DNA shed from head and neck tumors detected in blood and saliva

Source: www.medicalexpress.com
Author: Wang et al., Science Translational Medicine (2015)
Schematic showing the shedding of tumor DNA from head and neck cancers into the saliva or plasma. Tumors from various anatomic locations shed DNA fragments containing tumor-specific mutations and human papillomavirus DNA into the saliva or the circulation. The detectability of tumor DNA in the saliva varied with anatomic location of the tumor, with the highest sensitivity for oral cavity cancers. The detectability in plasma varied much less in regard to the tumor’s anatomic location. Credit: Wang et al., Science Translational Medicine (2015)


On the hunt for better cancer screening tests, Johns Hopkins scientists led a proof of principle study that successfully identified tumor DNA shed into the blood and saliva of 93 patients with head and neck cancer. A report on the findings is published in the June 24 issue of Science Translational Medicine.

“We have shown that tumor DNA in the blood or saliva can successfully be measured for these cancers,” says Nishant Agrawal, M.D., associate professor of otolaryngology—head and neck surgery—and of oncology at the Johns Hopkins University School of Medicine. “In our study, testing saliva seemed to be the best way to detect cancers in the oral cavity, and blood tests appeared to find more cancers in the larynx, hypopharynx and oropharynx. However, combining blood and saliva tests may offer the best chance of finding cancer in any of those regions.”

Agrawal explains that inborn genetic predispositions for most head and neck cancers are rare, but other mutations that don’t generally occur in normal cells have long been considered good targets for screening tests.

In the case of head and neck cancers associated with HPV—tumors on the rise among Americans—Agrawal and his colleagues searched patients’ blood and saliva samples for certain tumor-promoting, HPV-related DNA. For non-HPV-related cancers, which account for the worldwide majority of head and neck tumors, they looked for mutations in cancer-related genes that included TP53, PIK3CA, CDKN2A, FBXW7, HRAS and NRAS.

The major risk factors for head and neck cancers are alcohol, tobacco—including chewing tobacco—and HPV infection.

For the study, 93 patients with newly diagnosed and recurrent head and neck cancer gave saliva samples, and 47 of them also donated blood samples before their treatment at The Johns Hopkins Hospital and MD Anderson Cancer Center in Texas. The scientists detected tumor DNA in the saliva of 71 of the 93 patients (76 percent) and in the blood of 41 of the 47 (87 percent). In the 47 who gave blood and saliva samples, scientists were able to detect tumor DNA in at least one of the body fluids in 45 of them (96 percent).

When the scientists analyzed how well their tumor DNA tests found cancers in certain regions of the head and neck, they found that saliva tests fared better than blood tests for oral cavity cancers. All 46 oral cavity cancers were correctly identified through saliva tests, compared with 16 of 34 oropharynx cancers (47 percent), seven of 10 larynx cancers (70 percent) and two of three hypopharynx cancers (67 percent).

The oral cavity refers to areas within the mouth, including the lips, front of the tongue, cheeks and gums. The oropharynx and hypopharynx are located in the back of the throat. The larynx, also in the throat, is typically known as the voice box.

“One reason that saliva tests may not have been as effective for cancer sites in the back of the throat is because we didn’t ask patients to gargle; we only asked them to rinse their mouths to provide the samples,” says Agrawal, a member of Johns Hopkins’ Kimmel Cancer Center and Ludwig Center.

Blood tests correctly identified tumor DNA more often in 20 of 22 oropharynx cancers (91 percent), six of seven larynx cancers (86 percent) and all three hypopharynx cancers. Taken together, blood and saliva tests correctly identified all oral cavity, larynx and hypopharynx cancers and 20 of 22 oropharynx cancers (91 percent).

Agrawal says the sensitivity of the tests overall depended on the cancer site, stage and HPV status, ranging between 86 to 100 percent. He also reports that saliva tests performed better for early-stage cancers, finding all 20 cancers, compared with blood tests that correctly identified seven of 10. He and his team found the opposite was true for late-stage cancers: Blood tests found more late-stage cancers (34 of 37), compared with saliva tests (51 of 73). Blood tests also correctly identified HPV-related tumors, occurring in 30 of the 93 patients, more often than saliva tests, probably because HPV-related tumors tend to occur in the back of the throat, which may not have been reached with the saliva rinse.

