Navigation Links
Mayo Clinic researchers find genetic secrets to common kidney cancer
Date:5/18/2010

JACKSONVILLE, Fla. By examining expression of every human gene in clear cell renal cell carcinoma (ccRCC) compared to normal kidney cells, researchers at Mayo Clinic's campus in Florida have discovered gene signatures they say explain much of the biology of this common and difficult-to-treat kidney cancer.

In the May 18 issue of PLoS ONE, the researchers report they have discovered: a biological pathway signature of ccRCC for a group of altered genes that give this distinct cancer its "clear cell" appearance; other genes that confer stem cell-like properties to the cancer; and a set of master genes lost in ccRCC that they believe likely pushes initial development of the cancer.

"Understanding these genes and the pathways they regulate could provide valuable insight into how to treat ccRCC," says hematologist/oncologist Han W. Tun, M.D., the study's first author.

This cancer makes up 80 percent of all kidney cancer and is often resistant to both chemotherapy and radiation treatment, Dr. Tun says. It accounts for just 3 percent of all cancers in the United States, but is the sixth leading cause of cancer death.

"Up until this point, ccRCC was largely a mystery, but now we have new and exciting clues that seem to reveal the origin and development of this cancer," says senior investigator John Copland, Ph.D., a cancer biologist.

The research team, which included scientists from the University of Texas Medical Branch in Galveston, used a comprehensive genome-wide gene expression analysis to look at expression of about 25,000 genes in the human genome. The gene chip measures the amount of messenger RNA (mRNA) that is transcribed from genes as part of the protein production process.

They used this tool to measure levels of mRNA for each gene in tissue samples taken from kidneys that were removed from 10 ccRCC patients. The kidneys were removed at the time of surgery and contained both normal tissue as well as tumor, so the scientists compared gene expression between the two to see what genes in the cancer were either over- or under-expressed, compared to normal cells.

Researchers found that 13,729 genes had altered expression in the cancer a figure Dr. Copland calls "just astounding, especially in trying to develop new treatments and in understanding the causes of kidney cancer." They used novel software that grouped these genes into meaningful biological pathways which helped them discover master genes. Each of these master genes regulates hundreds of "downstream" genes.

Researchers confirmed these gene expression findings in 20 kidneys removed from other ccRCC patients. Then, they validated gene expression at the protein level in kidneys taken from a different group of 50 ccRCC patients. To provide biological relevance, researchers then grew live normal kidney and ccRCC cells in a culture mediuam and conducted experiments.

Among the research findings are:

  • The top three biological pathways found included genes regulating normal kidney function and metabolic functions lost in ccRCC. Genes in immune pathways were also over-expressed.
  • A gene expression signature responsible for adipogenesis, which is the accumulation of globules of fat inside cells that is the reason for the "clear" appearance of ccRCC. Using a novel cell culture technique, they turned ccRCC cell lines into fat-acquiring "clear cells," mimicking what happens in patients. In patient-matched normal cells, fat is not produced.
  • The loss of four developmental transcriptional factor genes in ccRCC that are important for normal kidney development. One of these genes, GATA3, controls many genes through transcriptional regulation of cell growth, immune function and inhibition of adipogenesis. Its loss is known to be critical to development of breast cancer. These four genes are known to control hundreds of other genes.
  • That ccRCC cells behave like stem cells undifferentiated cells that have the ability to become any type of cell in the body. ccRCC, but not normal kidney cells, has the capacity to undergo development of fat-producing cells or bone-making cells, depending on which laboratory culture medium they are placed in.
  • A gene expression signature for a biological process called epithelial-mesenchymal transition (EMT), a characteristic feature of invasive cancer and cells undergoing proliferation. EMT may be important for kidney cancer development.

The stem cell-like properties found in ccRCC may explain why this cancer is so resistant to treatment, says Dr. Tun. But it also suggests that newer classes of drugs designed to target stem cells may offer a new alternative to treatment for this cancer, he says.

Additionally, one of the study's biggest surprises is that immune genes are being expressed in ccRCC cells, which may be the reason why ccRCC is one of the few cancers that responds to immunotherapy, says Dr. Tun. One such gene, TLR2, can help control the chronic inflammation that is integral to the disease process. Down-regulating these immune genes may therefore be another good strategy.

