Monthly Archives: May 2006

Angiogenesis inhibitors: New cancer drugs stop tumor growth

  • 5/24/2006
  • Rochester, MN
  • staff
  • Mayo Clinic (www.mayoclinic.com)

Researchers hope that stopping angiogenesis could make cancer a more manageable disease.

As with all living things, even cancer needs oxygen and nutrients to help it grow and thrive. To get the fuel they need, tumors develop a network of new blood vessels in a process called angiogenesis. Angiogenesis is an area of intense focus by cancer researchers who hope that stopping angiogenesis could mean stopping cancer from growing and spreading.

Numerous drugs that may one day help prevent, stop or reverse angiogenesis are under investigation. These drugs are referred to as angiogenesis inhibitors or anti-angiogenic drugs. Only one drug that acts solely as an angiogenesis inhibitor is currently approved for use, but researchers are finding that many cancer drugs intended to attack cancer cells in other ways may also act as angiogenesis inhibitors. Researchers hope that stopping or reversing angiogenesis could leave tumors small and manageable.

What is angiogenesis?
Angiogenesis describes the formation of new blood vessels within your body. For instance, an embryo uses angiogenesis to develop inside the womb, a woman experiences angiogenesis as a normal part of menstruation, and body tissues use angiogenesis to help heal wounds.

Angiogenesis also refers to the process by which a tumor develops a blood supply. Small tumors can survive without a network of blood vessels to deliver oxygen and nutrients. These small tumors rely on nearby tissue to deliver small amounts of energy.

In order to grow larger and spread (metastasize), a tumor needs its own blood supply. Blood vessels give a tumor the oxygen and nutrients it needs to maintain rapid growth. Blood vessels also offer access to other areas of the body. Without a blood supply, a tumor remains very small and localized.

What causes angiogenesis in tumors?
Angiogenesis begins when your body’s own defenses can no longer hold back a tumor’s growth signals. Your body naturally makes chemicals that prevent angiogenesis from occurring when it isn’t needed. This keeps tumors very small — less than a few millimeters in size, or about the size of a pencil eraser. Researchers aren’t sure what happens to throw off the balance of power between your body and the tumor. Whether the tumor’s growth signals become stronger or something happens to weaken your own defenses, the result is what’s called the “angiogenic switch.” This term refers to the change from a small, localized tumor to a growing, spreading cancer.

How does angiogenesis occur?
Once the angiogenic switch has been turned on, the tumor begins sending out signals to the cells lining nearby blood vessels (endothelial cells). These signals cause the endothelial cells to grow and multiply. The endothelial cells direct enzymes to clear a pathway to the tumor. The blood vessels form stems that reach to the tumor. Once the blood vessel stems connect, the tumor uses the new blood vessels to receive oxygen and nutrients. It also sends out cancer cells to spread elsewhere in the body.

Much like cancer cells themselves, a tumor’s blood supply grows out of control and without order. Your body’s normal, healthy blood vessels are organized in a logical, orderly way. A tumor’s blood vessels are mangled and twisted.

How can angiogenesis be stopped?
Researchers are investigating a number of ways to stop or alter the angiogenesis process, including:

1. Blocking initial signals from the tumor. A tumor sends out signals, called growth factors, to stimulate the endothelial cells to start making new blood vessels. A number of these signals exist, each working in its own way to connect new blood vessels to the tumor. Some tumors send out several different signals. Others may send out only one or two. The most common signal is vascular endothelial growth factor (VEGF).

The only signal-blocking angiogenesis inhibitor currently available is bevacizumab (Avastin), which is approved to treat colon cancer. Bevacizumab intercepts a tumor’s VEGF signals and stops them from connecting with the endothelial cells.

2. Making initial signals from the tumor less effective. When a tumor sends out VEGF signals, those chemicals attach to receptors on the endothelial cells. The endothelial cells read the signal and begin to multiply. Drugs that clog those receptors stop VEGF from attaching and completing its mission. Other drugs, called small molecule drugs, can get inside the endothelial cells and stop the cells from acting on the signals.

Two small molecule drugs that interfere with a receptor called tyrosine kinase have been approved for use. Sorafenib (Nexavar) was approved in late 2005 to treat kidney cancer. Sunitinib (Sutent), for kidney cancer and gastrointestinal stromal tumors (GIST), was approved in early 2006.

3. Stopping the enzyme pathway. The enzymes that clear a pathway for blood vessels to extend to the tumor are also targets of angiogenesis inhibitors. Without the pathway, the endothelial cells can’t connect to the tumor. This stops the formation of blood vessels.

