Navigation Links
Skin cancer study uncovers new tumor suppressor gene
Date:3/29/2009

National Institutes of Health (NIH) researchers have identified a gene that suppresses tumor growth in melanoma, the deadliest form of skin cancer. The finding is reported today in the journal Nature Genetics as part of a systematic genetic analysis of a group of enzymes implicated in skin cancer and many other types of cancer.

The NIH analysis found that one-quarter of human melanoma tumors had changes, or mutations, in genes that code for matrix metalloproteinase (MMP) enzymes. The findings lay the foundation for more individualized cancer treatment strategies where MMP and other key enzymes play a functional role in tumor growth and spread of the disease.

Tumor suppressor genes encode proteins that normally serve as a brake on cell growth. When such genes are mutated, the brake may be lifted, resulting in the runaway cell growth known as cancer. In contrast, oncogenes are genes that encode proteins involved in normal cell growth. When such genes are mutated, they also may cause cancer, but they do so by activating growth-promoting signals. Cancer therapies that target oncogenes usually seek to block or reduce their action, while those aimed at tumor suppressor genes seek to restore or increase their action.

The new study may help to explain the disappointing performance of drugs designed to treat cancer by blocking MMP enzymes. Because members of the MMP gene family were thought to be oncogenes and many tumors express high levels of MMP enzymes, researchers have spent decades pursuing MMPs as promising targets for cancer therapies. However, when MMP inhibitors were tested in people with a wide range of cancers, the drugs failed to slow -- and in some cases even sped up -- tumor growth.

Now, it turns out that one of the most often mutated MMP genes in melanoma is not an oncogene at all. In its study, the team led by researchers from the National Human Genome Research Institute (NHGRI) found that MMP-8 actually serves as a tumor suppressor gene in melanoma. Consequently, in the estimated 6 percent of melanoma patients whose tumors harbor a mutated MMP-8 gene or related tumor suppressor(s), it may not be wise to block all MMPs. The study suggests that a better approach may be to look for drugs that restore or increase MMP-8 function or for drugs that block only those MMPs that are truly oncogenes.

"This research is an illustrative proof of concept that shows the value of genomic strategies for understanding cancer and possible therapies," said NHGRI Scientific Director Eric Green, M.D., Ph.D. "It is gratifying to see that genomic technologies are guiding scientific discovery, advancing cancer research, especially melanoma research."

Melanoma is the most serious form of skin cancer. In the United States and many other nations, melanoma is becoming more common every year. A major cause is thought to be overexposure to the sun. The ultraviolet radiation in sunlight can damage DNA and lead to cancer-causing genetic changes within skin cells.

MMP enzymes help the body to break down and recycle proteins, playing a crucial role in the process of remodeling skin after sunburns, cuts or other injuries. The MMP gene family has been associated with tumor growth in a variety of cancers, including breast, colon and melanoma.

To explore the role of MMP genes in melanoma, the NHGRI researchers studied a bank of tumor and blood samples collected from 79 patients with aggressive melanoma by collaborator Steven Rosenberg, M.D., Ph.D., chief of surgery at the National Cancer Institute (NCI). Specifically, they compared the sequence of MMP genes in tumors and normal DNA from the same patients, looking for mutations in all 23 members of the MMP gene family.

The researchers identified 28 different mutations in eight MMP genes in the melanoma tumors studied. These mutations were found to be distributed in different frequencies and patterns among the tumor samples. Nearly one-quarter of the tumors analyzed had at least one MMP gene mutation. Some mutations were found in as few as 3 percent of tumors, while more than 6 percent of tumors had mutations in MMP-8 and more than 7 percent had mutations in MMP-27, which codes for an enzyme very similar to MMP-8.

"We often talk about cancer as though it is one disease, and cancers do have many common denominators. But when we look at the DNA level, we see that different cancers have different genetic profiles, and so do different patients who have the same cancer," said the study's senior author, Yardena Samuels, Ph.D., an investigator in the Cancer Genetics Branch of the NHGRI's Division of Intramural Research.