“Our ultimate goal is to develop better screening tests to find head and neck cancers among the general population and improve how we monitor patients with cancer for recurrence of their disease,” says Bert Vogelstein, M.D., the Clayton Professor of Oncology at the Johns Hopkins Kimmel Cancer Center, co-director of the Ludwig Center at Johns Hopkins and a co-author of the study.

The scientists caution that further study of their tumor DNA detection method in larger groups of patients and healthy people is needed before clinical effectiveness can be determined, and that refinements also may be needed in methods of collecting saliva and the range of cancer-specific genes in the gene test panel.

In addition, Agrawal says: “We don’t yet have definitive data on false positive rates, and won’t until there are more studies of the tests in healthy people.” However, he notes, the formulas used to analyze their blood and saliva tests are designed to weed out questionable results.

False results in gene tests arise when DNA are copied many times, sequenced and analyzed. The scientists used a method they developed and tested previously in cervical fluid to find ovarian and cervical cancers. Specifically, they attach a kind of genetic bar code—a random set of 14 DNA base pairs—to trace each copied DNA fragment to its original one. DNA copies lacking the bar code are suspected to be an artifact of the process, and any mutation found in it is disregarded.

Agrawal says that tests like the one his team used, if used commercially, likely would cost several hundred dollars, and “our long-term goal is to create a test that costs less than $50 so it can be administered by physicians or dentists.”

To screen for head and neck cancers, which occur in more than 50,000 people in the U.S. each year, doctors conduct physical examinations. Biopsies are taken of suspicious-looking lesions, but “this method is not ideal, as evidenced by the fact that most head and neck cancers are rarely found at very early stages, when they are most curable,” says Agrawal.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

Genetic markings could spot cancer before it develops

Source: www.thealmagest.com
Author: press release

Unique DNA markings on certain genes may “predict” the risk of developing head and neck cancer, according to new research led by Queen Mary University of London.

The findings, published in the journal Cancer, raise the potential for the development of non-invasive tests which could pick up these tell-tale signs of early cancer initiation.

Head and neck cancers are cancers that develop anywhere in the head and neck, including mouth cancer and throat cancer. About 16,000 people in the UK are diagnosed with head and neck cancer every year*.

In this study scientists analysed clinical specimens of malignant tissue from 93 cancer patients from Norway and the UK. These were compared with either tissue donated by healthy individuals undergoing wisdom tooth extractions, or with non-cancerous tissue from the same patients.

They were trying to identify whether there were any epigenetic changes in the cancerous cells which were not seen in the healthy cells. Epigenetics is the study of changes in gene expression caused by mechanisms other than changes in the underlying DNA sequence.

Not all genes are active all the time and there are many ways that gene expression is controlled. DNA methylation marks act as ‘switches’, either turning genes on or off. Abnormal DNA methylation is known to precede cancer initiation.

Lead researcher Dr Muy Teck-Teh, from the Institute of Dentistry at Queen Mary, said: “In this study we have identified four genes which were either over or under-expressed in head and neck cancer. The expression of these genes was inversely correlated with particular DNA methylation marks, suggesting the genes are epigenetically modified in these cancers.

“These epigenetic markers could be clinically exploited as biomarkers for early pre-cancer screening of head and neck cancer. However, further work is needed, as we are purely at the discovery stage at the moment and have not used this as a diagnostic test as yet.

“The eventual aim would be to test asymptomatic patients and/or people with unknown mouth lesions. An advantage of epigenetic DNA markers is that it may be possible to measure them using non-invasive specimens. So it could enable the use of saliva, buccal scrapes or blood serum for early cancer screening, diagnosis and prognosis.”

Consultant oral and maxillofacial surgeon Professor Iain Hutchison, co-author on the study, said he was excited by the possibility of diagnostic tests as a result of the research.