4. Normalizing mangled blood vessels. When a tumor has already attracted a network of blood vessels, it may be possible to rearrange or normalize those blood vessels. Some researchers believe angiogenesis inhibitors could do this, making an easier route to deliver chemotherapy and other cancer treatments to the tumor. That would explain why angiogenesis inhibitors are usually more effective when combined with chemotherapy.

5. Preventing the switch from turning on. Some genes that turn normal cells into cancer cells (oncogenes) have been found to also play a role in causing the angiogenesis process to begin. Drugs that target these oncogenes could prevent the angiogenic switch from being turned on, keeping a tumor small and dormant. Examples include gefitinib (Iressa), approved for use in lung cancer, and cetuximab (Erbitux), approved for use in colon cancer and head and neck cancers.

It’s possible for a single drug to work on more than one aspect of the angiogenic process.

Other drugs have been found to interfere with angiogenesis, though they weren’t originally developed for that reason. Examples include chemotherapy drugs such as paclitaxel (Taxol) and cyclophosphamide (Cytoxan, Neosar), COX-2 inhibitors such as celecoxib (Celebrex), and thalidomide (Thalomid).

What’s in the future for angiogenesis research?
Researchers hope a better understanding of the angiogenesis process will help them target treatments to different cancers. One day a treatment could be devised for you based on the growth factors your cancer uses to cause angiogenesis. A specific combination of angiogenesis inhibitors, possibly combined with chemotherapy, could be used to stop your cancer from growing.

Researchers are also investigating ways to alter the way a tumor interacts with the lymph system. Similar to how a tumor attracts blood vessels, a tumor can also attract lymph vessels — a process called lymphangiogenesis. Lymph vessels are part of your lymphatic system, which clears bacteria, viruses and waste products from your body. Your lymphatic system provides another way for cancer to spread. One day, doctors may be able to stop both methods of angiogenesis, effectively stopping cancers’ ability to spread

May, 2006|Archive|

UC Davis Researchers Reveal Apples’ Protective Ways

  • 5/23/2006
  • Davis, CA
  • staff
  • Life Science News (news.biocompare.com)

Doctors have long been encouraging Americans to add more fruits and vegetables to their daily diets. Now, UC Davis researchers have discovered one way in which flavonoid-rich apples inhibit the kinds of cellular activity that leads to the development of chronic diseases, including heart disease and age-related cancers.

“We’ve known for a long time that it’s the flavonoids in fruits that are protecting the body. We just haven’t known exactly how. Now, at least in the case of apples, we have a good idea about what’s going on,” said Eric Gershwin, professor of allergy, rheumatology and immunology at the UC Davis School of Medicine.

Gershwin and his colleagues found that apple extract was able to protect cells from damage and death by interfering with communication between cells.

The current findings appear in the latest issue of Experimental Biology and Medicine. Earlier studies have shown that flavonoids–which are found in chocolate and green tea, as well as other fruits and vegetables–behave as anti-oxidants, taking up free oxygen radicals that can damage precious DNA. The UC Davis study takes that research further by looking beyond the antioxidant effects of apple flavonoids.

In the current study, Gershwin and his colleagues exposed human endothelial cells to an extract of an apple mash made from different apple varieties. The researchers then challenged these cells by exposing them to tumor necrosis factor (TNF), a compound that usually triggers cell death and promotes inflammation via a mechanism called the “nuclear factor (NF) kappa B pathway.” This pathway involves chemical signaling between cells. The apple extract was able to protect the cells from the normal lethal effects of TNF.

“Our study showed that the flavonoids in apples and apple juice can inhibit signals in this pathway that would otherwise damage or kill cells in the body,” Gershwin explained.

The method by which apple extract protects cells is different than that reported for other flavonoid-rich foods. Grape seed extracts, for example, do not affect the NF kappa B pathway, the authors wrote. In addition, they said, other studies indicate that it is not just the flavonoids in the apple extract that are important in protecting cells from genetic damage.

“The differences are likely due to the other biologically active ingredients found in the different fruits,” Gershwin said. “We need to know more about how fruits like apples are able to protect us from disease.

Source: University of California, Davis – Health System

May, 2006|Archive|

Protein Expression Holds Promise For Head And Neck Cancer Detection

  • 5/18/2006
  • Augusta, GA
  • press release
  • Biocompare Life Science News (www.biocompare.com)

The blood of patients with head and neck cancer appears to have unique patterns of protein expression that one day could serve as a screening test for the highly aggressive cancer that is often diagnosed too late, researchers say.

Studies comparing protein expression in 78 patients with head and neck cancer to 68 healthy controls revealed numerous differences in protein expression, Medical College of Georgia researchers say.

