Functional Analysis of Chromosome 18 in Pancreatic Cancer: Strong Evidence for New Tumour Suppressor Genes

Abstract

In a previous work, we demonstrated that loss of heterozygosity of 18q is a frequent event significantly associated with poor prognosis in pancreatic cancer. We hypothesized that restoration of heterozygosity of chromosome 18 in pancreatic cancer cells would reduce their tumorigenicity. This study was intended to provide functional evidence for the existence of new tumour suppressor gene(s) located on chromosome 18. Restoration of heterozygosity was achieved by introducing a normal copy of chromosome 18 into pancreatic ductal carcinoma using a microcell-mediated chromosome transfer technique. The tumorigenicity and metastatic ability of both the parental cells and resulting hybrids were assessed in vitro and in vivo. In vitro growth of hybrid clones was significantly delayed compared to parental cells. This was paralleled by a significantly lower rate of promoting invasive carcinoma in nude mice and a longer latency with hybrid cells compared with parental tumour cells. Hybrid clones showed significant suppression in the number of surface lung metastases when compared with parental cells. These data represent strong functional evidence that chromosome 18q encodes strong tumour and metastasis suppressor activity that is able to switch human pancreatic cancer cells to a dormant phenotype.