Tumours grow faster without blood-supply promoting molecule
Dense networks of blood vessels thought to spur cancer's growth could actually hinder rather than promote tumour progression, according to a new study at the University of California, San Diego. The findings partly explain why drugs designed to treat cancer by strangling its blood supply have been disappointing when used alone and why those treatments are more effective when combined with traditional chemotherapy.
Despite their rapid progression, tumours fed by more normal vascular were also more vulnerable to the effects of standard chemotherapy drugs, the team reports in this week's early online edition of the journal Nature.
Nascent tumours take off as new blood vessels invade, an event called angiogenesis that many see as key to the development of malignancy. But those pathological vessels form tangled structures that are far from normal.
'Tumour blood vessels become more chaotic, disorganised and leaky,' said Randall S. Johnson, professor of molecular biology at UC San Diego who led the study. 'They become dysfunctional in many ways as a blood vessel network.'
Cellular secretions within tumours promote the invasion. The first drugs designed to curtail cancer's blood supply targeted one of these, called VEGF for vascular endothelial growth factor. Inflammatory cells, which infiltrate many types of tumours, provide one source of VEGF.
Johnson's team created a strain of mice in which most inflammatory cells were missing the gene for VEGF, then cross-bred them with a strain that reliably develops mammary tumours and is commonly used to study breast cancer.
'The blood vessels look more organised and less leaky in the engineered mice,' said Christian Stockmann, a molecular biology postdoctoral fellow and the first author of the paper.
The blood supply to tumours in these mice was also sparse compared to mice with intact VEGF genes.
'A lot of these classic hallmarks of tumour blood vessels disappeared when the inflammatory cells couldn't make VEGF,' Johnson said.
But the cancer grew faster.
All of the mice developed tumours, but at 20 weeks of age, those with low levels of VEGF from inflammatory cells had larger growths that were more likely to have progressed to a later stage of cancer.
'The tumours seemed much happier when they didn't have this chaotic vasculature,' Johnson said.
The scientists also injected a cancerous cell line into normal and engineered mice and found that the introduced cells invaded normal tissues more readily without VEGF from inflammatory cells and developed more normal blood supplies.
The tumours that formed were also more susceptible to two different chemotherapy drugs in the mice lacking VEGF from inflammatory cells.
By identifying the cellular source of the critical factor for one pathology associated with cancer, the researchers say their findings may open new avenues for treatment.
Experts to share how research is tackling cancer
Cancer touches many people, but few have the chance to meet the researchers who have dedicated their lives to tackling the disease.
This month two world renowned cancer researchers will give a free public lecture in Newcastle to explain how their research is contributing to a better understanding of cancer and more effective treatments.
The Hunter Medical Research Institute (HMRI) Public Lecture, to be held on Friday September 12 at Newcastle Town Hall, will feature Professor Elizabeth Blackburn from the University of California and Professor John Forbes from the University of Newcastle and Calvary Mater Newcastle.
"People often ask 'why does it take so long to come up with better treatments?'. This event is a chance for the community to discover what is involved in cancer research from the laboratory bench, all the way to the clinic," said Dr Jennette Sakoff, a cancer researcher at Calvary Mater Newcastle and a member of HMRI's Cancer Research Program.
Professor Blackburn has been named one of Time Magazine's Top 100 most influential people in recognition of her research, which has revealed why cancer cells keep growing.
"Professor Blackburn's discovery of a protein called telomerase is considered the holy grail of cancer research. Her research has allowed us to understand how cancer cells keep growing over time, which has opened up avenues for new treatments in cancer and other diseases," said Dr Sakoff.
Professor John Forbes leads the Australian New Zealand Breast Cancer Trials Group, recognised as one of the premier breast cancer clinical trials research organisations. He was recognised in 2007 as one of the top 10 most cited scientists in the world, for peer-reviewed publications in 2005-2006. He was the only Australian named on the list.
"National and international clinical trials, led by Professor Forbes, have improved survival outcomes for women in the Hunter and internationally, through early detection, prevention, and better treatments for breast cancer," said Dr Sakoff.
"New clinical treatments are based on really good science, so it's appropriate that we are bringing together a scientist and a clinician who are working at the two ends of cancer research."
Once suspect protein found to promote DNA repair, prevent cancer
An abundant chromosomal protein that binds to damaged DNA prevents cancer development by enhancing DNA repair, researchers at The University of Texas M. D. Anderson Cancer Center report online this week in the Proceedings of the National Academies of Science.