“We found scores and scores of proteins that were differentially expressed,” says Dr. Christine Gourin, MCG otolaryngologist specializing in head and neck cancer and the study’s lead author. “We found there are at least eight proteins whose expression significantly differs between controls and people with cancer.”

This protein fingerprint correctly classified study participants as cancer patients with a high degree of sensitivity and specificity – 82 percent and 76 percent, respectively, according to research published in the current issue of Archives of Otolaryngology.

“If these results hold up over time, they would suggest that this would be a good screening test for at-risk people,” Dr. Gourin says. “Right now there is no good, effective screening test for head and neck cancer short of physical examination. Unfortunately it takes the development of symptoms to warrant a visit to the doctor, such as a sore throat; ear, tongue or mouth pain; painful eating or swallowing; or a change in the voice. Sometimes the first sign is a lump in the neck which is already a sign of an advanced tumor that has spread to the lymph nodes.”

Belated diagnoses translate to fairly dismal survival rates: less than 50 percent five years following diagnosis of stage three or four tumors, Dr. Gourin says. The rare patient who is diagnosed early faces much better odds: voice box cancer caught in stage one has about a 95 percent five-year survival, for example.

The goal is to screen high-risk populations – those with a history of alcohol and/or tobacco use – as well as those with head- and neck-specific complaints who don’t have those risk factors, says Dr. Gourin. She notes that about 20 percent of head and neck cancer patients have no history of alcohol or tobacco use.

Advanced proteomics technology – which can be applied to many tumor types – enables protein expression to be plotted on graphs that illustrate peaks and valleys. “Sometimes the underexpression of a protein may be significant,” Dr. Gourin says.

The unique patterns surfacing may one day provide more than screening. Study findings indicate the protein fingerprint also is highly successful at classifying specific types of head and neck cancer, correctly classifying 83 percent of oral cavity tumors and 88 percent of laryngeal tumors, as examples, researchers say.

Also, in a small subset of 12 patients, protein expression helped researchers correctly classify how cancers responded to treatment, indicating its effectiveness in long-term follow-up, Dr. Gourin says. “We could easily use this to follow patients for life and detect any recurrence early as well as improve our ability to detect a second primary tumor, which occurs in about 8 percent of people,” she says.

Clinical availability of a screening test for head and neck cancer is still years away, says Dr. Bao-Ling Adam, MCG cancer researcher and study co-author. But the researchers are continuing to make progress, already collecting more patient data to ensure that the patterns they have identified in the blood are effective biomarkers for head and neck cancer. Dr. Gourin is considering opening the study to other medical centers to increase numbers possibly into the thousands.

They also want to know if protein expression patterns found in the blood are expressed by cancer cells themselves, says Dr. Adam, who has begun doing proteomics studies on the cancerous tissue of surgery patients to find out. “What we see in the blood could be from the cancer cells or from the body’s response to cancer,” she says.

If they are the same, the proteins also could yield novel therapeutic agents, Dr. Adam says.

This will help solidify the link between the protein patterns and cancer as well. “For screening you really have to use body fluids: blood, saliva, urine,” says Dr. Adam. “When the normal cell transforms to a cancer cell, we want to see the changes within the cells. When we find the protein differences between cancer cells and normal cells, we can use this information to detect head and neck cancer.”

Interestingly, to date they have not found any proteins expressed by cancer that are not expressed normally; the difference is a matter of degrees of expression, says Dr. Adam, who also is using proteomics to find a better biomarker than prostate specific antigen, or PSA, for prostate cancer.

Source:
Medical College of Georgia

May, 2006|Archive|

Examining the Need for Neck Dissection in the Era of Chemoradiation Therapy for Advanced Head and Neck Cancer

  • 5/18/2006
  • Chicago, IL
  • Laura A. Goguen, MD et al.
  • Arch Otolaryngol Head Neck Surg. 2006;132:526-531

Objectives:
To (1) determine clinical factors that predict pathologic complete response (pCR) on neck dissection after sequential chemoradiotherapy (SCRT) for advanced head and neck cancer and (2) compare survival parameters between those who underwent neck dissection and those who did not among those patients with a clinical complete response (cCR) in the neck after SCRT, thus assessing the benefit of neck dissection in patients with a cCR in the neck.

Design:
Retrospective review with a mean follow-up of 3.5 years.

Setting:
Regional cancer center.

Patients:
The study population comprised 55 patients undergoing SCRT for advanced head and neck cancer with N2 or N3 neck disease. Three patients developed progressive disease and were excluded, and 28 patients underwent neck dissection.

Interventions:
Patients were assessed by physical examination and radiographically after SCRT.

