Scientific progress in biology typically relies on incremental advances that explain
a small piece of an impossibly complex puzzle. But sometimes, understanding that one
piece is enough. Scientists have long known that a rare cancer syndrome, called von
Hippel–Lindau (VHL), had a hereditary component. First seen clustering in families
over a century ago, the disease is characterized by vascular tumors, including retinal
and central nervous system “hemangioblastomas” and clear-cell carcinomas of the kidney
and adrenal glands. Just ten years ago, scientists identified the tumor suppressor
gene, called VHL, that causes the disease and later discovered how loss of VHL leads
to cancer.
It had appeared this pathway was uncommonly simple. VHL regulates HIF (hypoxia-inducible
factor), a transcription factor that controls cellular responses to below-normal oxygen
levels in the blood or tissue, a condition known as hypoxia. In the presence of oxygen,
the VHL gene product pVHL forms a complex with other proteins and targets HIF for
degradation. In response to hypoxia, HIF activity increases and induces the expression
of a number of proteins that help cells adapt to low levels of oxygen. If VHL function
is lost, it cannot target HIF, leading to a stable accumulation of HIF and a corresponding
overproduction of the hypoxia-induced proteins. When aberrantly produced, these proteins
contribute to tumor formation and growth through angiogenesis (the mass of blood vessels
characteristic of hemangioblastomas) and unregulated cell growth. But subsequent studies
suggested that VHL might have other targets, raising the possibility that HIF might
not be the sole, or even primary, mediator of tumor formation in cells lacking pVHL.
Now William Kaelin and colleagues report that inhibiting HIF is not only necessary
to support pVHL's function as a tumor suppressor, but that it is also enough.
The researchers set out to determine whether the inhibition of HIF was specifically
responsible for pVHL's reported tumor suppressive effects. When pVHL is reintroduced
into human renal carcinoma cells lacking pVHL and overexpressing HIF2α, HIF2α levels
go down, hypoxia-inducible gene expression goes down, and tumorigenesis is suppressed.
Kaelin et al. found that introducing HIF2α variants lacking specific pVHL-binding
sites into such cells was sufficient to negate pVHL's tumor suppressor activity, implying
that inhibition of HIF is necessary for pVHL to suppress tumor growth. To see whether
simply removing HIF2〈 would mimic the tumor suppressor activity of pVHL, the researchers
introduced “short hairpin” RNAs (shRNAs) to “silence” HIF2α protein production. The
shRNA-treated cells (which lacked functional VHL genes) showed decreased levels of
HIF2α activity and were grossly impaired with respect to facilitating tumor formation
in mice. These results suggest that, while pVHL may have multiple functions, inhibition
of HIF can account for its ability to suppress tumor growth, at least in the context
of renal carcinoma.
Tumor suppressor genes are defined by what happens in their absence—while their normal
function is not always apparent, it is clear that their loss of function results in
cancer susceptibility—and by the fact that they usually require loss of both versions,
or alleles, for damage to occur. While patients with VHL inherit one mutated copy
and later acquire a mutation in the second copy, patients with similar but nonhereditary
vascular cancers have also lost both VHL alleles. Knowing HIF's role as the fulcrum
between health and disease, scientists can now concentrate on just that one piece
of the puzzle—HIF and its target genes—to develop customized preventive and therapeutic
treatments not only for VHL patients but for those living with nonhereditary tumors,
such as kidney cancers, that frequently result from pVHL inactivation.