Session 2:

HIF-dependent and -independent tumor suppressor functions of VHL

Agenda - Abstracts -Thursday - Friday - Saturday

Thursday detail part1 part2

Dr. Arnim Pause, Session Chair, opened the session and introduced Dr. Patrick H. Maxwell

Dr. Patrick H. Maxwell, Professor of Nephrology, Imperial College, London, England, delivered the plenary seminar on Activation of HIF in Humans with VHL Mutations. In his research he found that CAIX (pronounced CA-nine) is expressed in even the earliest RCC lesions. VHL status influences the "tight junctions" and communications between cells. Claudin influences permeability. As RCC tumors progress, he sees a switch from HIF-1 to HIF-2 production. The loss of HIF-1 production results in a three-fold increase in the risk of metastasis.

Spinal cord hemangioblastomas express HIF-2 only in precursor cells, and express both HIF-1 and HIF-2 in lesions. The "second hit" occurs before development is complete. The incidence of new tumors falls with age Hemangioblastomas are rare as a sporadic event.

By contrast, in renal cell carcinoma, the "second hit" can occur throughout life. The incidence of new tumors rises with age, and they are common as a sporadic event.

Dr. Stephen Lee, Professor of Molecular Medicine at the University of Ottawa, Canada, spoke about HIF-activated Oncogenic Pathways in VHL tumors. The silencing of HIF-2alpha prevents tumor formation in nude mice. HIF-1 is not sufficient to drive tumor growth, but HIF-2 is sufficient by itself. Renal cells enter quiescence in low serum. RCC cells lacking VHL go into "autonomous proliferation". This state of "autonomous proliferation" is the "hallmark of cancer" -- not spread, but autonomous proliferation.

Transforming Growth Factor (TGF-alpha) is expressed in the earliest lesions.

Once VHL is lost, any one of the following may occur:

VHL loss -> HIF-1 -> angiogenesis -> autonomous growth -> tumor

VHL loss -> HIF2 -> TGF-alpha -> EGFR - autonomous growth -> tumor

VHL loss -> other defects -> autonomous growth -> tumor

If you block EGFR, the tumor stops growing.

Dr. Lee hypothesizes that inhibition of EGFR can be blocked either through tyrosine kinase inhibitors or by neutralizing antibodies. But tyrosine kinase inhibitors are not working well in practice. Tumor necrosis-alpha converting enzyme (TACE or ADAM17) is a zinc-dependent protease. TACE mediates the ectodomain cleavage of EGFR ligands. Drugs targeting ADAM17 exist for inflammation. He suggests trying TACE inhibitors to see if they slow or stop the growth of kidney tumors. He has a published paper on this topic. See "Multiple Acquired Renal Carcinoma Tumor Capabilities Abolished upon Silencing of ADAM17". (Cancer Res. 2006 Aug 15;66(16):8083-90.)

Dr. Eijiro Nakamura, Department of Urology, Kyoto University, Graduate School of Medicine, Kyoto, Japan, reported on the work he has been doing in collaboration with the Laboratory of Dr. William Kaelin, HIF-independent function of pVHL and its role in the Development of familial pheochromocytoma. They have found Clusterin to be a marker for a HIF-independent function of the VHL protein that might be linked to the development of pheochromocytoma. The regulation of JunB appeared to be due to the ability of pVHL to inhibit atypical PKC, which acts upstream of JunB. They propose that the deregulation of NGF signaling s the relevant unifying feature of the mutations linked to hereditary pheochromocytoma. Mutations in these genes might cause pheochromocytoma and paragaglioma because certain neuronal precursor cells from which these tumors are derived are not properly culled during embryonic development. See Clusterin is a secreted marker for a hypoxia-inducible factor-independent function of the von Hippel-Lindau tumor suppressor protein. Am J Pathol. 2006 Feb;168(2):574-84.

Dr. Jodi Maranchie of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, shared her research on NOX4. She has found NOX4 to be critical for expression and activation of HIF2-alpha, even in the absence of VHL. She has found NOX4 to be necessary for the development of renal cancer tumors, and proposes NOX4 as a candidate for targeted RCC therapy.

Dr. Dorus A. Mans, Medical Oncology, University Medical Center, Utrecht, the Netherlands,