Dr Sarah Gunningham, Dr Margaret Currie, Assoc Prof
Vicky Cameron, Assoc Prof Bridget Robinson
The development of new blood vessels is essential to support the
growth and spread of tumour cells. We have data suggesting that a
novel receptor
involved in the growth of blood vessels, neuropilin-1, is particularly
associated with the spread of tumour cells to other sites. Our data
also suggests that a soluble form of neuropilin-1, that is antagonistic
to
this process, is significantly reduced in precancerous colorectal
disease. Understanding the functional mechanisms by which this occurs
is a necessary
first step to being able to target this process and design predictive
tests for cancer.
Funding Bodies: Genesis Oncology Trust; Canterbury Medical Research
Foundation
- HRP activated paracetamol as anti-vascular gene
therapy of cancer.
Research Staff: Dr Gabi Dachs, Dr Adam Patterson, Assoc Prof Bridget
Robinson.
Gene therapy as cancer treatment is being tested in hundreds of clinical
trials worldwide. ‘Suicide’ gene therapy is a system that
consists of two components, namely delivery of an enzyme-encoding gene
followed by administration of an inactive prodrug which is activated
to a toxin by the enzyme. The peroxidase from horseradish (HRP) is
an enzyme able to turn harmless agents into toxic chemicals. HRP can
turn
paracetamol into a toxic product and kill HRP-modified cancer cells.
Our study aims to use HRP/paracetamol to destroy the tumour vasculature.
The tumour vasculature is a good target for the following reasons:
the microvasculature is a known primary target of paracetamol, the
vasculature
is accessible for delivering genes and prodrugs, all tumours rely on
blood supply for oxygen and nutrients, and minor vascular damage can
amplify into tumour infarction.
Funding Body: Cancer Society NZ, Robert McClelland Trust, University
of Otago.
- Breast cancer stem cells: hypoxia and angiogenesis.
Research Staff: BA Robinson, G Harris, M Currie, S Gunningham, G
Dachs, B Dijkstra.
Breast cancer is the commonest cancer affecting New Zealand women.
Recent evidence suggests that breast cancer stem cells in the tumour,
identified
by immunohistochemistry (IHC) as CD44+/CD24-/low, are associated
with invasiveness and metastasis, and in in vitro models, with
angiogenesis.
These aggressive characteristics are also associated with tumour
hypoxia (low oxygenation). However, a gene array study of breast
cancer stem
cells has not shown the expected over-expression of hypoxia and angiogenesis
genes. To determine the reason for this apparent discrepancy, a total
of 300 human breast samples from the Cancer Society Tissue Bank will
be prepared as tissue micro-arrays, and studied by IHC for expression
of proteins, including the vascular endothelial growth factors and
their receptors, hypoxia inducible factor-1 (HIF-1a), other hypoxia–related
proteins and hormone receptors. The IHC staining pattern of the CD44+/CD24-/low
cells will be compared with that of other cells, tumour and stromal.
The data will be matched to clinicopathological details of each tumour
and with clinical outcome of the women. These results will add to
understanding of cancer stem cell biology, may provide new prognostic
markers, and
will help direct therapy targeted at tumour angiogenesis and hypoxia.
Funding Bodies: Genesis Oncology Trust
- Tie2 RTK; a potential target for DMXAA.
Research Staff: Dr Margaret Currie, Dr Bronwyn Siim/Prof Bruce Baguley
5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a synthetic flavonoid
that has shown excellent experimental anti-tumour activity as well
as promising anti-vascular effects in Phase I clinical trials. Although
many of the biochemical pathways underlying the activity of DMXAA
have
been elucidated, the molecules targeted by DMXAA within the first
few hours after administration remain unclear.
Flavonoids are known to inactivate kinases by binding to their ATP
binding sites. Tie2 is a receptor tyrosine kinase that is found on
endothelial
cells, and is an important regulator of tumour blood vessel formation.
We hypothesise that Tie2 is an early target of DMXAA, and that DMXAA
inhibits Tie2 phosphorylation by binding to its ATP binding site.
We aim to investigate these hypotheses using endothelial cell culture
experiments
and human tumour xenografts grown in mice. These studies will help
clarify the early molecular action of DMXAA, and inform future rational
design
of more potent anti-vascular agents.
Funding Body: Cancer Society NZ
- Ethnicity and cancer biology.
Research Staff: Maiko Kano, Ekaterina Volkova, Dr Gabi Dachs, Dr
Margaret Currie, Associate Professor Bridget Robinson
Maori have disparately poorer outcome following cancer diagnosis,
which has been attributed to social factors, but these do not explain
all the
difference. We hypothesise that there are differences in tumour biology,
and our pilot studies have supported this.
Funding Bodies: University of Otago, Cancer Society of New Zealand,
Canterbury/West Coast Division
- Vascular targeting of solid tumours using gene therapy - PhD project.
Research Staff: Michelle Hunt, Dr Gabi Dachs, Dr Margaret Currie,
Dr Adam Patterson, Assoc Prof Bridget Robinson.
