|
 Hypoxia
and Interstitial Fluid Pressure in
Tumour Progression and
Metastasis
Richard P. Hill and Mike
Milosevic
The
microenvironment in tumours is heterogeneous. There are regions
of hypoxia, acidic pH, and poor nutrient supply that relate to
the poorly organized vascular network that exists in many
tumours. Most
tumours also have increased interstitial fluid pressure (IFP) as
a result of the abnormal vasculature and the lack of functional
lymphatics. The
underlying hypotheses of our work are that tumour hypoxia plays
an important role in tumour progression and metastasis and that
more than one molecular mechanisms is likely to be involved. We
further hypothesise that different IFP levels in tumours may be
linked to different levels of acute hypoxia in tumours and that
these are important for the relationship between IFP levels and
treatment outcome and metastasis. Two objectives of our studies
are: 1) to investigate possible mechanisms for the effects of
hypoxia on tumour progression and metastasis formation
particularly in relation to acute hypoxia and oxidative stress
and 2) to examine whether elevated IFP predisposes to
fluctuating blood flow and acute hypoxia, and whether IFP
influences response to radiation and altered gene expression.
These
objectives are being addressed in three related groups of
studies using
cell and animal tumour models to facilitate the translation of
information from fundamental cellular and molecular studies to
clinical application and vice versa.
1)
We are examining possible molecular and cellular
mechanisms by which different levels of hypoxia may promote
invasion and metastasis in different tumour cell lines. This
includes studies of the effect of hypoxia on the expression of
specific genes both in cell lines and in vivo in an orthotopic
xenograft model of cervix Ca. We plan to extend these studies to
biopsy specimens taken directly from human tumours.
Further studies will also extend our findings of the
importance of hypoxia-induced resistance to apoptosis in
metastasis.
2)
We are also continuing our investigation of whether cyclic
hypoxia can influence tumour progression over the longer term
using transgenic models predisposed to cancer induction. These
studies focus on the role of oxidative stress and the effects of
interfering with the ability of cells to repair oxidative
damage.
3)
Finally we are investigating the potential relationship between
IFP and acute hypoxia and metastasis formation in rodent tumour
and xenograft models. These studies will also investigate the
effects of IFP on radiation sensitivity of tumours and examine
the effect, on IFP and microvascular parameters, of blocking
PDGF signaling .
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Hill Lab Annual Summer
Picnic - 2006 |
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