Main Outcome Measures:
Physical examination and radiographic assessments of residual neck disease were compared with pathologic findings in those patients who underwent neck dissection. Survival comparisons were made between patients with a cCR in the neck who underwent neck dissection and those who did not.

Results:
Of 28 patients who underwent neck dissection, 8 had persistent pathologically positive nodal disease: 5 (45%) of 11 had N3 and 3 (18%) of 17 had N2 disease. Individual clinical neck assessments after SCRT were fairly predictive of a negative pathologic finding at neck dissection. The negative predictive values were physical examination (75%), computed tomography or magnetic resonance imaging (71%), and positron emission tomography (75%). However, when physical examination, imaging studies, and positron emission tomography all indicated a complete response, this accurately predicted a pCR on neck dissection. There appeared to be no improvement in survival parameters when a neck dissection was performed on patients with a cCR in the neck.

Conclusions:
Patients with N3 disease are at high risk for residual neck metastasis after SCRT. Patients with N2 disease can be assessed with physical examination, imaging studies, and positron emission tomography. If these all indicate a cCR, then neck dissection is likely not needed. Neck dissection did not appear to further improve survival parameters for patients with a cCR in the neck.

Author Affiliations: Division of Otolaryngology, Department of Surgery (Drs Goguen, Norris, Annino, and Sullivan), and Departments of Medical Oncology (Drs Posner, Wirth, and Haddad), Radiation Oncology (Dr Tishler), and Biostatistics (Dr Li), Brigham and Women’s Hospital and the Dana Farber Cancer Institute, Boston, Mass. Dr Sullivan is currently with the Department of Otolaryngology, Wake Forest University Health Sciences, Winston-Salem, Mass.

Authors:
Laura A. Goguen, MD; Marshall R. Posner, MD; Roy B. Tishler, MD, PhD; Lori J. Wirth, MD; Charles M. Norris, MD; Donald J. Annino, MD, DMD; Christopher A. Sullivan, MD; Yi Li, PhD; Robert I. Haddad, MD

Authors’ affiliations:
Author Affiliations: Division of Otolaryngology, Department of Surgery (Drs Goguen, Norris, Annino, and Sullivan), and Departments of Medical Oncology (Drs Posner, Wirth, and Haddad), Radiation Oncology (Dr Tishler), and Biostatistics (Dr Li), Brigham and Women’s Hospital and the Dana Farber Cancer Institute, Boston, Mass. Dr Sullivan is currently with the Department of Otolaryngology, Wake Forest University Health Sciences, Winston-Salem, Mass.

May, 2006|Archive|

Mitochondrial and Nuclear DNA Damage Induced by Curcumin in Human Hepatoma G2 Cells

  • 5/18/2006
  • Toxicological Sciences 2006 91(2):476-483; doi:10.1093/toxsci/kfj153

Curcumin is extensively used as a spice and pigment and has anticarcinogenic effects that could be linked to its antioxidant properties. However, some studies suggest that this natural compound possesses both pro- and antioxidative effects.

In this study, we found that curcumin induced DNA damage to both the mitochondrial and nuclear genomes in human hepatoma G2 cells. Using quantitative polymerase chain reaction and immunocytochemistry staining of 8-hydroxydeoxyguanosine, we demonstrated that curcumin induced dose-dependent damage in both the mitochondrial and nuclear genomes and that the mitochondrial damage was more extensive. Nuclear DNA fragments were also evident in comet assays. The mechanism underlies the elevated level of reactive oxygen species and lipid peroxidation generated by curcumin.

The lack of DNA damage at low doses suggested that low levels of curcumin does not induce DNA damage and may play an antioxidant role in carcinogenesis. But at high doses, we found that curcumin imposed oxidative stress and damaged DNA. These data reinforce the hypothesis that curcumin plays a conflicting dual role in carcinogenesis. Also, the extensive mitochondrial DNA damage might be an initial event triggering curcumin-induced cell death.

Authors:
Jun Cao1, Li Jia2, Hui-Min Zhou3, Yong Liu4 and Lai-Fu Zhong1

Authors’ affiliations:
1 Department of Toxicology,
2 College of Laboratory Medicine, and
3 Department of Microbiology, Dalian Medical University, Dalian 116027, China; and
4 Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, the Chinese Academy of Sciences, Dalian 116023, China

May, 2006|Archive|

Smokers at Higher Risk for Undetected Antibody for Oncogenic Human Papillomavirus Type 16 Infection

  • 5/16/2006
  • Los Angeles, CA
  • Dorothy J. Wiley et al.
  • Cancer Epidemiology Biomarkers & Prevention Vol. 15, 915-920, May 2006

Objective:
To determine the association between tobacco smoking and serologic evidence of human papillomavirus type 16 (HPV16)–specific antibodies among HPV16 DNA–positive women.