The protein, HMGB1, was previously hypothesized to block DNA repair, said senior author Karen Vasquez, Ph.D., associate professor in M. D. Anderson's Department of Carcinogenesis at the Science Park - Research Division in Smithville, Texas.
Identification and repair of DNA damage is the frontline defence against the birth and reproduction of mutant cells that cause cancer and other illnesses.
Pinpointing HMGB1's role in repair raises a fundamental question about drugs under development to block the protein, Vasquez said. The protein also plays a role in inflammation, so it's being targeted in drugs under development for rheumatoid arthritis and sepsis.
"Arthritis therapy involves long-term treatment," Vasquez said. "Our findings suggest that depleting this protein may leave patients more vulnerable to developing cancer."
Long known to attach to sites of damaged DNA, the protein was suspected of preventing repair. "That did not make sense to us, because HMGB1 is a chromosomal protein that's so abundant that it would be hard to imagine cell repair happening at all if that were the case," Vasquez said.
In a series of experiments reported in the paper, Vasquez and first author Sabine Lange, a doctoral candidate in the Graduate School of Biomedical Sciences, tracked the protein's impact on all three steps of DNA restoration: access to damage, repair and repackaging of the original structure, a combination of DNA and histone proteins called chromatin.
First, they knocked out the gene in mouse embryonic cells and then exposed cells to two types of DNA-damaging agents. One was UV light, the other a chemotherapy called psoralen that's activated by exposure to darker, low frequency light known as UVA. In both cases, the cells survived at a steeply lower rate after DNA damage than did normal cells.
Next they exposed HMGB1 knockout cells and normal cells to psoralen and assessed the rate of genetic mutation. The knockout cells had a mutation frequency more than double that of normal cells, however, there was no effect on the types of mutation that occurred.
Knock out and normal cells were then exposed to UV light and suffered the same amount of damage. However, those with HMGB1 had two to three times the repair as those without. Evidence suggests that HMGB1 works by summoning other DNA repair factors to the damaged site, Vasquez said.
The last step in DNA repair is called chromatin remodelling. DNA does not exist in a linear structure in the chromosome, but wraps around specialized histone proteins. This chromatin structure permits access to DNA when it is loose, or opened up, and blocks access when it is more tightly wrapped. Presence of HMGB1 resulted in a much higher rate of chromatin assembly in both undamaged and UVC-damaged cells.
Lange and Vasquez hypothesize that HMGB1 normally binds to the entrance and exit of DNA nucleosomes, so is nearby when DNA damage occurs. It then binds to and bends the damaged site at a 90-degree angle, a distortion that may help DNA repair factors recognize and repair the damage. After repair it facilitates restructuring of the chromatin.
New HPV infections will plummet by 2010
The number of new human papillomavirus (HPV) infections in Australian females is expected to more than halve by 2010 and fall by 92 per cent by 2050, thanks to extensive HPV vaccination, according to a new study by Cancer Council.
The study, published in the International Journal of Cancer, looks at the predicted impact of the National HPV Vaccination Program in Australia, which began in April 2007. HPV immunisation has the potential to prevent up to 70 per cent of cervical cancers.
“We expect to see a very fast reduction in the number of new HPV infections, largely due to the high school vaccination program, which we estimate has achieved high coverage of just over 80 percent of 12 to 13 year-old girls,” says Dr Karen Canfell, from Cancer Council’s Research Division in NSW and lead author of the report.
"But we cannot afford to rest on our laurels. This reduction will only occur if we maintain this high vaccination coverage amongst younger age groups, as it will provide immunity against HPV before girls are exposed to the virus," she said.
Co-author Dr Julia Brotherton, from the National Centre for Immunisation Research and Surveillance, agrees saying: “Parents of girls in Years 7 to 10 need to take the opportunity for their daughters to be vaccinated now, as the free vaccination program for all girls only runs until 2009. This could save your daughter’s life.”
According to Dr Canfell it will still take some time for the reduction in HPV to translate to a significant decrease in cervical cancer. “Cervical cancer is a slow developer, but we do know that HPV immunisation has the potential to prevent a large proportion of cervical cancers.
“While this is all very positive news, we must remind all women to continue being screened through regular Pap testing, even those who have been vaccinated,” added Dr Canfell. “The HPV vaccine doesn’t protect against all types of cancer-causing HPV, so regular screening is absolutely essential to detect abnormal cell changes that can be treated before cancer develops.”
