History of Research
DCC's biological role in cancer has had a long, controversial history. Although DCC has been studied for many years, a significant amount of the data collected is contradictory and much of the focus has been on getting clear picture of the basics.
When the genetic abnormalities that occur in advanced colorectal cancer were first identified, one of the most frequent events was found to be loss of heterozygosity (LOH) of region 18q21. One of the first genes sequenced in this region was DCC, and it was subsequently analyzed for tumour suppressor activity. However, the lack of somatic DCC mutations made it seem likely that the nearby SMAD2 and SMAD4 genes were the reason for 18q21 LOH. The fact that DCC heterozygotes had no increased rates of cancer, even when crossed with mice carrying Apc mutations, solidified this viewpoint. The finding that DCC was a receptor for netrin-1 involved in axon guidance initially moved research away from DCC in cancer. It was later realized that DCC may be involved in directing cell motility, which has direct implications for metastatic cancer.
The first direct evidence for DCC as a tumour suppressor gene was published in 1995. Researchers found that addition of DCC to an immortalized cell line suppressed tumorigenicity rather definitively. However no mechanism for this suppression was obvious, and it took several years to propose one.
Nearly ten years after DCC was discovered, studies were published that showed that DCC was involved in apoptosis. Instead of studying loss of DCC as was commonly done, the authors looked at human embryonic kidney cells transfected with DCC. They found an increase in apoptosis that corresponded to DCC expression, which was completely eliminated when netrin-1 was co-transfected or simply added to the media.
When it was understood that DCC apoptosis may also be overcome by netrin-1 overexpression, colorectal cancers were assessed for netrin-1 overexpression, and a small but significant percent of these cancers were found to vastly overexpress the molecule.
Read more about this topic: Deleted In Colorectal Cancer
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