Things Are Looking Up for Liver Cancer Patients
What's Hot in Biology; March/April 2011
by Jeremy Cherfas
Liver cancer is a big problem. The fifth most common form of cancer worldwide is the number three cause of cancer deaths, and it is not easy to treat, in part because liver cells are adapted to metabolize and destroy potentially effective drugs. Two new papers in the Top Ten list offer the strong possibility that better therapies are not too far away.
Perhaps most promising is the #5 paper, from Joshua Mendell at Johns Hopkins University School of Medicine in Baltimore and his team. In a comprehensive series of experiments they have shown that a microRNA can suppress the development of tumors in a mouse model of liver cancer.
MicroRNAs (miRNAs) are small pieces of RNA that play an important role in regulating the expression of many genes (see Science Watch March/April 2008 ). They have been implicated in many diseases, and almost all cancers have an abnormal pattern of miRNA expression, with miRNAs having roles in several cell processes associated with transformation in tumor cells and subsequent proliferation.
Mendell and his group had previously shown that Myc, a gene associated with many types of cancer, results in the suppression of several kinds of miRNA, and expression of specific miRNAs can suppress tumor formation. Over a Thanksgiving dinner Mendell, his father Jerry Mendell, and his wife Kathryn O’Donnell (all among the co-authors on paper #5), cooked up a possible therapeutic scenario: use a viral vector to deliver a specific miRNA to transformed liver cells.
Step One was to look for an miRNA that was highly expressed in normal tissues but suppressed in hepatocarcinoma cells in a mouse model, O’Donnell’s speciality. The best candidate was miR-26a, being the most downregulated in transformed liver cells. It was also almost absent from human liver cell cultures.
Transfecting the human liver cancer cells with a mouse virus containing miR-26a stopped the normal cell cycle at the G1 stage. The cells are blocked at this stage because miR-26a inhibits two cyclins, D2 and E2, that are needed for the cell to move into the proliferative phase of the cell cycle. It does not, however, interact at all with the Myc gene in the mouse model.
Would miR-26a work in the mouse model? Jerry Mendell is an expert in the use of viruses to deliver gene therapy, and worked to develop an adeno-associated virus (AAV) vector that would deliver miR-26a and a fluorescent marker gene into liver cells. Three weeks after injection into normal mice, more than 90% of the liver cells were expressing both the green marker gene and miR-26a. Importantly, there was no evidence that the gene therapy had any untoward effect on normal liver cells.
Time for the acid test. Mice programmed to develop liver cancer were given the therapeutic AAV or a negative control at a time when they would normally have developed many small or medium tumors. Three weeks later, the team assessed the tumor burden.
Six of the eight control mice had developed massive tumors. Eight of the 10 experimental mice "were dramatically protected, exhibiting only small tumors or a complete absence of tumors upon gross inspection." The two that did develop tumors had far fewer transfected liver cells, suggesting "technical failure rather than biologic resistance."
"If patients who will not respond can be identified early, they can be spared the side-effects and the cost of treatment."
It seems that the restored miRNA function causes tumor cells, but not normal cells, to undergo apoptosis and die, even though the miRNA does not target the original oncogene, and that effectively kills the tumor. It is, as Mendell says, proof-of-principle.
At #7 is an apparently unrelated paper by Masashi Mizokami and his group at the Nagoya City University in Japan. They looked at one specific cause of liver cancer, hepatitis C virus (HCV), and in particular at why more than half of all patients fail to respond to the standard treatment, a combination of pegylated interferon-alpha and the anti-viral ribavirin. Treatment is expensive and often has bad side-effects.
If patients who will not respond can be identified early, they can be spared the side-effects and the cost of treatment. Mizokami’s team carried out genome-wide association studies on a Japanese population that did not respond to therapy.
They found two candidate markers near the gene IL28B, which were confirmed in another cohort. People with the markers had lower levels of IL28B expression in white blood cells.
This discovery brings the era of personalized medicine a little closer, but is there any prospect of bringing miRNAs to bear on unresponsive HCV patients? Joshua Mendell pointed Science Watch to a recent paper by Henrik Ørum and his group, who have shown that silencing miR-122, which is essential for HCV accumulation, suppresses the virus in chronically infected chimpanzees (R.E. Lanford, et al., Science, 327[5962]: 198-201, 2010).
There is also a link between miR-26 and interferon therapy. Liver cancer is up to six times more common in men than in women. Xin Wei Wang and his team at the National Cancer Institute have shown that women express higher levels of miR-26 in non-tumor cells, and that although patients with lower levels of miR-26 in tumor cells had shorter overall survival, they responded better to interferon therapy than patients with less-suppressed miR-26 (J.F. Ji, et al., New Engl. J. Med., 361[15]: 1437-47, 2009).
Dr. Jeremy Cherfas is Science Writer at Bioversity International, Rome, Italy.
What's Hot in Biology | |||
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Rank | Paper |
Cites This Period Sep-Oct 10 |
Rank Last Period Jul-Aug 10 |
1 | D.R. Bentley, et al., "Accurate whole genome sequencing using reversible terminator chemistry," Nature, 456(7218): 53-9, 6 November 2008. [7 European and U.S. institutions] *369DH | 41 | 3 |
2 | D.E. Harrison, et al, "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice," Nature, 460(7253): 392-5, 16 July 2009. [7 U.S. institutions] *470MO | 35 | † |
3 | S.B. Ng, et al., "Targeted capture and massively parallel sequencing of 12 human exomes," Nature, 461(7261): 272-6, 10 September 2009. [U. Washington, Howard Hughes Med. Inst., Seattle; Agilent Technologies, Santa Clara, CA] *492KN | 34 | † |
4 | Q. Pan, et al., "Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing," Nature Genetics, 40(12): 1413-5, December 2008. (U. Toronto, Canada] *376XI | 31 | † |
5 | J. Kota, et al., "Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model," Cell, 137(6): 1005-17, 12 June 2009. [Nationwide Children’s Hosp., Columbus, OH; Johns Hopkins U., Baltimore MD; Ohio State U., Columbus] *457GL | 28 | † |
6 | J.J. Qin, et al., "A human gut microbial gene catalogue established by metagenomic sequencing," Nature, 464(7285): 59-65, 4 March 2010. [14 institutions worldwide] *563GZ | 28 | † |
7 | Y. Tanaka, et al., "Genome-wide association of IL28B with response to pegylated interferon-a and ribavirin therapy for chronic hepatitis C," Nature Genetics, 41(10): 1105-9, October 2009. [17 Japanese institutions] *500UG | 27 | † |
8 | M. Paez-Ribes, et al., "Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis," Cancer Cell, 15(3): 220-31, 3 March 2009. [Catalan Inst. Oncology, L’Hospitalet de Llobregat, Spain; U. Calif., San Francisco; Osaka Med. Ctr. Cancer & Cardio. Dis., Japan; U. Barcelona, Spain] *416IC | 25 | † |
9 | P.O. McGowan, et al., "Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse," Nature Neuroscience, 12(3): 342-8, March 2009. [Douglas Mental Health U. Inst., Montreal, Canada; McGill U., Montreal; Singapore Inst. Clin. Sci.] *410LF | 25 | † |
10 | E.D. Pleasance, et al., "A comprehensive catalogue of somatic mutations from a human cancer genome," Nature, 463(7278): 191-6, 14 January 2010. [7 institutions worldwide] *543MQ | 25 | † |
SOURCE: Thomson Reuters Hot Papers Database. Read the Legend. |