Cancer Council recommends that all women aged 18-70 who have ever had sex should have regular Pap tests, as per the National Medical Health and Research Guidelines which recommend testing every two years.
New role for sharks - saving lives
La Trobe University scientists are pioneering the use of modified shark antibodies in the quest for new and better therapies against diseases such as malaria, cancers and rheumatoid arthritis.
The process takes genes from sharks and modifies them in a laboratory by adding proteins that cause random mutations – mimicking the way the human immune system works – to develop antibodies capable of defensive responses against a range of diseases.
Developed by La Trobe molecular biologist Associate Professor Mick Foley, an international leader in malarial research, and his CSIRO colleague Dr Stewart Nuttall, the scientists have built the world's first test tube 'library' of disease-targeting antibodies based on modified shark antibodies.
According to the scientists, because shark antibodies are much smaller, chemically more robust and biologically more stable than conventional antibodies, they are well suited for targeted therapy – raising the prospect of new therapies that can be taken orally instead of injected.
The scientists recently showcased their emerging technology at the BIO-2008 convention in San Diego, California.
Announcing this potentially innovative role for sharks, Victorian Premier Mr John Brumby said there was a multibillion- dollar global market for antibody treatments and the shark gene extraction technique had attracted significant interest at BIO-2008.
'While Victorian scientists are not the first to recognise the potential of shark antibodies as a new line of defence against disease, existing technologies require shark handlers immunising the shark and letting the shark develop the antibodies,' Mr Brumby said. 'This technology has been patented and bears all the hallmarks of being the next generation of antibody-based diagnostic and therapeutic treatments.'
Scientists at AdAlta, the Melbourne-based company now developing the technology at La Trobe University, say that shark antibodies are highly effective in killing malarial parasites in vitro, through a unique protein-binding process that blocks molecular function.
Dr Foley, AdAlta's chief scientific officer, and Dr Stewart Nuttall, the company's consultant scientist, made this discovery in 2004, revealing that a shark antibody has a long, finger-like loop that projects from the surface and binds into a cavity on the target protein.
The antibody disrupts the normal signalling chain of command and inhibits malaria protein from invading human red blood cells.
Irreverently tagged as 'giving malaria the finger', this sub-cellular sabotage conjured images of the development of the anti-influenza pharmaceutical Relenza.
'When we saw the pictures of the shark antibody binding to a hole in the protein, we immediately thought of a situation like the flu,' Dr Foley says. 'It's like covering up part of a keyhole. You don't have to cover the whole keyhole; if you cover up part of it, you can't get the key in.'
The scientists have since completed many studies showing that if a shark antibody selected from the library binds to a malaria protein and is then put into a malaria parasite in culture, it kills the parasite. Other biotechnology companies are also working in this area, including Haptogen, a Scottish company recently acquired by Wyeth pharmaceuticals.
Unlike AdAlta, Dr Foley says, Haptogen obtains shark antibodies by immunising sharks and harvesting their blood.
'We take the genes from normal sharks and put them into a genetic vector, then add in random bits of protein, similar to what the human immune system does. This "library" is in a single test tube in the freezer. We can select antibodies in the laboratory and by maturing and optimising these you will get something that binds very tightly,' he says.
'The aim is to use these shark antibodies as a way of finding high-affinity binding agents to bind to anything we want – such as a molecule on cancer cells, or inflammatory proteins that you could then use in therapy.'
Unlike their UK-based competitors who recently advertised for 'experienced biologists with sharkhandling abilities', Dr Foley says AdAlta's work is strictly lab and land- based. 'Because their intellectual property depends on immunising the shark and letting it develop the antibodies, they need shark handlers. We don't. It's all done in the laboratory. It is quicker, more efficient – and a bit safer,' he says.
Beating depression for cancer patients
A new treatment programme for cancer patients with clinical depression can significantly boost their quality of life according to new research published in the Lancet today.
Cancer Research UK scientists devised the treatment programme which offers patients one-to-one sessions with specially trained cancer nurses to help them manage their depression more effectively.
They found that, after three months of receiving the new treatment, almost 20 per cent fewer patients were depressed compared with patients who received standard NHS treatment. The difference was still evident after one year.
The study recruited 200 cancer patients with clinical depression and compared the new strategy – "Depression Care for People with Cancer" – with the standard NHS treatment.
