The cell-signaling molecule Akt is a primary trigger that leads malignant melanomas on the skin's surface to begin growing vertically beneath the skin and turn into deadly invasive cancers, scientists have found. Understanding this key molecular difference between radial melanomas that spread on the surface of the skin and melanomas that grow vertically and invasively could provide new targets for the development of drugs to treat individuals with advanced stage melanomas.
Radial melanomas that have not spread below the skin can be treated surgically and have a survival rate of 98 percent beyond five years, according to the American Cancer Society. But when melanomas grow downward, the tumors become highly resistant to chemotherapy and radiation and the five-year survival rate falls rapidly, to 64 percent if the disease has reached the lymph nodes and 16 percent if it has spread to other organs.
The discovery of Akt's significant role in the progression of melanomas was made by scientists in the Department of Dermatology at Emory University School of Medicine and published in the March issue of the Journal of Clinical Investigation. Senior author is Jack L. Arbiser, MD, PhD, and lead author is Baskaran Govindarajan, PhD.
When the scientists introduced the gene for Akt into radial growth melanoma cells, the cells expressed nearly eight times as much of the growth factor protein VEGF. VEGF is known to be a powerful stimulator of angiogenesis Ð the growth of microscopic blood vessels that nourish cancerous tumors and lead to unregulated cell growth. When melanoma cells overexpressing Akt were introduced into immunocompromised (nude) mice, the mice developed aggressive tumors that expressed high levels of VEGF, whereas a control group of mice developed no tumors.
Another result of Akt overexpression was the increased production of reactive oxygen (ROS). Reactive oxygen is created during cellular metabolism and has long been associated with triggering angiogenesis and the resulting growth of tumors. The scientists also found that the Akt-induced melanoma cells produced more of the enzyme NOX4, one of the NOX family of genes known to increase generation of ROS and to trigger angiogenesis.
The scientists also found that in cells with greater Akt expression, there was an increase in impaired mitochondria-- the energy factories of cells. Their research showed, however, that these mutations in mitochondria were likely the result of the prolonged exposure to increased oxidative stress caused by Akt overexpression, but that the mitochondrial mutations were not essential for the aggressive growth of melanomas induced by Akt.
"Our research shows that Akt overexpression on its own is sufficient to transform radial growth melanoma cells into highly invasive tumors via reactive oxygen pathways," says Dr. Arbiser. "This could provide us with promising targets for anti-cancer drug therapy. We will continue to work on refining the exact mechanisms of how Akt influences the aggressive growth of melanomas."
Showing posts with label Cancer Research. Show all posts
Showing posts with label Cancer Research. Show all posts
Monday, June 11, 2007
Drug screen for cancer patients found
PHILADEPHIA, Pa., March 9 (UPI) -- Researchers at the University of Pennsylvania have found a way to screen cancer patients to see if they're suitable for a promising class of anti-cancer drugs.
The researchers propose screening cancer patients for proteasome inhibitors by testing for p53, a tumor-suppressor protein.
The anti-cancer proteasome inhibitors might be ineffective in patients whose tumors do not produce p53, said the researchers at the university's schools of medicine and veterinary medicine.
However, proteasome inhibitors are highly effective against lymphomas that do produce p53, the researchers said.
"Proteasomes resemble paper shredders - they break down proteins such as p53 into smaller pieces," said associate pathology professor Andrei Thomas-Tikhonenko. "A proteosome inhibitor effectively jams the shredder so that p53 is not immediately broken down."
The study appears online in the journal Blood , in advance of print publication in Ju
ne 2007
The researchers propose screening cancer patients for proteasome inhibitors by testing for p53, a tumor-suppressor protein.
The anti-cancer proteasome inhibitors might be ineffective in patients whose tumors do not produce p53, said the researchers at the university's schools of medicine and veterinary medicine.
However, proteasome inhibitors are highly effective against lymphomas that do produce p53, the researchers said.
"Proteasomes resemble paper shredders - they break down proteins such as p53 into smaller pieces," said associate pathology professor Andrei Thomas-Tikhonenko. "A proteosome inhibitor effectively jams the shredder so that p53 is not immediately broken down."
