Abstract:
Infantile haemangioma (IH), considered a primary tumour of the
microvasculature, is the most common tumour of infancy affecting about 10% of
Caucasian infants. IH predominantly affects white, female and premature infants. IH
typically undergoes an initial rapid proliferation during infancy (proliferative phase)
characterised by aggressive angiogenesis, followed by spontaneous involution over
the next 1-5 years (involuting phase) and continued improvement up to 10 years
(involuted phase), often with a fibro-fatty residuum. IH consists of cells of various
lineages, with the presence of mesenchymal stem cells, endothelial progenitor cells,
endothelial cells, myeloid haematopoietic cells, and pericytes. This thesis
demonstrates the expression of primitive (stem/progenitor cell) markers on the
endothelium of IH. The expression of the transcription factors brachyury, Tal-1 and
GATA-2, along with the demonstration of erythropoiesis in IH explants in vitro
supports the hypothesis that IH consists of a primitive endothelium similar to an
embryonic haemogenic endothelium. The expression of the erythropoietin receptor
and haemoglobin zeta chain by the endothelium of IH further strengthens the notion
that IH is a haemogenic endothelium. Consistent with the primitive embryonic origin,
the expression of the placental markers human chorionic gonadotrophin (hCG) and
human placenta lactogen (hPL), but not cytokeratin 7 (CK7) or human leucocyte
antigen- G (HLA-G) by the endothelium in IH, supports a placental chorionic villous
mesenchymal core cell, and not a trophoblast, origin for IH. IH thus has an extraembryonically
derived primitive mesodermal origin. This primitive mesoderm is able
to account for the haemogenic endothelium phenotype of the endothelium of
proliferating IH microvessels with its capacity for both erythropoietic and
mesenchymal differentiation.
Additionally, data are presented to show that IH expresses key components
of the renin-angiotensin system (RAS), angiotensin converting enzyme (ACE),
angiotensin II (ATII), angiotensin receptor 2 (ATR2). Cultured IH-derived stem cells
can be induced to proliferate and form blast colonies in response to ATII treatment.
The crucial regulatory role of RAS in the proliferation and differentiation of the
stem/progenitor cell population within IH accounts for the natural progression of IH. A
model is proposed to provide a rational explanation for the serendipiditous discovery
of the dramatic effect that the β-blocker, Propranolol has in accelerating involution of
IH. The hypothesis that Propranolol exerts its action on IH through modulation of the
RAS by blocking renin activity and preventing the conversion of angiotensinogen to
angiotensin I, thereby reducing ATII levels, has led to a clinical trial using Captopril,
an ACE inhibitor in the treatment of problematic proliferating IH. The observed
accelerated involution of IH by Captopril which blocks the conversion of angiotensin I
to ATII confirms a key regulatory role for RAS in the biology of IH This discovery
underpins the development of potentially safer and novel treatment modalities for this
enigmatic condition.