“All of us mouth cancer surgeons want to catch the cancer early when the chances of cure are high and the effects of surgery on the patient are minimal. A simple test using the patient’s blood or saliva could mean many patients with pre-cancer changes in the mouth or throat will be treated early and the cancer will never progress.”

The study was partly funded by the research charity Saving Faces – The Facial Surgery Research Foundation. Professor Hutchison founded the charity, which aims to reduce facial injuries and diseases through medical research.

December, 2013|Oral Cancer News|

HPV Can Damage Genes and Chromosomes Directly, Whole-Genome Sequencing Study Shows

Press release from the James Cancer Center 


COLUMBUS, Ohio – The virus that causes cervical, head and neck, anal and other cancers can damage chromosomes and genes where it inserts its DNA into human DNA, according to a new study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

It’s long been known that cancer-causing types of human papillomavirus (HPV)  produce two viral proteins, called E6 and E7, which are essential for the development of cancer. However, they are not sufficient to cause cancer. Additional alterations in host-cell genes are necessary for cancer to develop. Here, scientists identified a new mechanism by which HPV may damage host DNA directly and contribute to cancer development.

Published in the journal Genome Research, this laboratory study used whole-genome sequencing to investigate the relationship between the HPV and host genomes in human cancers.

“Our sequencing data showed in vivid detail that  HPV can damage host-cell genes and chromosomes at sites of viral insertion,” says co-senior author David Symer, MD, PhD, assistant professor of molecular virology, immunology and medical genetics at the OSUCCC – James.

“HPV can act like a tornado hitting the genome, disrupting and rearranging nearby host-cell genes,” Symer explains. “This can lead to overexpression of cancer-causing genes in some cases, or it can disrupt protective tumor-suppressor genes in others. Both kinds of damage likely promote the development of cancer.”

“We observed fragments of the host-cell genome to be removed, rearranged or increased in number at sites of HPV insertion into the genome,” says co-senior author Maura Gillison, MD, PhD, professor of medicine, epidemiology and otolaryngology and the Jeg Coughlin Chair of Cancer Research at the OSUCCC – James. “These remarkable changes in host genes were accompanied by increases in the number of HPV copies in the host cell, thereby also increasing the expression of viral E6 and E7, the cancer-promoting genes.”

HPV causes about 610,000 cancers annually worldwide, including virtually all cervical cancers, and many anogenital and head and neck cancers. How it causes cancer isn’t completely understood.

The two cancer-causing proteins, E6 and E7, silence two key tumor-suppressor genes in host cells, contributing to cancer development. “E6 and E7 are critically important for the virus to cause cancer. Our findings shed light on how HPV, and perhaps other viruses, can disrupt the structure of host chromosomes and genes and thereby contribute to cancer development,” Gillison explains.

For this study, Symer, Gillison and their colleagues examined 10 cancer-cell lines and two head and neck tumor samples from patients. Along with whole-genome sequencing, the scientists used several molecular assays, including RNA sequencing, spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH).

Key technical findings included:

• The genome-wide analysis, at single nucleotide resolution, identified a striking and recurrent association between HPV integrants and adjacent genomic amplifications, deletions and translocations;

• The HPV integrants mapped broadly across the human genome, with no evidence of recurrent integration into particular chromosomal hotspots;

• The researchers proposed a “looping” model by which abnormal viral replication results in the extraordinary damage that occurs to host chromosomes at the sites of viral DNA insertion.

“Our study reveals new and interesting information about what happens to HPV in the ‘end game’ in cancers,” Symer says. “Overall, our results shed new light on the potentially critical, catastrophic steps in the progression from initial viral infection to development of an HPV-associated cancer.”

Funding from the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James), the Ohio Supercomputer Center, an Ohio Cancer Research Associate grant, the Oral Cancer Foundation and the Intramural Research Program of the National Institutes of Health, National Cancer Institute Center for Cancer Research, supported this research.


Black raspberries reduce DNA damage in oral cancer survivors

Source: www.prweb.com
Author: press release

New research presented Wednesday, April 10, at the American Association for Cancer Research Annual Meeting 2013 in Washington, DC, suggests that a food-based cancer prevention study aimed at oral cancer survivors was effective at attenuating highly reactive oxygen molecules that can damage DNA and trigger cancer. In the study, a phase 1b clinical trial conducted at The Ohio State University, participants consumed 4 – 8 grams of black raspberries daily for six months. The berries were well tolerated by the participants and adherence to the regimen was good.