The study appears online in the journal Blood , in advance of print publication in Ju
ne 2007
Gene Switch turns stem cells into cancer killers
A gene has been discovered that turns stem cells into cancer killers, promising new treatments that boost the body's ability to destroy tumors.
South Korean scientists from the Korea Research Institute of Bioscience and Biotechnology in Daejeon say that the gene, Vitamin D3 Upregulated Protein 1 (VDUP1), spurs stem cells to become natural killer cells.
These components of the immune system can eliminate virus-infected and cancerous cells. Research leader Inpyo Choi says the team observed that VDUP1 plays a decisive role in causing stem cells to become natural killers.
The discovery was made by examining mice bred to lack the gene. The mice had a dramatic reduction in the number and activity of natural killer cells.
Besides determining the gene's importance to the immune system, Choi and colleagues have developed technology needed to spur the creation of natural killers from a person's own bone marrow stem cells.
Choi calls this "the first step toward developing new treatments using our own immune system to fight cancers and other serious diseases."
South Korean scientists from the Korea Research Institute of Bioscience and Biotechnology in Daejeon say that the gene, Vitamin D3 Upregulated Protein 1 (VDUP1), spurs stem cells to become natural killer cells.
These components of the immune system can eliminate virus-infected and cancerous cells. Research leader Inpyo Choi says the team observed that VDUP1 plays a decisive role in causing stem cells to become natural killers.
The discovery was made by examining mice bred to lack the gene. The mice had a dramatic reduction in the number and activity of natural killer cells.
Besides determining the gene's importance to the immune system, Choi and colleagues have developed technology needed to spur the creation of natural killers from a person's own bone marrow stem cells.
Choi calls this "the first step toward developing new treatments using our own immune system to fight cancers and other serious diseases."
Arsenic and Thalidomide may be used to fight cancer
A gathering of more than a thousand medical researchers in Sydney, Australia, has been told that arsenic and Thalidomide — banned in the 1960s after being linked to gross birth abnormalities — held hope as a basis for new treatments, extending the lives of patients with an so-far incurable bone marrow cancer, multiple myeloma.
Diagnosis of the disease has increased by 45% in Australia since 1992. It is the most lethal form of cancer, and the topic of discussion, at the 10th International Myeloma Workshop, continuing until the 16th of April.
The two treatments had advantages over existing chemotherapy treatments, including lessened side-effects, and reducing the need for chemo- and radiotherapy. They may also be usable to treat other illnesses. Both were still under test.
"The development of arsenic dates back many years when it was used for lowering the blood counts in patients, even at the turn of the century," Professor Miles Prince, of the Peter MacCallum Cancer Centre, told Australian Associated Press for the 10th International Myeloma Workshop.
"Subsequently [arsenic] was used in China since the 1960s for treating certain forms of Leukaemia," he said.
It could be used to induce the cell to "commit suicide".
"The side effects with Thalidomide are much less than with chemotherapy because it's not damaging innocent bystander cells - so you don't get low blood counts, you don't lose your hair, you don't get a sore mouth," he said.
"It was originally thought to work because [Thalidomide] blocks the blood vessel growth in tumours, and that is still true, but the research that we've done has shown that one of its major causes of action is to stimulate [ immune system ] T-cells which are directly against the tumour, and these T-cells help patients with myeloma fight their disease," Professor Douglas Joshua, head of Haemotology at Royal Prince Alfred Hospital in Sydney, told Australian radio.
"There's no doubt that with the new combinations of drugs - we've got Thalidomide, the sons of Thalidomide, Velcade and arsenic - we're adding years onto patient's lives and certainly it could add up to five years or more," according to Prof. Prince
Diagnosis of the disease has increased by 45% in Australia since 1992. It is the most lethal form of cancer, and the topic of discussion, at the 10th International Myeloma Workshop, continuing until the 16th of April.
The two treatments had advantages over existing chemotherapy treatments, including lessened side-effects, and reducing the need for chemo- and radiotherapy. They may also be usable to treat other illnesses. Both were still under test.
"The development of arsenic dates back many years when it was used for lowering the blood counts in patients, even at the turn of the century," Professor Miles Prince, of the Peter MacCallum Cancer Centre, told Australian Associated Press for the 10th International Myeloma Workshop.
"Subsequently [arsenic] was used in China since the 1960s for treating certain forms of Leukaemia," he said.