Design, Setting, and Participants:
Baseline health history, physical examination, and laboratory data for 205 HPV16 DNA–positive women with no prior cytologic evidence of squamous intraepithelial lesions who were enrolled subsequently in a randomized clinical trial.

Main Outcome Measure:
HPV16-L1 antibody (anti-HPV16 antibody) detected from serum using RIA or ELISA.

Results:
Eighty-seven percent (179 of 205) of women tested positive for HPV16 DNA using cervicovaginal swabs or lavage specimens, and 26 women showed similar results using swab specimens of external genitalia alone. HPV16-infected women who reported increasingly greater levels of daily cigarette smoking were less likely to test positive for anti-HPV16 antibodies than nonsmoking women (P = 0.02).
Smokers were twice as likely as nonsmokers to test negative for anti-HPV16 antibodies, even after controlling for the effects of other covariates in the analyses (adjusted odds ratio, 0.5; 95% confidence limits, 0.2-0.9). Although Papanicolaou test findings and smoking characteristics were poorly correlated (r2 = 0.01), women who showed atypical cells of unknown significance or squamous intraepithelial lesion were twice as likely to test anti-HPV16 antibody positive as women who showed normal Papanicolaou tests (adjusted odds ratio, 2.0; 95% confidence limits, 1.1-3.7).

Conclusion:
These data suggest that smoking may influence the long-term risk for cancer by perturbing early immune responses to the virus and may increase the likelihood of persistent infection. Patient education messages should alert women to this additional risk of smoking. A clinical trial of smoking cessation should be explored as a therapeutic intervention for primary HPV16 infection. (Cancer Epidemiol Biomarkers Prev 2006;15(5):915–20)

Authors:
Dorothy J. Wiley1, Edward Wiesmeier2,4, Emmanuel Masongsong1, Karen H. Gylys1, Laura A. Koutsky5, Daron G. Ferris6, Eliav Barr7, Jian Yu Rao3 The Proof of Principle Study Investigative Group

Authors’ affiliations:
1 Division of Primary Care, School of Nursing;
2 Departments of Obstetrics and Gynecology and
3 Pathology and Laboratory Medicine, University of California at Los Angeles School of Medicine;
4 Arthur Ashe Student Health Center, University of California at Los Angeles, Los Angeles, California;
5 Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington;
6 Departments of Family Medicine and Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia; and
7 Department of Biologics Clinical Research, Merck Research Laboratories, West Point, Pennsylvania

May, 2006|Archive|

Cancer is color-blind

  • 5/15/2006
  • Evergreen, VA
  • staff
  • Physorg.com

We may look different on the outside, but inside we are all the same -so much has been scientifically proven. Research at the University of Bergen has shown that the pathways that lead to cancer are similar, no matter where you come from.

At any rate, there are remarkable genetic similarities among cancer tumours from Norway, Sudan, Sri Lanka, India, the UK and Sweden.

“We had actually expected to find a greater range of variation,” says post-doctoral fellow Salah Osman Ibrahim of the University’s Department of Biomedicine. He is first author of an article that has been published in the prestigious American journal “Clinical Cancer Research”. The article is the product of collaboration among several departments and units at the University of Bergen, Western Norway Regional Health Trust and a number of national and international scientists.

The researchers compared patients in Norway and Sudan with head and neck squamous cell carcinomas (HNSCC). There are wide variations in the global incidence of HNSCC, which is a form of cancer that seems to be more common in developing countries than in our art of the world. The aim of the study, therefore, was to find out whether differences in life-style, diet or ethnic background could explains these variations.

The scientists used cDNA micro-matrix studies to compare patterns of gene expression in cancerous cells and cells from healthy tissue, in order to determine which genes had been switched on or off in the tumours.

“We looked at a total of 15,000 genes in each patient,” explains Ibrahim. It turned out that out of these, 136 genes are expressed differently in tumours and normal cells in Sudanese patients and 154 in Norwegian patients. Seventy-three of these genes are common to both groups.

The same pathways lead to cancer

But what may be even more important is that several of these genes are found in particular patterns that are related to cancer. The scientists talk of biological pathways: particular genes that create a particular mechanism or lead to a given alteration in the cells. Just how cells divide is an example of a biological pathway. Alterations in individual pathways of this sort may lead to cancer.

In this study, Ibrahim has found three such common pathways that occur in cancer patients in Sudan and Norway and which appear to exist independently of the patients’ background and life-style.