This study provides compelling data that indicate biochemical markers of cancer-causing DNA damage were reduced in participants who adhered to the food-based regimen and supports other evidence from a phase 2 human trial linking application of black raspberry gel to precancerous lesions to a reduced risk of developing oral cancer.

Black raspberries, not to be confused with blackberries, are almost exclusively grown in Oregon, on the west coast of the United States. They have been studied extensively because of their high concentration of certain phytonutrients and antioxidants. BerriProducts, an Oregon-based company, has been supplying black raspberry products to research universities across the country for the last four years.

April, 2013|Oral Cancer News|

Researchers document molecular tumor subtypes of head and neck cancer

Source: www.oncologynurseadvisor.com
Author: Kathy Boltz, PhD

Head and neck squamous cell carcinoma (HNSCC) is the seventh most common form of cancer in the United States. However, other than an association with the human papillomavirus (HPV), no validated molecular profile of the disease has been established. By analyzing data from DNA microarrays, a study has confirmed the presence of four molecular classes of the disease. Also, previous results have been extended by suggesting an underlying connection between the molecular classes and observed genomic events, some of which affect cancer genes. This study also demonstrated the clinical relevance of the classes and certain genomic events, paving the way for further studies and possible targeted therapies.

“Cancer is a disease caused by alteration in the DNA and RNA molecules of tumors. A cancer results when broken molecules initiate a cascade of abnormal signals that ultimately results in abnormal growth and spread of tissues that should be under tight control within the body,” said Neil Hayes, MD, MPH, of the University of North Carolina Lineberger Comprehensive Cancer Center and of The Cancer Genome Atlas.

“However, most common tumors, including head and neck cancer, have relatively little information in the public record as to how these signals coordinate to create different patterns of abnormalities. This study is among the largest ever published to document reproducible molecular tumor subtypes. Subtypes, such as those we describe, represent attractive models to understand and attack cancers for treatment and prognosis.”

The team analyzed a set of nearly 140 HNSCC samples. By searching for recurrent patterns known as gene expression signatures, they detected four gene expression subtypes. These subtypes are termed basal, mesenchymal, atypical, and classical, based on similarities to established gene expression subtypes in other tumor types and expression patterns of specific genes. For potential clinical use, these subtypes are complementary to classification by HPV status and the putative high-risk marker CCND1 copy number gain.

In spite of being the seventh most common form of cancer in the United States, HNSCC is relatively understudied in comparison to other tumor types (eg, breast and lung). By leveraging the similarities found in the gene expression subtypes, the results of this study provide a connection to a range of well-established findings and additional insight into the disease.

Source: This study was published in PLOS ONE (2013; doi:10.1371/journal.pone.0056823).

March, 2013|Oral Cancer News|

DNA adducts linked to oral cancer in smokers

Source: www.news-medical.net
Author: Sarah Guy, medwireNews Reporter

Having a high susceptibility to certain types of DNA damage caused by tobacco smoking could significantly increase the risk for oral cancer, show results of a Taiwanese study.

Levels of BaP 7,8-diol 9,10-epoxide (BPDE) – a metabolite of Benzo[a]pyrene, an important carcinogen found in cigarette smoke – correlated positively with smoking status in a cohort of individuals with oral cancer, report the researchers.

The findings also indicate a significantly increased risk for oral cancer among individuals with high DNA adduct levels compared with their peers with low levels.

“Based on our finding, we suggest that detected BPDE-like DNA adducts could be used as a biomarker for oral cancer risk,” write Huei Lee (Taipei Medical University) and colleagues in the Archives of Oral Biology.

The team analyzed BPDE-DNA adduct levels in oral tissue samples from 158 oral cancer patients and 64 individuals without cancer (controls), using immunohistochemistry and enzyme-linked immunosorbent assay (ELISA).