It could be used to induce the cell to "commit suicide".
"The side effects with Thalidomide are much less than with chemotherapy because it's not damaging innocent bystander cells - so you don't get low blood counts, you don't lose your hair, you don't get a sore mouth," he said.
"It was originally thought to work because [Thalidomide] blocks the blood vessel growth in tumours, and that is still true, but the research that we've done has shown that one of its major causes of action is to stimulate [ immune system ] T-cells which are directly against the tumour, and these T-cells help patients with myeloma fight their disease," Professor Douglas Joshua, head of Haemotology at Royal Prince Alfred Hospital in Sydney, told Australian radio.
"There's no doubt that with the new combinations of drugs - we've got Thalidomide, the sons of Thalidomide, Velcade and arsenic - we're adding years onto patient's lives and certainly it could add up to five years or more," according to Prof. Prince
Cancer antidote in the attic
Researchers have discovered that “junk” RNA, which has the power to check unbridled cell growth, can help in developing anti-cancer treatments
A scientist born in India and his colleagues at Oxford seem to have unearthed an antidote to cancer from the “junkyards” of the human genome.
Aroul Ramadass and his associates in Alexandre Akoulitchev’s lab at Sir William Dunn School of Pathology, University of Oxford , have discovered RNA (ribonucleic acid) that is capable of stopping the runaway proliferation of cells. The amazing control that this particular RNA — whose role was previously unknown — showed of genes involved in cell division may lead to tools that can prevent the growth of tumour cells, the scientists hope. Their findings were published on January 21 in the online edition of the journal, Nature.
Cancer is a class of diseases characterised by uncontrolled cell division and the ability of these cells to invade tissues of neighbouring or faraway organs. Normally, unregulated growth is caused by damage to DNA, resulting in mutations in genes that encode for proteins controlling cell division. Thus, intervention at the genetic level could offer a lasting solution — present-day therapy revolves mainly around the destruction of malignant cells — feel experts.
Typically, RNA plays an important and direct role in the synthesis of proteins, the building blocks of our bodies. But the RNA that the Oxford scientists studied belongs to the type of RNA not directly involved in protein synthesis.
Significantly, the RNA was located in that part of the genome which scientists once considered “junk”. The Human Genome Project completed early this century found that some 34,000 genes, constituting just three per cent of the genome, are responsible for producing proteins. The rest of the genome does not seem to have any function. According to the latest estimates, this “junk” DNA produces around half a million varieties of RNA of unknown functions. And to be politically correct, scientists have of late dropped the word “junk” and are instead using “non-coding”, meaning the parts of the genome which do not encode for proteins useful to the host genome.
Explaining the mechanisms involved in the process, Ramadass said that the RNA molecule is capable of shutting down the gene dihydrofolate reductase (DHFR). The DHFR gene produces an enzyme that controls the production of thymine, one of the four bases of DNA. Thymine is necessary for cell multiplication.
“By slowing down the replication process, it prevents any ordinary cell from becoming cancerous,” Ramadass, who completed his master’s degree in molecular biology and biotechnology in 2000 from New Delhi ’s Indian Agricultural Research Institute, told KnowHow.
To demonstrate this, the scientists applied the technique “RNA silencing” which won two US scientists — Andrew Fire and Craig Mello — the 2006 Nobel Prize for physiology and medicine.
They specifically targeted the “interfering” RNA and nullified its effect on the DHFR gene. This, in turn, prevented the DHFR gene shutdown, leading to rapid cell multiplication.
“There’s been a quiet revolution taking place over the last few years regarding the role of RNA,” says Dr Alexandre Akoulitchev. “Scientists have begun to see ‘junk’ DNA as having a very important function. The variety of RNA types produced from this ‘junk’ is staggering and the functional implications are huge.”
Inhibiting the DHFR gene could help prevent the growth of neoplastic cancerous cells, ordinary cells which develop into tumour cells, such as in prostate cancer cells,” explains Dr Akoulitchev. “In fact, the first anti-cancer drug, Methotrexate, acts by binding and inhibiting the enzyme produced by this gene,” he says.