Because a functional vascular network is essential for the survival,
growth and spread of solid tumours, the concept of targeting the
tumour vasculature may present a selective, yet universal therapy
against solid
tumours. An attractive alternative to current small molecule anti-vascular
approaches is gene therapy. Although anti-vascular gene therapy is
still at the early pre-clinical stage, it has several advantages
over current
gene therapy approaches: the vasculature is accessible for delivery
of therapeutic agents, all solid tumours rely on blood supply for
oxygen
and nutrients, and minor vascular damage can amplify into massive
tumour infarction.
Suicide gene therapy, which has reached Phase III clinical testing,
consists of two components: 1) delivery of an enzyme-encoding gene
to target cells,
followed by 2) administration of an inactive prodrug which is converted
to a toxin by the enzyme, causing cell death. This system allows
careful targeting and non-invasive monitoring of gene delivery and
expression
prior to drug administration and activation. The aim of this project
is to compare the effectiveness of four enzyme-encoding genes in
combination with both clinically established and novel prodrugs (provided
by our
collaborators at the Auckland Cancer Society Research Centre) in
targeting tumour vessels, using endothelial cell culture. Restricting
enzyme production
to tumour vasculature and targeting viral delivery specifically to
tumour endothelial cells will also be explored.
Funding Bodies: University of Otago Postgraduate Scholarship, South
Canterbury Finance Research Scholarship, Postgraduate Tassell Scholarship
in Cancer
Research.
- Tumour angiogenesis: the role of metabolic syndrome
and insulin resistance – PhD
project.
Research Staff: Ekaterina Volkova, Dr Margaret Currie, Dr Gabi Dachs,
Dr Jinny Willis, Assoc Prof Bridget Robinson.
This project aims to investigate the effects of metabolically regulated
Hypoxia Inducible Factor-1 (HIF-1) on tumour endothelium. We hypothesize
that obesity-related metabolic dysregulation leads to HIF-1 protein
accumulation, and that the consequent increase in tumour angiogenesis
contributes to
a more aggressive tumour phenotype, greater metastatic potential,
and increased tumour resistance to therapy. The reslts generated
from this
current proposal will shed new light on the mechanisms underlying
regulation of tumour angiogenesis and cancer progression.
Funding Body: Tertiary Education Commission Top Achiever Doctoral
Scholarship
- Why are skin cancers more aggressive in renal
transplant patients? –MMedSci/PhD
project.
Research Staff: Dr Katarzyna Mackenzie, Dr Margaret Currie, Dr Gabi
Dachs, Assoc Prof Bridget Robinson, Prof Justin Roake
Advances in the field of renal transplantation have added years to
many patients’ lives. The reduced graft rejection, and increased
survival of these patients, is largely due to the introduction of
more powerful
immunosuppressive drugs. However, this lifelong immunosuppressive
therapy is associated with an increased risk of nonmelanoma skin
cancers (NMSCs).
The most common of these are squamous cell carcinoma (SCC) and basal
cell carcinoma (BCC), which together account for more than 90% of
all skin cancers in transplant recipients. The incidence of SCC and
BCC in
immunocompromised renal transplant recipients (RTRs) is higher (up
to 250-fold) than in immunocompetent individuals (ICIs), and NMSCs
metastasize
in 5-8% of RTRs, a rate that is approximately 10-fold higher than
that seen in the immunocompetent population.
The most metastatic SCCs are those that develop in highly vascular
tissues, such as the lips, suggesting that development of a rich
vascular network
is a determining risk factor in malignant progression of SCC in RTRs.
We hypothesize that the aggressive phenotype and increased metastatic
potential of NMSCs in RTRs is due to increased tumour blood vessel
formation (tumour angiogenesis), and that this increased tumour angiogenesis
is
driven by molecular pathways that lead to increased levels of HIF-1?
and VEGF-A protein.
Funding Body: Robert McClelland Trust
- A new role for Vitamin C: control of the hypoxic
response in cancer cells – PhD project.
Research Staff: Caroline Kuiper, Dr Margreet Vissers, Dr Margaret
Currie, Dr Gabi Dachs
Many cancer cells survive because they can adapt to a low oxygen
environment through the action of a transcription factor known as
hypoxia-inducible
factor (HIF)-1am which is normally not present, but which appears
when the oxygen supply is limited. HIF-1a regulates the production
of new
blood vessels and influences tumour growth and survival, making cancer
cells resistant to chemotherapy. We have previously found that intracellular
Vitamin C (ascorbic acid, ascorbate) can influence HIF-1a, and its
availability may prove to be important for cancer treatment. In this
project we intend
to investigate the effects of Vitamin C on the regulation of HIF-1a
in cultured tumour cells.
Funding Body: Canterbury Medical Research Foundation, University
of Otago Scholarship.
- Cancer Society Tissue Bank.
Research Staff: Helen Morrin, Amanda Fahy, Associate Professor Bridget
Robinson
The Cancer Society Tissue Bank underpins all research using human
samples, and provides tissue for researchers both in Christchurch
and also other
NZ centres. This bank started in 1996, leads NZ in its development
and provides a wide range of tissue and blood preparations as well
as clinicopathological
data. More than 35 studies have now used samples from the bank, and
there are 10 currently active projects drawing tissues. Studies
can be completed
more expeditiously due to prospective banking of tissues, leading
to more competitive research. New interests can also be met by
the bank
with specialised banking to suit the need.
Funding Bodies: Cancer Society of New Zealand, Canterbury/West Coast
Division
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