The results also showed that the anatomical location of HNSCC tumours in Norwegian tissue samples and the use of a type of chewing tobacco known as toombak in tissue samples from Sudan play an important role in patterns of gene expression. This was particularly the case when cancers have arisen where tissue has been in contact with chewing tobacco. There are differences from one country to another in where these tumours occur in the mouth, but these variations appear to be related to where users put the tobacco in their mouths.

Lethal chewing tobacco

“Chewing tobacco may not be so common in Norway, but it is more common in countries in which HNSCC occurs frequently,” explains Ibrahim. In Sudan, the variant of snuff known as Toombak has become increasingly popular as an alternative to smoking tobacco. Toombak has a higher concentration of nitrosamines, which are well known for their carcinogenic properties.

HNSCC, which is assumed to be related to the use of toombak, is also a much more common type of cancer in Sudan than in Norway, where it accounts for only one or two percent of all cancers. In Sudan, no less than 17 percent of cancer patients have HNSCC, while in Asian countries such as India it is estimated that more than half of all cancers are HNSCC.

“The use of chewing tobacco is also very common in India,” says Ibrahim, who is currently leading a new multinational study, whose preliminary results appear to support the previous findings.

Could save more lives in developing countries

Now, there is hope that the knowledge produced by the project can be used for early diagnosis and as part of the treatment process.

“Our aim is to identify biomarkers that can be used in the field, particularly in regions where access to primary health services is poor,” says Ibrahim. If we can easily find out when the genes that are associated with this type of cancer are switched off or on, we can start treatment early and save more lives.

Cancers of this sort are often extremely aggressive. When they have been diagnosed it is often already too late to do anything about them,” he explains.

Post-doctoral fellow Salah Osman Ibrahim of the Department of Biomedicine and his colleagues have identified 73 genes that are activated in cancerous tumours in both Sudan and Norway. Now, they are continuing the hunt in tumours from other parts of the world.

DNA micro-matrices

DNA micro-matrix studies are used to look at alterations in genetic activity under given conditions, for example after treatment with various drugs, in order to generate new knowledge of how such medications operate. One way of using the technique is to culture a particular type of cell and divide the culture into two parts. One sample is subjected to a given treatment while the other acts as a control group. After treatment, RNA is isolated from the two samples.

The treated sample is stained red, while the control sample is stained green and the two samples are mixed and placed in a DNA micro-matrix together with several thousand gene fragments, with each human gene being represented by a point on the matrix. RNA from both samples finds its way back to its own genes. When the matrix is illuminated with light emitted by a laser at a particular wavelength, the genes that have been activated by the treatment appear as points of red and those that were switched off show up as green, while genes that were not affected by the treatment will be yellow.

Source:
University of Bergen

May, 2006|Archive|

UCLA School of Dentistry Researchers Discover Natural Tumor-Suppressive Function of RNA-Building Protein

  • 5/15/2006
  • Los Angeles, CA
  • press release
  • UCLA News (www.newsroom.ucla.edu)

UCLA School of Dentistry researchers studying a basic human protein essential in processing and metabolizing RNA have discovered it works as a natural tumor suppressor effective against head and neck cancer.

These findings are reported in the May 15 issue of Clinical Cancer Research, one of the leading peer‑reviewed journals of the American Association for Cancer Research.

The protein, heterogeneous nuclear ribonucleoprotein G (hnRNP G), was until now perhaps the least investigated of a class of 30 ribonucleic acid-binding proteins with diverse biological functions.

While the researchers readily detect hnRNP G in healthy skin tissue, they report they do not find the protein in the vast majority of precancerous and cancerous tissues. Moreover, the UCLA scientists present evidence that hnRNP G injected into human oral squamous cell carcinoma (HOSCC) cells is effective in inhibiting the proliferation and tumor-forming capacity of HOSCC in test tubes and in an animal model.

While the scientists acknowledge that hnRNP G’s particular mechanisms of action require further investigation, these findings suggest the protein’s value in the development of new ways to diagnose and treat HOSCC.

According to the National Cancer Institute, most head and neck cancers can be attributed to this type of cancer, which begins in the squamous cells that line the mucosal surfaces in the head and neck. It is estimated that nearly 40,000 people will develop a form of head and neck cancer this year.

“If we know that hnRNP G is present in healthy cells, but absent in precancerous and cancerous cells, then we should be able to design a test to diagnose HOSCC by measuring the level of this protein present in a tissue sample,” said Dr. No-Hee Park, professor of diagnostic and surgical sciences, dean of the UCLA School of Dentistry, and a member of UCLA’s Jonsson Cancer Center. “Our examination of the unique biological properties and functions of hnRNP G represents one small step toward a better understanding of carcinogenesis as well as improved methods of early diagnosis and treatment.”

