HIF-1α overexpression is correlated with the progression of astrocytoma — an oxygen-dependent early-stage brain tumour — so the authors began by investigating whether HIF-1α controls astrocytoma formation. They generated the transformed astrocyte cell line HIFwt, deleted HIF-1α to produce the HIF-1α-null astrocytoma cell line HIFko, and then used both cell lines to compare tumour growth in poorly-vascularized subcutaneous tissue or the vessel-rich brain parenchyma. Subcutaneous (SC) injection of HIFko or HIFwt cells into nude mice produced encapsulated tumours with similar morphology and — as expected — SC-HIFko tumours were slow growing and contained extensive hypoxic and necrotic areas. Although intracranial (IC) injection of HIFko or HIFwt cells produced high-grade astrocytomas, IC-HIFko tumours, surprisingly, contained fewer hypoxic regions than IC-HIFwt tumours. In addition, HIFwt tumour cells were only detected close to astrocytomas, whereas HIFko cells were detected throughout the brain parenchyma, indicating that loss of HIF-1α in the IC region promotes tumour invasion. As SC and IC HIFko tumours have completely different phenotypes, could HIF-1α have a different effect on tumour vascularization at these two tissue sites?
The authors showed that SC-HIFko tumours were poorly vascularized compared with SC-HIFwt tumours, which contained 50% more blood vessels. Conversely, IC-HIFko tumours were highly vascularized, containing 50% more blood vessels than IC-HIFwt tumours. However, the most striking differences were seen between SC- and IC-HIFko tumours. SC tumours were 80% less vascularized then IC tumours and contained small, distorted blood vessels, but the vascular network of IC tumours resembled that of normal brain. So, it seems that both SC and IC tumours require HIF-1α for angiogenesis, but as IC tumours grow in a vascular-rich region, they are able to use the normal brain vasculature to grow. So, how could the tumours hijack these blood vessels?
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