A newly discovered protein variant known as carboxypeptidase E-delta N, or CPE-delta N, appears to be a powerful biomarker for predicting metastasis in patients with hepatocellular carcinoma, pheochromocytoma, paraganglioma, and possibly other types of cancer, a new study shows.
High levels of messenger RNA encoding CPE-Delta N in cancer cells predicted tumor metastasis and recurrence with high sensitivity and specificity in those three specific types of tumors, an international team of investigators reported online in the Feb. 1 issue of the Journal of Clinical Investigation.
High levels also were found in cell lines derived from highly metastatic colon, breast, and head and neck tumors, when compared with matched tumor cell lines with low metastatic potential, said Dr. Terence K. Lee, Dr. Saravana R. K. Murthy, and their colleagues. Dr. Lee is with the University of Hong Kong, Pokfulam, and Dr. Murthy of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, Md.
The findings could lead to improvements in cancer treatment via development of new tests for predicting the likelihood of metastasis, as well as new treatments for directly preventing metastasis, the investigators said (J. Clin. Invest. 2011 Feb. 1 [doi:10.1172/JCI40433]).
CPE-delta N is an N-terminal truncated splice isoform of the prohormone processing enzyme carboxypeptidase E. It was found in this study to drive tumor metastasis, invasion, and recurrence.
The investigators measured levels of CPE-delta N RNA in samples from tumors and surrounding tissue from a retrospective cohort of 99 patients with hepatocellular carcinoma (HCC), and found that the CPE-delta N RNA levels were double those in the surrounding tissue in 92% of patients whose cancer recurred or metastasized within 2 years in the tumor samples. Conversely, the levels were less than double in 76% of patients who had no metastasis or recurrence within 2 years. Similar values (sensitivity and specificity of 90% and 78%, respectively) were seen at three years, the investigators found.
In a separate evaluation of 18 patients with stage II liver cancer as determined by conventional staging, 5 were found to have very high levels of CPE-delta N RNA, and 4 of those went on to develop metastasis within 2 years following surgery, Dr. Y. Peng Loh, the senior investigator on the study, said during a telebriefing on the findings.
This is a particularly important finding, because stage II patients generally are thought to have good prognosis following resection, and often don’t receive further treatment after surgery, explained Dr. Loh of the NICHD.
"So CPE-delta N is a better indicator of the seriousness of the disease than [are] current staging techniques, and with more prospective studies, which we are currently doing in collaboration with a liver network in Taiwan, CPE-delta N will likely prove to be a very valuable biomarker in guiding the course of action and treatment for stage II (liver cancer) patients post-surgery, depending on the CPE-delta N RNA levels in their tumor," she said.
Similarly, of 12 patients with stage IV disease, 5 were found to have very low CEP-delta N levels, and those patients had no recurrences in 2 years post-surgery. Generally, stage IV patients have little hope of survival and often don’t receive further treatment because of their prognosis, but a low CEP-delta N level could give "hope of longer survival and psychological comfort."
Furthermore, such a finding might encourage physicians to actively treat these patients with chemotherapy, given their reduced risk of recurrence, she said.
Experiments in mice lend further credence to the conclusion that CPE-delta N levels are associated with metastasis and could lead to the development of treatments to prevent metastasis. Specifically, suppression of the expression of CPE-delta N in liver cancer tumors in the mice was associated with decreased tumor growth and metastasis potential.
Control mice who did not receive CPE-delta N suppression had tumor intensity that was more than 16-fold greater than in treated mice; similarly, mice transplanted with tumor tissue from the control mice had tumor intensity that was nearly 14-fold greater than in mice transplanted with tumor tissue from the treated mice.
"This offers the potential for developing a cure for certain types of cancers using antisense to CPE-delta N to suppress its expression," Dr. Loh said.
To test the effects of CPE-delta N in other types of cancer, the investigators also studied 14 patients with two rare and often deadly types of tumors – pheochromocytomas and paragangliomas (PHEO/PGL), which are tumors of endocrine origin, and for which no reliable markers predict malignant potential.
In these small tumors, surrounding tissue could not be sampled, and therefore the levels of CPE-delta N in those that spread were compared with levels in those that did not spread. CPE-delta N mRNA copy numbers of greater than 1 million/200 mcg of tissue correlated with poor outcome, while copy numbers of less than 250,000/200 mcg of tissue correlated with disease-free survival. Sensitivity and specificity were 100%, Dr. Karel Pacak, another investigator on the study, said during the telebriefing.