Half were given standard care for depression either from their GP or hospital specialist. The other half received the special programme which entailed sessions on: understanding depression and the effects of antidepressants; problem-solving therapy to help patients overcome feelings of helplessness; liaison with oncologist and GP to collaborate in treatment of depression; monthly monitoring of progress by telephone and providing optional "booster" sessions.
After three months, the patients who were treated in this way found there was an improvement in anxiety and fatigue as well as depression.
Professor Michael Sharpe, from the Psychological Medicine Research group at the University of Edinburgh which carried out the study, said: "Ten per cent of cancer patients experience clinical depression and, unfortunately, it is not always adequately treated. This new treatment could substantially improve the way we manage depression in people with cancer and also in people with other serious medical conditions.
"This is the first time that this type of depression treatment has been evaluated in cancer patients and the results are very encouraging."
Cancer Research UK, which funded the study, has recently awarded Professor Sharpe's research team more than L4 million to continue their work in finding better ways to treat depression and other symptoms in cancer patients.
Dr Lesley Walker, Cancer Research UK's director of cancer information, said: "As well as finding ways to prevent and treat cancer, the charity is committed to improving the quality of life for people who are living with the disease."
Melanoma on the rise among young women in the US
A review of 30 years of surveillance and epidemiological records shows that incidence of melanoma, the most lethal form of skin cancer, is increasing among young Caucasian women but not among young men in the US. The reviewers did not establish if this is due to increased exposure to ultraviolet radiation or some other factor and suggested this should be investigated further.
Led by Mark Purdue of the National Institutes of Health, the study is published in the 10th July advanced online issue of the Journal of Investigative Dermatology.
Purdue and colleagues said that recent studies had shown that incidence of non-melanoma skin cancer was rising in young adults, and in young American women in particular and they wanted to find out if the trends were similar for melanoma, a more deadly form of skin cancer.
Some studies suggest that melanoma incidence has been rising for older Americans for several decades, but that for younger adults the figures for those born after 1945 have been stabilising. But a 2001 study of data from SEER, the Surveillance, Epidemiology, and End Results Program, covering incidence rates from 1973 to 1997, showed there was evidence of a rise in melanoma incidence in women born after 1960. So Purdue and colleagues extended that analysis to include a further 7 years of data, taking it from 1973 to 2004.
Purdue and his team looked at data on melanoma incidence among Caucasians captured in nine SEER registries since 1973. These included records from Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle and Utah. They calculated the age-adjusted incidence of invasive cutaneous melanoma and deaths due to the disease among men and women aged 15 - 39 years.
Using recognised statistical software published by the National Cancer Institute, they assessed various types of trends and how they progressed successively over the decades involved.
The results showed that:
The overall age-adjusted annual incidence of melanoma among young men went up from 4.7 cases per 100,000 persons in 1973 to 7.7 per 100,000 in 2004.
The overall rise among young women over the same period was much steeper, from 5.5 in 1973 to 13.9 in 2004.
And the shape of the trend over that period was also different for young men than for young women.
Around 1980, the annual incidence trend for men levelled off and remained stable right through to 2004, but for young women, the annual incidence rate went down from 1978 to 1987, stabilised from 1987 to 1992, and then increased again.
Incidence of both thinner and thicker melanomas among women from the 1990s onwards went up and was greater for regional and distant tumours than localised lesions.
Deaths due to melanoma among young men and women went down from 1981 onward.
Reflecting on their results, Purdue and colleagues wrote that it was important to consider whether these patterns reflected changes in data quality, diagnosis or surveillance rather than what was really happening in the population. For instance, there is evidence of underreporting in SEER going up over time (perhaps as much as 17 per cent of cases in two of the registries), but this would not explain the increased incidence among young women.
A change in the way melanoma is diagnosed would not affect the findings said the investigators, because it doesn't explain the gender differences in the trends.
Earlier detection due to changes in screening methods may explain the higher rate of increase among superficial localised tumours compared to thicker lesions and more advanced forms of the disease, and the decrease in mortality after 1981 is consistent with earlier detection and increased surveillance.
But, the analysis showed that the increasing trend among young women from the early 1990s was also found to be in incidence of thicker and more advanced tumours, which are less susceptible to mis-diagnosis and incorrect classification, wrote the researchers, plus, after adjusting for age and period effects (to eliminate things like changes in surveillance methods), they maintain that their figures show a robust indication of "changes in disease risk factor prevalence across birth cohorts".