The results of these assays significantly and positively correlated , so that immunohistochemistry-negative patients did not have detectable DNA adduct levels using ELISA and vice versa.

DNA adduct levels also positively correlated with smoking status among the cancer patients, note the researchers, with significantly higher adduct levels among smokers than nonsmokers, at 93.18 versus 0.04 adducts per 108 nucleotides.

Lee and co-workers also observed that cancer patients had significantly higher DNA adduct levels than controls, at a range of 0-358.00 versus 0-39.50 adducts per 108 nucleotides.

Indeed, DNA adduct level was an independent risk biomarker for oral cancer in multivariate analysis, which indicated a 9.94-fold increased risk for the disease among individuals with high levels, defined as more than two standard deviations above the mean adduct level in the low group – which equates to 34.03 adducts per 108 nucleotides.

“These results strongly suggest that a high susceptibility to DNA damage derived from exposure to cigarette carcinogens is associated with the high risk of oral cancer in Taiwanese oral cancer patients,” conclude Lee et al.

Source: medwireNews

January, 2013|Oral Cancer News|

DNA alone inadequate to identify HPV-related cancers

Source: www.oncologypractice.com
Author: Mary Ann Moon

Testing for the presence of human papillomavirus DNA alone, especially using polymerase chain reaction methods, is not adequate to identify which head and neck squamous cell carcinomas are caused by the virus, according to two studies published online Sept. 18 in Cancer Research.

Identifying HPV-driven malignancies is important because they respond better to treatment and have better outcomes than those unrelated to HPV infection. Indeed, treatment of head and neck squamous cell carcinoma (HNSCC) may soon be guided by the tumor’s HPV status, since trials are now underway to determine whether de-escalation of chemo- and radiotherapy is safe and effective in such patients.

At present, however, the biomarkers that are best suited to making this identification are unclear.

Case Series Assesses Biomarkers
In the first study, researchers assessed the usefulness of four biomarkers in determining which HNSCCs in a case series were driven by HPV. They began by examining fresh-frozen tumor biopsy samples from 199 German adults diagnosed as having oropharyngeal squamous cell cancer between 1990 and 2008.

The four biomarkers were HPV-16 viral load, viral oncogene RNA (E6 and E7), p16INK4a, and RNA patterns similar to those characteristic of cervical carcinomas (CxCa RNA), said Dr. Dana Holzinger of the German Cancer Research Center at Heidelberg (Germany) University and her associates.

The simple presence of HPV DNA in a tumor sample was found to be a poor indicator of prognosis, likely because it often signaled past HPV infections or recent oral exposure, rather than active HPV infection that progressed to malignancy, the investigators said (Cancer Res. 2012 Sept. 18).

Instead, “we showed that high viral load and a cancer-specific pattern of viral gene expression are most suited to identify patients with HPV-driven tumors among patients with oropharyngeal cancer. Viral expression pattern is a completely new marker in this field, and viral load has hardly been analyzed before,” Dr. Holzinger said in a press statement accompanying the publication of these findings.

“Once standardized assays for these markers, applicable in routine clinical laboratories, are established, they will allow precise identification” of cancers that are or are not HPV-driven, which will in turn influence prognosis and treatment, she added.

Results Back Combination Approach
In the second study, Dr. Caihua Liang of Brown University, Providence, R.I., and her associates examined 488 HNSCC samples as well as serum samples collected in a population-based study in the Boston area during 1999-2003.

As in the first study, these investigators found that the mere presence of HPV-16 DNA in these tumors, particularly when detected by PCR analysis, did not accurately predict overall survival or progression-free survival.

Instead, “our study strongly suggests that the combination of detection of HPV-16 DNA in HNSCC tumors [plus] p16 immunostaining with E6/E7 antibodies represents the most clinically valuable surrogate marker for the identification of patients . . . who have a better prognosis,” they said (Cancer Res. 2012 Sept. 28).

“Assessment of HPV DNA using polymerase chain reaction methods as a biomarker in individual head and neck cancers is a poor predictor of outcome, and is also poorly associated with antibody response indicative of exposure and/or infection by HPV,” senior author Dr. Karl T. Kelsey added in the press statement.