"Based on these findings, we propose a cancer model for the development of ccRCC," says Dr. Copland. "Developmentally, kidneys are mesenchymal in origin and develop by biological processes, which include mesenchymal epithelial transition (MET). In our model, normal renal epithelial cells experience loss of normal renal function (dedifferentiation) and EMT as well as preferential adipogenic differentiation.

"We think that these processes turn normal kidney cells into cancer cells with stem cell-like qualities. Since our samples came from patients with early-stage ccRCC, it appears that EMT may play a prominent role in renal carcinogenesis," he says.

The researchers are conducting experiments in which they knock out the four developmental genes from normal kidney cells, to see if cancer develops. They are also introducing these same genes into patient-derived ccRCC cell lines to see if cancer growth stops.


'/>"/>

Contact: Kevin Punsky
punsky.kevin@mayo.edu
904-953-0746
Mayo Clinic
Source:Eurekalert

Related medicine news :

1. Drug Information Association (DIA) Announces New Clinical Safety and Pharmacovigilance Certificate Program
2. FDA Issues Guidance to Help Streamline Medical Device Clinical Trials
3. Clinical course of subepithelial lesions
4. Pluromed Announces Completion of Enrollment in LeGoo™ Cardiac Bypass Clinical Trial
5. Landmark Textbook Aims to Improve Clinician, Consumer Understanding of Lesbian Health
6. NHLBI funds preclinical tests on devices for infants and children with congenital heart defects
7. Chiropractors at Lyn Lake Chiropractic Clinic Provide Minneapolis, MN, Resource As Official MyFoxTwinCities.com ASK THE EXPERTS Sponsor
8. Medpedia Launches New Clinical Trial Platform
9. Macomb County Announces New Location for Four Upcoming H1N1 Clinics
10. Most Antidepressants Miss Key Target of Clinical Depression
11. Dr. David Williams Announces Launch of New Online Digestion Clinic
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:1/20/2017)... ... 20, 2017 , ... Source Vitál Apothecary, a skin and body care company ... the company had a successful visit to the 2017 ECRM Diet, Vitamin & Sports ... work in the nutritional, sports and health industries a chance to meet in private ...
(Date:1/20/2017)... ... 20, 2017 , ... ATP Science, an Australian-based company focused ... the January ECRM Trade Show in Hilton Head, SC, benefiting from outstanding meetings ... of supplements that keep the body functioning at its peak performance by providing ...
(Date:1/20/2017)... York, NY (PRWEB) , ... January 20, 2017 ... ... – VW+ 001 and its sugar-free alternative VW+ 002. The drinks have been ... body with optimal conditions to perform during your workout. , After a successful ...
(Date:1/20/2017)... ... January 20, 2017 , ... “I Forgive You”: a fine examination of how God handles ... the creation of published author, Stephen Miller, who, for over ten long years has been ... him. Born in Trinidad and Tobago, he has been serving the Lord for over twenty ...
(Date:1/20/2017)... ... January 20, 2017 , ... “Knowledge is God’s Lighthouse”: a ... “Knowledge is God’s Lighthouse” is the creation of published author, Gene Gaapf, a retired ... collections. , “I have been writing since high school and have many different ...
Breaking Medicine News(10 mins):
(Date:1/21/2017)... Jan. 20, 2017  Faruqi & Faruqi, LLP, a leading ... or the "Company") (NASDAQ: KMPH ) of the ... certain officers and directors and underwriters of the Company,s April ... role of lead plaintiff. The lawsuit has been ... for Johnson County on behalf of ...
(Date:1/20/2017)... , January 20, 2017 Stock-Callers.com ... (NASDAQ: SGYP ), Novo Nordisk A/S (NYSE: ... ), and Pernix Therapeutics Holdings Inc. (NASDAQ: PTX ... on Thursday, January 19 th , 2017, finishing near its ... Care Index dropped over 0.7%, while shares of health care ...
(Date:1/20/2017)... 20, 2017 Entscheidung ... Nothilfe   Die internationale humanitäre Stadt soll um ... schaffen   Seine Hoheit Scheich Muhammad ... sowie Herrscher von Dubai , hat ... Hilfe (International Humanitarian City IHC) zu verdreifachen, um den ...
Breaking Medicine Technology: