BHD and VHL disease – Part II: HIF Independence

My previous post concerning VHL disease centered on HIF dependent mechanisms of tumourigenesis and how this could provide insights into how this phenotype arises in BHD. It’s always best to keep your eye the bigger picture  and an alternative HIF independent role for VHL has been implicated in renal tumourigenesis.  This is mediated through VHLs interaction with the extracellular cell matrix (ECM) and primary cilium maintenance.

VHL has been shown to interact with COL4A2, a component of extracellular matrix (ECM). Significantly, all VHL based disease exhibit impaired ECM assembly capabilities and sporadic renal carcinomas show reduced fibronectin staining (fibronectin is also a component of the ECM). It would be really interesting to examine the histological expression of fibronectin or COL4A2 in BHD tumours.

Regulation of the primary cilium has been linked to VHLs effect on the stabilisation of microtubules at the cell periphery. Loss of cilia function in the kidney leads to excessive proliferation of tubular epithelial cells, formation of fluid filled sacs and kidney failure. Bonnet et al (2009) have recently shown that this is linked to renal cyst development in a Tuberous Sclerosis animal model. This is really interesting since tuberous sclerosis is one of the syndromes that has partial phenotypic overlap with BHD and is intrinsically involved with mTOR signalling too.

So essentially what conclusion can we come to? For me, it’s really about being aware of the research that’s being carried out in the periphery of your field and this is a perfect example: we know the VHL disease and BHD share a kidney carcinoma phenotype and that ‘classically’, this is tied into HIF dependent mechanism. However, by investigating the other facets of VHL function I’m now aware of the role of planar cell polarity defects in kidney tumourigenesis in VHL and Tuberous sclerosis, another rare genetic syndrome that has phenotypic overlap with BHD syndrome!

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