“We may not be diagnosing these tumors as accurately and precisely as we need to for adjusting treatments,” said Dr. Kelsey, a professor in the department of epidemiology and the department of pathology and laboratory medicine at Brown University.

Dr. Holzinger’s study was funded in part by the European Commission, BMBG/HGAF-Canceropole Grand-Est, and the German Research Foundation. Her associates reported ties to Qiagen and Roche. Dr. Liang’s study was supported by the National Institutes of Health and the Flight Attendant Medical Research Institute, and one associate reported ties to Bristol-Myers Squibb.

September, 2012|Oral Cancer News|

Predicting oral cancer

Source: www.dailyrx.com

Oral cancers can occur anywhere in the mouth. As with any cancer, the sooner it’s found, the better. A new tool helps doctors know when oral cancer may be in a patient’s future.

A recent study finds that a set of molecular markers can help judge which lesions in the mouth are most likely to turn into oral cancer.

The Oral Cancer Prediction Longitudinal Study was conducted in Canada at the Oral Cancer Prevention Program at the BC Cancer Agency in Vancouver.

“The results of our study should help to build awareness that not everyone with a low-grade oral premalignant lesion will progress to cancer,” said Program Director, Miriam Rosin, PhD. “However, they should also begin to give clinicians a better idea of which patients need closer follow-up.”

Every year, cancer shows up in the mouths of nearly 300,000 people around the globe. Some of these start as spots – or lesions – in the mouth that have not yet become cancerous.

It’s always been difficult to tell which of these pre-malignant lesions will progress to full blown cancer.

In an earlier study, Rosin’s team had analyzed the DNA of tissue that eventually turned into oral cancer. This research provided a method for grouping patients according to risk.

For this study, researchers examined pre-cancerous tissue from nearly 300 patients, who were followed over a period of years. These patients were placed into either low-, intermediate- or high-risk groups.

Two additional DNA markers were used to zero in on a patient’s oral cancer risk factors.

“Compared with the low-risk group, [the] intermediate-risk patients had an 11-fold increased risk for progression, and the high-risk group had a 52-fold increase in risk for progression,” Dr. Rosin said.

Only about 3 percent of the people in the low-risk group developed cancer within five years.For those in the intermediate-risk, just over 16 percent saw the disease progress to cancer, while about 63 percent of high-risk patients developed oral cancer within five years.

To translate, this means that two out of every three high-risk lesions are progressing toward cancer, Dr. Rosin says.

“Identifying which early lesions are more likely to progress may give clinicians a chance to intervene in high-risk cases, and may help to prevent unnecessary treatment in low-risk cases,” Dr. Rosin said.

This study was published August 21 in Cancer Prevention Research, a journal of the American Association for Cancer Research. No financial information was available.

September, 2012|Oral Cancer News|

Molecular markers help predict oral cancer progression

Source: DrBicuspid.com

August 21, 2012 — A group of molecular markers has been identified that can help clinicians determine which patients with low-grade oral premalignant lesions are at high risk for progression to oral cancer, according to data from the Oral Cancer Prediction Longitudinal Study published in Cancer Prevention Research (August 21, 2012).

“The results of our study should help to build awareness that not everyone with a low-grade oral premalignant lesion will progress to cancer,” said Miriam Rosin, PhD, director of the Oral Cancer Prevention Program at the British Columbia (BC) Cancer Agency, in a press release issued by the American Association of Cancer Research, which publishes the journal. “However, they should also begin to give clinicians a better idea of which patients need closer follow-up.”

In 2000, Rosin and colleagues used samples of oral premalignant lesions in which progression to cancer was known to have subsequently occurred to develop a method for grouping patients into low- or high-risk categories based on differences in their DNA.

In their current population-based study, the researchers confirmed that this approach was able to correctly categorize patients as less or more likely to progress to cancer. They analyzed samples from 296 patients with mild or moderate oral dysplasia identified and followed over years by the BC Oral Biopsy Service, which receives biopsies from dentists and ear, nose, and throat surgeons across the province. Patients classified as high-risk had an almost 23-fold increased risk for progression.

