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Role of Angiogenesis in Cancer and its
j Therapeutic Implications
Ming Kei Leo Li, Biomedical Sciences
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Tumour angiogenesis: the growth of new heterogeneous
blood vessels from existing blood vessels caused by
chemical signals released by tumours and the infected
host tissue
Required for continued tumour proliferation and
metastatic spread of cancer
Supplies adequate oxygen and nutrient supply and
removes waste products
Triggered by overexpressed angiogenic factors or
suppressed angiogenic inhibitors
Correlation between breast tumour angiogenesis
formation of leaky unorganized microvasculature and
metastasis prompts scientists to study potential
angiogenic treatments (illustrated in Figure 1)
Drug Implications Discussion
Results
Introduction
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Both microvessel count (p=0.003) and density grade (P≤0.001)
correlated with metastatic disease (see Table 1)
Invasive breast cancer patients mean count= 101±49.3 and
mean density=2.95±1.00
Non-invasive breast cancer patients mean count=45±21.1 and
mean density=1.38±0.82
Each increase in microvessel density grade is a 5.17 fold increase
in risk of metastasis
Each 10 microvessel count increase is a 1.59 fold increase risk of
metastasis & a 1.17 fold increase risk of distant metastasis
(p=0.029)
Thus, angiogenesis is a good predictor/indicator of invasive
breast carcinoma (see Figure 4)
Results attributed to progressively poorly organized and
permeable mass of microvessel development (see Figure 5&6)
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Goal: Angiogenesis inhibitor drugs inhibit further
proliferation of tumours by limiting resources
needed for growth (see Figure 7)
Most in phase I or phase II experimental stages
Side effects: prolonged coagulation time, artery
clots, hypertension and proteinuria
Angiogenic Factor Antagonist
• When inhibitors of
angiogenic factor VEGF
were injected into nude
mice, results indicated
decreased density of
vessels and size of the
tumours. (see Figure 8).
Figure 7: Angiogenic factor antagonist strategies include
(1) thinning of tumor blood vessel decreases vascular
permeability, (2) inhibit VEGF receptor 1 or 2 to inhibit
attachment of tumour cells to secondary sites and (3)
prevent avascular micrometastases becoming
macrometastases
Figure 1: Shows increased permeability in tumors seen in leakage of
injected red dextran dye from capillaries.
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Methods
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30 patients with invasive breast carcinoma and 19 without
metastasis investigated
Each tumour’s highest neovascularization area had its
microvessels counted and graded for density
-counting technique: 200x field (see Figure 2)
-density technique: criteria 1-4+ using
immunoperoxidase technique dyed factor VIII for
Scarff-Bloom-Richardson analysis
Probability of metastasis measured by a logistic regression
model (see Figure 3)
Problem: The tumour stage during administration of AntiVEGF drug is critical, as more mature tumours express >1
angiogenic factors, resulting in resistance selection for
colonies that produce non-targeted angiogenic factors. (see
Figure 9)
Figure 8: The impact of VEGF receptor
Table 1: Shows tumor grade, size, age
andmean microvessel count of cancer
with metastasis and without metastasis.
Figure 4: Shows correlation of
prevalence of metastatic disease and
microvessel count. Note there is 100%
chance of metastasis in counts of
more than 100 per 200x field.
Combinational Therapy- Antigionegenic drug with
inhibitors on the proliferation of tumour
Chemotherapy
in mice compared to control with only
• potential to increase tumour cell exposure and response to
VEGF.
chemotherapy
• normalization of vasculature allow better tumour blood
perfusion and increase drug efficacy
prolong usage leads to decrease blood flow and hypoxia,
decreasing drug uptake
Figure 9: Figure 8: Shows
increasing angiogenic factors as
breast cancer progresses.
Figure 5: Shows capillary bed of normal
Figure 3: Shows P=
and neoplastic tissue
probability of metastasis,
X=vessel count at 200x, and
A and B constant from the
experiment (-2.614 and
0.0464 respectively).
References
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Figure 2: Shows stain for factor VIII.
Arrows indicate a single distinct
microvessel (brown stain with clear space
from adjacent microvessels, tumour cells
and other connective tissue elements)
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Figure 6a: Shows correlation between
Figure 6b: Shows progressive
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intensity of angiogenesis and invasiveness.
recruitment of capillaries from
tumor.
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