The technology transfer office at UCLA is actively filing for intellectual property protection of the discovery of hnRNP G’s tumor-suppressive ability and is in the process of speaking with potential commercial partners concerning possible clinical applications.

“HOSCC is associated with both high morbidity and high mortality with a survival rate of only 50 percent,” said Dr. Earl Weinstein, who handles life sciences business development and licensing for UCLA’s Office of Intellectual Property Administration. “We are therefore excited by the potential to develop these findings into a new diagnostic marker and, longer term, into a new therapeutic approach to this unmet medical need.”

In the meantime, Park and his colleagues plan to continue studying hnRNP G. In particular, they are interested in determining whether the protein’s ability to inhibit the growth of tumors is as effective against other types of cancers as it is against HOSCC. The hope is that their initial discovery will have wide implications for future cancer research.

“The findings reported by No-Hee Park’s lab may lead scientists at UCLA and elsewhere to look for ways to use this protein to diagnose and treat not only HOSCC, but also other cancers such as breast and prostate cancer,” said Dr. Judith C. Gasson, director of UCLA’s Jonsson Cancer Center and a professor of medicine and biological chemistry.

In addition to Park, the paper’s authors include Ki-Hyuk Shin, Mo K. Kang, Reuben H. Kim and Russell Christensen.

The hnRNP G research project was supported in part by grants funded by the National Institute of Dental and Craniofacial Research.

May, 2006|Archive|

OHSU researcher develops first animal model to treat devasting head and neck cancers

  • 5/15/2006
  • Portland, OR
  • press release
  • EurekAlert (www.eurekalert.org)

An Oregon Health & Science University Cancer Institute research laboratory has developed a novel mouse model designed specifically to study the often devastating head and neck squamous cell cancers. Xiao-Jing Wang, M.D., Ph.D., and colleagues report their research breakthrough in the May 15 issue of Genes & Development.
“This is the first animal model that mimics human head and neck cancer at both the pathological and the molecular levels with 100 percent incidence,” Wang said.

While scientists have identified some genes involved in head and neck squamous cell carcinoma (HNSCC), overall, progress has been hampered by the lack of an animal model to study the development and progression of the disease.

“This model will provide a valuable tool to screen for novel therapeutic and preventive approaches for this often deadly cancer,” said Wang, head of the Division of Molecular Biology of Head and Neck Cancer in the OHSU School of Medicine and a member of the OHSU Cancer Institute.

Head and neck squamous cell carcinoma is the sixth most common cancer in the United States. It has a low survival rate – fewer than 50 percent of head and neck patients survive beyond five years, and this rate has not changed in the past 20 years, despite progress in developing therapies for other cancers. Patients are usually resistant to routine chemotherapy and radiation therapy. In addition, the quality of life for survivors is usually miserable because the location of the cancer often destroys structures critical to speaking, breathing and swallowing.

In their research, Wang and her colleagues engineered a strain of mice to specifically lack expression of the transforming growth factor beta receptor II (TGFbRII) in epithelial cells of the oral cavity. By then introducing activating mutations in either the H-ras or K-ras (two different isoforms of the Ras GTPase), the researchers were able to induce invasive HNSCC with 100 percent incidence.

“Head and neck lesions developed from this mouse model have many molecular alterations similar to those found in HNSCC patients. Additionally, we have identified several new biomarkers that data suggest may be good targets for HNSCC therapy,” Wang said.

Wang was recruited to OHSU to study head and neck cancers. Through her research and through personal acquaintances, her passion was stirred to help people with this type of disfiguring cancer.

“Before I came to OHSU, a woman who was helping me here with my new house asked what was bringing me to Portland. When I told her it was to lead OHSU’s research on head and neck cancer, she said, ‘Oh, my god, we were meant to meet. My husband was just diagnosed with head and neck cancer.’ During my interactions with her after we moved to Portland, I realized how much this disease impacts patients and their family members. Then, only a few months later, a family friend was diagnosed with head and neck cancer. These two cases made me realize that this terrible disease could happen to people all around us, even our loved ones, and inspired me to my best effort in leading this study,” Wang said.

“It was a true team effort of the head and neck cancer research division, especially with Dr. Shilong Lu, the first author on this study, who made the major contribution to this model,” Wang said. Shilong LU, M.D., Ph.D., is research assistant professor of otolaryngology/head and neck surgery in the OHSU School of Medicine.