Thus Purdue and colleagues appear reasonably confident that their figures show a real trend of increasing incidence of melanoma among young women although they cannot rule out an effect due to changes in surveillance.
Speculating on causes, they said the pattern reflects reported trends in increased exposure to ultraviolet radiation, the main cause of melanoma, and reported figures that show sunburn is on the increase among American adults overall, although these do not show trends by age group.
However, among 16 to 18 year-olds, both the prevalence of sunburn and the average number of days spent at the beach went up between two sun surveys carried out in 1998 and 2004, and tanning bed use, which has been cited recently as a probable cause of melanoma is also going up among US adults and young women in particular.
Purdue and colleagues concluded that:
"Our analysis of SEER data suggests that melanoma incidence is increasing among young women."
They suggested further studies were needed to establish whether the increasing trends (for melanoma and non-melanoma skin cancers) were caused by changes to exposure to ultraviolet radiation or not.
What Is Cancer?
Cancer is the uncontrolled growth of cells in an organ (such as the breast, cervix, ovary or lung). Cancer cells grow together to form a mass called a tumor. Cancer is life threatening because cancer cells can invade surrounding tissue and spread through the bloodstream or lymphatic system to distant parts of the body (metastasize). Early detection before the cancer spreads provides the best chance of cure.
When someone tells you about a friend or family member having cancer, you often hear someone say, "He has cancer." Yet, cancer isn't just one disease. There are, in fact, more than 200 different cancers, and each kind can originate in any cell or organ in the body. All cancers have one thing in common - abnormal, uncontrolled cell growth.
Normally, cells grow and divide in an orderly fashion, involving a cycle to produce more cells only when the body needs them. This is a normal and healthy body process. Sometimes, however, cells keep dividing when new cells are not needed. These extra cells form a mass of tissue, called a growth or tumor.
(Cells in Cancer, Malignant Tumors, Benign Tumors, Metastatic Cancer)
Tumors can be benign or malignant:
Benign tumors are not cancerous. They can often be removed and, in most cases, they don't come back. Cells from benign tumors do not spread to other parts of the body. Most importantly, most benign tumors are not a threat to your life.
Malignant tumors, however, are cancerous. They are made up of abnormal cells that divide without control or order. They invade and damage nearby tissues and organs. Also, cancer cells can break away from a malignant tumor and enter the lymphatic vessels or bloodstream. That is how cancer spreads from the original cancer site to form new tumors in other organs. The spread of cancer is called metastasis.
When cancer spreads from its original location to another part of the body, the new tumor has the same kind of abnormal cells and is considered the same cancer type as the primary tumor but often has new genetic changes. For example, if lung cancer spreads to the brain, the cancer cells in the brain are actually lung cancer cells, and the disease is called metastatic lung cancer.
Forms of cancer:
There are three basic forms of cancer, which are named for the body tissues where they begin:
Sarcomas are found in fibrous or soft tissues, such as muscles, bone or blood vessels.
Carcinomas are found in the epithelium - cells that cover the body surface and line body organs, such as the breast, colon and lung.
Leukemias and lymphomas are found in blood cells of the bone marrow or lymph node cells.
Cancer can develop at almost any stage in life. There are some types of cancer that develop in early childhood, such as retinoblastoma (a cancer of the eye); others tend to develop in childhood, such as various forms of leukemia; and, of course, there are many forms that develop during adulthood, such as breast, colon and prostate cancers.
It can take a year or many years before a growing tumor (benign or malignant) can be detected, either on physical examination or on an x-ray or other test. Each form of cancer has its own growth rate.
A cancer that is "in situ carcinoma" - which in Latin means "in place" - refers to a cancer that is confined to one small area and is in an early stage of growth. Some consider it pre-cancer as it has not invaded or spread. Cancer or a "carcinoma" that is "in situ" may never develop further. However, because it may grow and become invasive and malignant, it is usually removed surgically, if possible.
Some cancers remain "in situ" or localized, while other cancers are "regional", invading adjacent body organs. Other cancers may metastasize (spread) into the bloodstream (vessels) or lymphatic vessels, where they are carried through the body to a distant site or sites.
There are different ways of treating cancer - mainly with surgery, radiation and/or chemotherapy. However, because there are so many different types of cancer, research so far hasn't found a single cause or single cure for cancer. Yet, due to improved diagnosis and newer cancer treatments, doctors are curing approximately 58 percent of cancer cases, and the current relative 5-year survival rate is about 63 percent for all types of cancer.