Next, the researchers added two additional DNA molecular risk markers related to loss of heterozygosity to the analysis in an attempt to better differentiate patients’ risks. They used the disease samples from the prospective study and categorized patients into low-, intermediate-, and high-risk groups.

“Compared with the low-risk group, intermediate-risk patients had an 11-fold increased risk for progression and the high-risk group had a 52-fold increase in risk for progression,” Rosin said.

Of patients categorized as low-risk, only 3.1% had disease that progressed to cancer within five years. In contrast, intermediate-risk patients had a 16.3% five-year progression rate and high-risk patients had a 63.1% five-year progression rate.

“That means that two out of every three high-risk cases are progressing,” Rosin said. “Identifying which early lesions are more likely to progress may give clinicians a chance to intervene in high-risk cases and may help to prevent unnecessary treatment in low-risk cases.”

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

August, 2012|Oral Cancer News|

Demystifying the immortality of cancer cells

Source: http://medicalxpress.com/

In cancer cells, normal mechanisms governing the cellular life cycle have gone haywire. Cancer cells continue to divide indefinitely, without ever dying off, thus creating rapidly growing tumors. Swiss scientists have discovered a protein complex involved this deregulated process, and hope to be able to exploit it to stop tumor formation in its tracks.

The telomeres can be seen as white dots on these chromosomes © National Institute of Health

All our cells come equipped with an automatic self-destruct mechanism; they are programmed to die after a certain number of divisions. This internal clock is of great interest to cancer researchers, because most forms of cancer exhibit a defect in this innate timing mechanism. Cancer cells continue to divide indefinitely, long past the moment at which a normal cell would self-destruct. A team of researchers from professor Joachim Lingner’s laboratory at EPFL has learned how this defect is regulated in a tumor. Post-doctoral researcher Liuh-Yow Chen led the team in publishing an article appearing in the journal Nature on the 4th of July 2012. Their hope is that the discovery will provide new targets for drug therapies to combat the deadly disease.

Cellular immortality, which is responsible for cancer formation, hearkens back to a critical function of the cells of the developing embryo. At the ends of every chromosome there is a special sequence of DNA known as a telomere, whose length is governed by the telomerase enzyme. This sequence represents the lifespan of the cell. Every time the cell divides, it is shortened, and when the telomere finally runs out, the cell dies. This reserve allows most cells to divide about 60 times – sufficient for the cell to play its given role in the organism, without succumbing to inevitable genetic mutation.

Cellular immortality, cancer’s common denominator
Normally, once the embryonic stage is completed, our cells stop producing telomerase – with the notable exception of somatic stem cells. But occasionally, a cell will mutate and reactivate production of the enzyme, so that when the cell divides, the telomere gets longer instead of shorter. This is what gives cancer cells their immortality.

“This mutation, on its own, is not enough to cause cancer,” explains Joachim Lingner, co-author and head of the lab. “But cellular immortality is a critical element in tumor formation in 90% of known cancers.” Researchers the world over hope to be able to stop the runaway growth of cancer cells by targeting this mechanism with drug therapy.

But interestingly enough, even in a cancer cell the telomere doesn’t grow indefinitely long. With each cell division it loses some 60 nucleotides, like most cells, but then the activated telomerase causes it to gain just as many back. The internal clock is reset to zero, and the cell becomes immortal. But there’s one interesting question here: What is stopping the telomere from getting indefinitely long?

Stopping the clock with three proteins
The EPFL team was able to provide an answer to this question; they identified three proteins that join together and then attach themselves to the telomere. A bit like a lid on a pot, this protein complex prevents telomerase from acting on the telomere. But in the cancer cell, their timing is off – their involvement takes place too late.

“If we could cause these proteins to act earlier, or if we could recreate a similar mechanism, the cancer cell would no longer be immortal,” explains Ligner. The cancer cells would die a normal death. Clinical applications are still a long way off, however, he insists. “Our discovery may allow us to identify potential targets – for example, a secondary protein to which these three proteins also attach. But right now our work is still in the basic research stages.”

Source: Cancer July 5, 2012