Interestingly, Methotrexate, the first-ever cancer drug to be approved by the US Food and Drug Administration in 1953, was designed and developed by the late Indian scientist, Yellapragada SubbaRow, who is often hailed as the “miracle man of miracle drugs”.
“This is not the first non-coding RNA originated from the non-coding part of the genome. But it is likely to be the first one to control the promoter (the gene that expresses the enzyme) in such a direct way,” Dr Akoulitchev told KnowHow.
Understanding how we can use the RNA to switch off or inhibit DHFR and other genes may help derive important therapeutic insights for developing new anti-cancer treatments, concludes the University of Oxford researcher
A scientist born in India and his colleagues at Oxford seem to have unearthed an antidote to cancer from the “junkyards” of the human genome.
Aroul Ramadass and his associates in Alexandre Akoulitchev’s lab at Sir William Dunn School of Pathology, University of Oxford , have discovered RNA (ribonucleic acid) that is capable of stopping the runaway proliferation of cells. The amazing control that this particular RNA — whose role was previously unknown — showed of genes involved in cell division may lead to tools that can prevent the growth of tumour cells, the scientists hope. Their findings were published on January 21 in the online edition of the journal, Nature.
Cancer is a class of diseases characterised by uncontrolled cell division and the ability of these cells to invade tissues of neighbouring or faraway organs. Normally, unregulated growth is caused by damage to DNA, resulting in mutations in genes that encode for proteins controlling cell division. Thus, intervention at the genetic level could offer a lasting solution — present-day therapy revolves mainly around the destruction of malignant cells — feel experts.
Typically, RNA plays an important and direct role in the synthesis of proteins, the building blocks of our bodies. But the RNA that the Oxford scientists studied belongs to the type of RNA not directly involved in protein synthesis.
Significantly, the RNA was located in that part of the genome which scientists once considered “junk”. The Human Genome Project completed early this century found that some 34,000 genes, constituting just three per cent of the genome, are responsible for producing proteins. The rest of the genome does not seem to have any function. According to the latest estimates, this “junk” DNA produces around half a million varieties of RNA of unknown functions. And to be politically correct, scientists have of late dropped the word “junk” and are instead using “non-coding”, meaning the parts of the genome which do not encode for proteins useful to the host genome.
Explaining the mechanisms involved in the process, Ramadass said that the RNA molecule is capable of shutting down the gene dihydrofolate reductase (DHFR). The DHFR gene produces an enzyme that controls the production of thymine, one of the four bases of DNA. Thymine is necessary for cell multiplication.
“By slowing down the replication process, it prevents any ordinary cell from becoming cancerous,” Ramadass, who completed his master’s degree in molecular biology and biotechnology in 2000 from New Delhi ’s Indian Agricultural Research Institute, told KnowHow.
To demonstrate this, the scientists applied the technique “RNA silencing” which won two US scientists — Andrew Fire and Craig Mello — the 2006 Nobel Prize for physiology and medicine.
They specifically targeted the “interfering” RNA and nullified its effect on the DHFR gene. This, in turn, prevented the DHFR gene shutdown, leading to rapid cell multiplication.
“There’s been a quiet revolution taking place over the last few years regarding the role of RNA,” says Dr Alexandre Akoulitchev. “Scientists have begun to see ‘junk’ DNA as having a very important function. The variety of RNA types produced from this ‘junk’ is staggering and the functional implications are huge.”
Inhibiting the DHFR gene could help prevent the growth of neoplastic cancerous cells, ordinary cells which develop into tumour cells, such as in prostate cancer cells,” explains Dr Akoulitchev. “In fact, the first anti-cancer drug, Methotrexate, acts by binding and inhibiting the enzyme produced by this gene,” he says.
Interestingly, Methotrexate, the first-ever cancer drug to be approved by the US Food and Drug Administration in 1953, was designed and developed by the late Indian scientist, Yellapragada SubbaRow, who is often hailed as the “miracle man of miracle drugs”.
“This is not the first non-coding RNA originated from the non-coding part of the genome. But it is likely to be the first one to control the promoter (the gene that expresses the enzyme) in such a direct way,” Dr Akoulitchev told KnowHow.
Understanding how we can use the RNA to switch off or inhibit DHFR and other genes may help derive important therapeutic insights for developing new anti-cancer treatments, concludes the University of Oxford researcher
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