Peter Andersen, M.D., F.A.C.S., associate professor of otolaryngology/head and neck surgery in the OHSU School of Medicine; and Christopher L. Corless, M.D., professor of pathology in the OHSU School of Medicine, and member of the OHSU Cancer Institute, are co-authors on this study.

May, 2006|Archive|

White Blood Cells From Cancer-resistant Mice Cure Cancers In Ordinary Mice

  • 5/15/2006
  • Wake Forest, IL
  • press release
  • Science Daily (www.sciencedaily.com)

White blood cells from a strain of cancer-resistant mice cured advanced cancers in ordinary laboratory mice, researchers at Wake Forest University School of Medicine reported today.

“Even highly aggressive forms of malignancy with extremely large tumors were eradicated,” Zheng Cui, M.D., Ph.D., and colleagues reported in this week’s on-line edition of Proceedings of the National Academy of Sciences.

The transplanted white blood cells not only killed existing cancers, but also protected normal mice from what should have been lethal doses of highly aggressive new cancers.

“This is the very first time that this exceptionally aggressive type of cancer was treated successfully,” said Cui. “Never before has this been done with any other therapy.”

The original studies on the cancer-resistant mice — reported in 2003 — showed that such resistance could be inherited, which had implications for inheritance of resistance in humans, said Mark C. Willingham, M.D., a pathologist and co-investigator. “This study shows that you can use this resistant-cell therapy in mice and that the therapy works. The next step is to understand the exact way in which it works, and perhaps eventually design such a therapy for humans.”

The cancer-resistant mice all stem from a single mouse discovered in 1999. “The cancer resistance trait so far has been passed to more than 2,000 descendants in 14 generations,” said Cui, associate professor of pathology. It also has been bred into three additional mouse strains. About 40 percent of each generation inherits the protection from cancer.

The original group of cancer-resistant mice, also described in Proceedings of the National Academy of Sciences, successfully fought off a range of virulent transplanted cancers.

“Now we know that we can take white blood cells from this strange mouse and put them into a normal mouse and these cells will still kill cancers,” said Willingham, professor of pathology and head of the Section on Tumor Biology. “This is therapy in a mouse that does not have this magical genetic inheritance.”

The transplanted white blood cells included natural killer cells, and other white blood cells called neutrophils and macrophages that are part of the body’s “innate immune system.” This system forms a first line of host defense against pathogens, such as bacteria.

“Their activation requires no prior exposure, but rather depends on a pre-determined mechanism to recognize specific patterns on the cancer cell surface,” the researchers said.

Moreover, preliminary studies show that the white blood cells also kill “endogenous” cancers — cancers that spring up naturally in the body’s own cells.

Cui and Willingham said the research produced many other surprises. For one thing, if a virulent tumor was planted in a normal mouse’s back, and the transplanted white blood cells were injected into the mouse’s abdomen, the cells still found the cancer without harming normal cells. The kind of cancer didn’t seem to matter.

A single injection of cancer-resistant macrophages offered long-term protection for the entire lifespan of the recipient mouse, something very unexpected, they said.

“The potency and selectivity for cancer cells are so high that, if we learned the mechanism, it would give us hope that this would work in humans,” said Cui. “This would suggest that cancer cells send out a signal, but normal white blood cells can’t find them.”

Cui said the findings “suggest a cancer-host relationship that may point in a new therapeutic direction in which adverse side effects of treatment are minimal.”

The next steps include understanding the molecular mechanism. “The real key is finding the mutation, which is an ongoing investigation in collaboration with several other laboratories,” said Willingham.

Cui, Willingham and their colleagues also showed that highly purified natural killer cells, macrophages and neutrophils taken from the cancer-resistant mice killed many different types of cancer cells in laboratory studies in test tubes.

Besides Cui and Willingham, the team includes Amy M. Hicks, Ph.D., Anne M. Sanders, B.S., Holly M. Weir, M.S., Wei Du, M.D., and Joseph Kim, B.A., from pathology, Greg Riedlinger, B.S., from cancer biology, Martha A. Alexander-Miller, Ph.D., from microbiology and immunology, Mark J. Pettenati, Ph.D., and C. Von Kap-Herr, M. Sc., from medical genetics, and Andrew J.G. Simpson, Ph.D., and Lloyd J. Old, M.D., of the Ludwig Institute for Cancer Research in New York.

The primary support for the research came from the Cancer Research Institute, a New York based group founded to foster the science of cancer immunology, on the premise that the body’s immune system can be mobilized against cancer. The research also had support from the National Cancer Institute and the Charlotte Geyer Foundation.

Source:
Wake Forest University Baptist Medical Center

May, 2006|Archive|