O104 (RA6190)
Over-expression of the Podocyte Derived VEGF Isoform -VEGF165b - Slows
Renal Cell Tumour Growth in Vivo
ES Rennel, J Woolard, DO Bates and SJ Harper
Microvascular Research Laboratories, Department of Physiology, University of
Bristol Southwell Street, Bristol, BS2 8EJ, United Kingdom
The growth of new vessels from pre-existing vasculature is an absolute requirement
for tumour survival and expansion beyond a few hundred microns in diameter.
Vascular Endothelial Growth Factor (VEGF) is the dominant growth factor by which
cancers promote angiogenesis. VEGF is over-expressed by all known solid tumours
and is correlated with vascularity, pathological grade and prognosis. There has been
much interest in the oncology community in a monoclonal antibody chemotherapy
(Bevacizumab) to target VEGF. Phase III clinical trials of Bevacizumab have shown
significant benefit in addition to conventional chemotherapy for metastatic colorectal
carcinoma (1). Phase III trials with VEGF inhibitors are underway in renal cancer.
Recently, we have identified, in human podocytes and human kidney, a splice variant
isoform of VEGF called VEGF165b which can act as a dominant negative isoform,
inhibiting VEGF-mediated angiogenesis in vivo and reducing tumour growth in
malignant melanoma (2). Although VEGF expression is increased in all tumours,
VEGF165b in contrast, is downregulated in renal and prostate cancer (2).
To investigate whether renal cell tumour growth could be inhibited by over-expression
of anti-angiogenic VEGF165b, human renal carcinoma cells (CaKi) were transfected
with 1mg pcDNA3 (control) vector or pcDNA3-VEGF165b cDNA. The mock and
VEGF165b variants became stably transfected each producing approximately
4fg/cell/day of total VEGF (angiogenic and anti-angiogenic).
106 cells of each line were injected subcutaneously into nude mice and tumour volume
growth curves created.
Mock transfected tumours grew at the predicted rate for this tumour line. In contrast
the VEGF165b transfected tumours grew very slowly. There was a significant
difference by day 9 (p<0.01). In parallel experiments, we have confirmed this
response with prostate and colonic cancer cell lines.
These findings suggest that a change in VEGF splicing may influence the rate of
growth of tumours and that further work on the control of splicing, or targeting antiVEGF therapy specifically towards the pro-angiogenic VEGF isoforms, may provide
novel therapies for renal and other cancers.
1. N Engl J Med. 2004 Jun 3;350(23):2335-42
2. Cancer Research 2004; 64(21):7822-35.).