Hypoxic patterning is a hallmark of solid tumors

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Hypoxic patterning is a hallmark of solid tumors
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(No Transcript)
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Loss of HIF-1a results in decreased fibrosarcoma
mass in subcutaneous tumors, regardless of the
immortalizing oncogene
Tumor mass in grams 21 days post-injection of 106
cells n40 or greater, p0.01 in each pair
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Loss of HIF-1a decreases VEGF expression in
a graded manner in tumors
HIF-1a f / f
HIF-1a - f /- f
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Loss of HIF-1a does not decrease vascular
density in SV40 largeT/H-ras transformed
fibrosarcomas
/
-/-
-f/-f
f/f
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Conclusions regarding fibroblast tumorigenesis
and HIF-1a

• Loss of HIF-1a in transformed fibroblasts reduces
  tumor growth in nude mice
• HIF-1a loss causes a reduced rate of tumor
  growth, but not an overall reduced rate of
  vascularization
• Loss of HIF-1a inhibits metabolic adaptation to
  hypoxia in fibroblasts

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Subcutaneous tumor growth parameters
proliferation
none
co-option of existing vessels
high
neo-vascularization
Angiogenic factor requirement
high
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A system for introducing cell-type specific null
mutant tumors into mice
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Cell growth of transformed astrocytes is
relatively similar in HIF-1a wild type and null
cells
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Deletion of HIF-1a in transformed astrocytes
results in loss of hypoxia-induced gene expression
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Subcutaneous astrocytoma formation
indicates HIF-1a is a negative factor in tumor
growth
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Subcutaneous wild type and HIF-1a null
astrocytomas have similar histological appearances
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Subcutaneous tumors are encapsulated
Loss of HIF-1a causes increased necrosis in
subcutaneous null tumors
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Vascular density in subcutaneous tumors is
reduced when HIF-1a is absent
Wild type vessels HIF-1a null vessels
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Loss of HIF-1a intra-cranially causes increased
mortality
wt
HIF null
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Proliferation and apoptotic rates reverse
relative in intracranial sites when HIF-1a is
mutated
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Wild type astrocytomas grow centrally in murine
brain as highly necrotic foci within the
injection site
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HIF-1a null mutants grow in a highly disseminated
fashion