New metastasis marker found

A new molecular marker can predict the likelihood that two types of cancer -- a liver cancer and rare neuroendocrine tumors -- will spread to other tissues in the body, a process known as metastasis and a major cause of death in cancer patients.

Micrograph of hepatocellular carcinoma, the most common form of primary liver cancer
Image: Wikimedia commons, Nephron

"This is a really nice paper," said molecular pathologist linkurl:Fahd Al-Mulla;http://www.hgm2011.org/fahd_al-mulla.html of Kuwait University, who was not involved in the study. "This is the first time that somebody has discovered a prognostic marker" for the spread of these types of cancer. "If you can identify a patient in the early stages who is at high risk for progression of disease, one can modify their therapy," linkurl:Stephen Hewitt;http://ccr.cancer.gov/staff/staff.asp?profileid=9256 of the National Cancer Institute, who participated in the research, said at a National Institutes of Health press conference last week. The results, published online today (February 1) in the Journal of Clinical Investigation, may also apply to a variety of other cancer types, and have implications regarding the treatment decisions for cancer patients.The first tumor to appear in a cancer patient, the primary tumor, is rarely the cause of death. More often, the disease becomes serious when cancer cells break away from the primary tumor and spread through lymph and blood vessels to form secondary tumors in other parts of the body. It's these secondary tumors that are the most common cause of death in cancer patients, but predicting whether or not a cancer is likely to spread has been a longstanding obstacle for researchers and physicians. Over the past several years, however, molecular biomarkers for metastasis have been identified in a handful of cancers, such as melanoma, prostate cancer, and lung cancer. But while these markers appear to have some predictive potential, researchers have yet to perform the trials needed to prove their utility in the clinic. "The market is lacking any biomarker to diagnose metastatic disease," said Al-Mulla, who recently helped identify a metastatic biomarker for colon cancer. Current diagnostic efforts, which depend largely on morphological and histological criteria, are not very accurate, failing to identify some patients with a high risk of metastasis, while incorrectly targeting others whose cancer may never spread. This misclassification can lead to treatments that are too aggressive or not aggressive enough. But genetic biomarkers could significantly improve these predictions. The latest discovery, for example -- a protein known as CPE-delta N -- can help researchers predict the occurrence of metastasis of one of the most common tumors worldwide -- a liver cancer known as hepatocellular carcinoma (HCC) -- with greater than 90 percent accuracy. Specifically, by comparing the levels of CPE-delta N RNA in primary tumors to RNA levels in surrounding tissues in liver cancer patients, researchers were able to predict with 92 percent accuracy if the cancer would recur or metastasize within two years, and with 76 percent accuracy if it wouldn't. CPE-delta N increases the levels of a known metastasis gene called Nedd9, by interacting with a histone modifier that upregulates the gene. More Nedd9 increases a cancer cell's ability to proliferate and invade surrounding areas. "Metastatic cancer is a major cause of death, and it's very important to know when a cancer is likely to spread so the practitioners can contain the cancer early," linkurl:Peng Loh,;http://f1000.com/thefaculty/member/1454449585822547 a researcher at the Section on Cellular Neurobiology of the National Institute of Child Health and Human Development and a senior author on the paper, said at the press conference. "Currently there are no accurate biomarkers that can achieve such predictions."The researchers also measured the CPE-delta N RNA levels in patients with rare neuroendocrine tumors, and again found it to have incredible predictive value. In patients with high levels of CPE-delta N RNA (more than 1 million per 200 micrograms of tissue), the cancer always recurred or metastasized, even if the tumors were characterized as benign or non-metastatic at the time of surgery. Patients with fewer than 250,000 copies did not show signs of cancer for up to eight years. If decreasing CPE-delta N levels could help prevent metastasis, the protein could have therapeutic as well as diagnostic potential. The finding suggests "the potential for developing a cure for certain types of cancers using antisense to CPE-delta N to suppress its expression," Loh said. Indeed, when the researchers suppressed the expression of CPE-delta N with antisense RNA in mouse models of liver cancer, they inhibited tumor growth and metastasis. The RNA levels of the new marker were also elevated in cell lines of metastatic liver, breast, colon, and head and neck cancers, suggesting "this biomarker may be useful for many types of cancers," Loh said.But these cell line experiments in diverse cancer types are not as conclusive as the patient studies of HCC and the neuroendocrine tumors, Al-Mulla noted, and more research is needed to determine if CPE-delta N is truly a universal marker of cancer metastasis.Furthermore, like the biomarkers identified for other cancer types, CPE-delta N must be put through the ringer of a randomized clinical trial with larger patient populations than the 14 to 100 patient cohorts tested in this study. "That's the only way to really make sure that you've got [a reliable marker]," Al-Mulla said.Still, he added, it's another step in the right direction for predicting metastasis. "It appears that every cancer has a way to metastasize," he said. "But there are now papers coming out saying there are metastasis detectors" that may one day allow physicians to predict when it's going to happen, and treat the patient accordingly.
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[3rd April 2008]*linkurl:Cancer stem cells drive metastasis;http://www.the-scientist.com/news/display/53583/
[12th September 2007]*linkurl:Metastasis genes identified;http://www.the-scientist.com/news/display/53062/
[11th April 2007]