A receptor protein involved in embryonic development and wound repair appears to encourage the progression of colorectal cancer, and may prove useful as a prognostic marker and as a drug target, according Richard Bates of the department of Pathology at the Beth Israel Deaconess Medical Center in Boston, who led a Harvard team’s investigation of the protein.
The team’s study of the protein — called ß6 — appeared in the Jan. 20 online version of The Journal of Clinical Investigation, and will be published in the Feb. 1 issue of the journal.
Several companies have been working on antibody drugs directed against ß6 due to its function in the TGF-ß activation loop, “to try to stop fibrosis,” said Bates. But he said he didn’t know how far any company had progressed in developing a drug.
“The beauty is that these drugs may have now some applicability to colon cancer, we would hope,” Bates said. Because ß6 is not normally expressed in the adult body, “potentially the side effects would be less if you can develop drugs against this,” he said.
But for now, ß6 seems to be an interesting candidate for use as a prognostic indicator. “What was really interesting was when we started screening — we screened 488 aggressive colon carcinoma samples, and we found it was expressed in about 40 percent of these cases,” said Bates. The survival curves of patients whose tissue samples showed low levels of ß6 or none at all were “essentially identical,” said Bates. “But those patients who had high levels of ß6 did significantly worse. By any statistical measure, this was a marker for aggressive disease,” he said.
Tissue samples having low levels or no ß6 had a median patient survival of 16.5 years, while those with high levels of ß6 averaged 4.8 years of survival. The five-year survival rate for those with low or no ß6 was 62 percent, while about 46 percent of patients with high ß6 levels survived five years.
In early-stage cancer patients, the difference was more striking, said Bates. Stage 1 and stage 2 patients with no ß6 had a five-year survival rate of 78 percent, he said. “Yet if they had low-stage — but they did have a lot of ß6 — that dropped from 78 to under 50 percent,” he said. No effect was observed in late-stage patients, he said.
The ß6 receptor is active in the epithelial-mesenchymal transition process, in which epithelial cells change shape and function to effect wound repair or as part of human development. The EMT process is driven by cytokines and hormones, particularly TGF-ß, to which ß6 binds and activates, said Bates. Tumor cells undergoing EMT become more invasive, he said.
The researchers have in vitro evidence — not all of it published — of a self-perpetuating process in which cells undergoing EMT produce TGF-ß of their own, along with the ß6 receptor, he said. “We still have to nail down the exact biology, but that potential is there, that it actually helps promote the process itself,” he added.
The ß6 receptor is a promising molecule for several reasons, said Bates. “One of the reasons it’s important is because 80 percent of human cancers are carcinomas — they arise from epithelial tissue. So potentially, it impacts 80 percent of human cancer,” he said. “From a cancer perspective, it’s nice to be able to target invading and metastasizing cells, and it also — as a prognostic marker — indicates those patients” who might need more aggressive treatment, he added.
In upcoming studies, the researchers plan to test the ability of ß6 antibodies or ß6-targeted drugs to block tumor-cell invasion in animals, Bates said.