Oesophageal Cancer Research Unit

Research highlights

The two major lifestyle risk factors for the development of oesophageal squamous cell carcinoma are tobacco smoking and alcohol consumption. This project showed a clear association between genetic polymorphisms in several detoxification genes and exposure toe tobacco smoke and smoke from burning wood and charcoal. Such studies on gene-environment interaction are becoming more important.

The effect of the tobacco smoke procarcinogen, benzo[a]pyrene, on gene expression profiles was also investigated in oesophageal cancer cells in culture. Treatment with benzo[a]pyrene resulted in increased expression of the cytochrome P450 1 family of Phase I xenobiotic metabolizing enzymes. DNA microarray analysis for differential expression of about 48000 transcripts was performed to investigate what other affected in response to benzo[a]pyrene treatment.

Studies on the matrix-mediated regulation of type I collagen gene expression  showed that growth of cells grown on a fibroblast-derived matrix results in the down-regulation of collagen promoter activity through activation of the MEK-ERK signaling cascade via a matrix regulatory element located in one of the collagen genes. The study strongly supported the critical role of transcription factors such as Sp1 and Fli1in the regulation of type I collagen synthesis.

The project on the development of novel ajoene-based anti-cancer agents are pursued in collaboration with Prof Hunter in the Department of Chemistry at UCT. We have developed a novel four-step synthetic route to synthesize ajoene analogues that retain the central vinyl disulfide / sulfoxide core but with varying functionality at the two terminal ends.

These analogues have been tested for their ability to inhibit tumour cell growth of cultured cancer cells and have been found to have improved anti-cancer activity compared to the parent natural product ajoene.  Our most active analogue synthesized to date is 15 fold more active at inhibiting cell growth of  DA-MB-231 breast cancer cells with an IC50 in the nano-molar range.  We plan to test these analogues for activity in a mouse model next year.

This study looks to determine what the role of the E6 proteins from a high-risk type HPV (HPV-18) and a low-risk type (HPV-11) is during cellular expression, as well as to compare the effects of the two types of HPV E6 proteins on cellular gene expression.