Dr. Samuels and her collaborators followed up their DNA sequencing work with cell and animal studies to see whether MMP-8 mutations affect enzyme function. Strikingly, the researchers showed that five of the mutations reduced activity of the MMP-8 enzyme. The researchers next studied whether MMP-8 mutations promote activities related to cancer. Indeed, cells with MMP-8 mutations showed increased ability to multiply outside the constraints of normal cells, a hallmark of cancer development known as anchorage-independent growth. Likewise, cells with MMP-8 mutations had a greater ability to migrate -- a key aspect of cancer metastasis -- than normal cells.

The researchers found that mice injected with cells expressing normal MMP-8 did not develop skin ulcers, which are one of the most important measures of cancer aggression in melanoma. In contrast, mice injected with cells expressing mutated MMP-8 went on to develop ulcerations and metastases in their lungs.


'/>"/>

Contact: Raymond MacDougall
macdougallr@mail.nih.gov
301-402-0911
NIH/National Human Genome Research Institute
Source:Eurekalert

Related biology news :

1. Getting down to cancer basics
2. Mayo Clinic researchers discover and manipulate molecular interplay that moves cancer cells
3. Scripps scientists find structure of a protein that makes cancer cells resistant to chemotherapy
4. New drug agent knocks out multiple enzymes in cancer pathway
5. Molecular fingerprints point the way to earlier cancer diagnosis and more targeted treatment
6. Lombardi research: Monoclonal antibodies primed to become potent immune weapons against cancer
7. Research yields potential target for cancer, wound healing and fibrosis
8. Lab-on-a-chip homes in on how cancer cells break free
9. TGens Dr. Von Hoff wins award for cancer research
10. Researchers identify genetic markers for aggressive head and neck cancer
11. Cancer: Another step towards medication
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:4/28/2016)... , April 28, 2016 First quarter 2016: ... up 966% compared with the first quarter of 2015 ... SEK 589.1 M (loss: 18.8) and the operating margin was 40% ... 0.32) Cash flow from operations was SEK 249.9 M ... revenue guidance is unchanged, SEK 7,000-8,500 M. The operating ...
(Date:4/26/2016)... , April 27, 2016 ... the  "Global Multi-modal Biometrics Market 2016-2020"  report to ... ) , The analysts forecast the ... CAGR of 15.49% during the period 2016-2020.  ... number of sectors such as the healthcare, BFSI, ...
(Date:4/15/2016)... , April 15, 2016  A new ... make more accurate underwriting decisions in a fraction ... timely, competitively priced and high-value life insurance policies ... screenings. With Force Diagnostics, rapid testing ... lifestyle data readings (blood pressure, weight, pulse, BMI, ...
Breaking Biology News(10 mins):
(Date:6/23/2016)... ... 23, 2016 , ... ClinCapture, the only free validated electronic ... showcase its product’s latest features from June 26 to June 30, 2016 for ... Disrupting Clinical Trials in The Cloud during the conference. DIA (Drug Information ...
(Date:6/23/2016)... ... June 23, 2016 , ... Velocity Products, a division ... tuned and optimized exclusively for Okuma CNC machining centers at The International Manufacturing ... collaboration among several companies with expertise in toolholding, cutting tools, machining dynamics and ...
(Date:6/23/2016)... , June 23, 2016 ... research report to its pharmaceuticals section with historic ... details and much more. Complete report ... 151 pages, profiling 15 companies and supported with ... http://www.reportsnreports.com/reports/601420-global-cell-culture-media-industry-2016-market-research-report.html . The Global ...
(Date:6/22/2016)... , June 22, 2016 Research and ... Global Markets" report to their offering. ... billion in 2014 from $29.3 billion in 2013. The market is ... of 13.8% from 2015 to 2020, increasing from $50.6 billion in ... projected product forecasts during the forecast period (2015 to 2020) are ...
Breaking Biology Technology: