Potential New Treatment Target Identified for Melanoma Skin Cancer

— New research from Western University has identified a potential new target for the treatment of melanoma, the deadliest of all skin cancers.
Silvia Penuela and Dale Laird have discovered a new channel-forming protein called Pannexin (Panx1) that is expressed in normal levels on the surface of healthy skin cells. But they found, in melanoma, Panx1 is over-produced to a pathological level.
The research is published in the August 17^th issue of the Journal of Biological Chemistry.
Malignant melanoma only accounts for four per cent of all skin cancers, and yet it's responsible for 79 per cent of skin cancer-related deaths. The World Health Organization says there are 200,000 cases of melanoma diagnosed each year and 65,000 melanoma-related deaths (2000 statistics).
"We think this over-production of Panx1 enables the melanoma to become very aggressive. The cells have these extra Panx1 channels and they can leave the primary tumor and invade other tissues," explained Laird, a Professor in the Department of Anatomy and Cell Biology.
"And when you find a protein that is highly up-regulated in a disease cell such as a melanoma, the question becomes, is there therapeutic value in targeting a drug to that protein to reduce its production or block its function. Would that be an effective treatment?"
"We now want to correlate our discovery to patient samples using the human melanoma bank through our collaboration with Dr. Muriel Brackstone and other clinicians at the London Health Sciences Centre, to see if this is a cancer marker," added Penuela, a Postdoctoral Fellow working in the Laird lab.
"So if a melanoma lesion has a lot of this protein, it might be a tool for prognosis, in saying this is more advanced, or going to be highly metastatic. And because it's on the skin, it would be more accessible for treatment."
Penuela suggests potential treatment might be in the form of a topical medication to use on melanoma lesions.

Missing Pieces of DNA Structure Is a Red Flag for Deadly Skin Cancer

— Melanoma is the most dangerous type of skin cancer and is the leading cause of death from skin disease. Rates are steadily increasing, and although risk increases with age, melanoma is now frequently seen in young people.

But what if we could pinpoint when seemingly innocuous skin pigment cells mutate into melanoma? Researchers at Brigham and Women's Hospital (BWH) have achieved this. Teams led by Yujiang Geno Shi, PhD, from BWH's Department of Medicine, and George F. Murphy, MD, from BWH's Department of Pathology have discovered a new biomarker for the lethal disease. The findings offer novel opportunities for skin cancer diagnostics, treatment and prevention.

The study will be published on Sept. 14, 2012 in Cell.

"Dr. Shi and colleagues have discovered an exciting new connection between the loss of a specific chemical mark in the genome and the development of melanoma," said Anthony Carter, PhD, of the National Institutes of Health's National Institute of General Medical Sciences, which mainly funded the research. "This work is a prime example of how basic research on mechanisms of epigenetic regulation can yield clinically significant insights that hold great promise for diagnosing and treating cancer."

The researchers found that certain biochemical elements in the DNA of normal pigment-producing skin cells and benign mole cells are absent in melanoma cells. Loss of these methyl groups -- known as 5-hmC -- in skin cells serves as a key indicator for malignant melanoma. Loss corresponded to more advanced stages of melanoma as well as clinical outcome.

Strikingly, researchers were able to reverse melanoma growth in pre-clinical studies. When the researchers introduced enzymes responsible for 5-hmC formation to melanoma cells lacking the biochemical element, they saw that the cells stopped growing.

"It is difficult to repair the mutations in the actual DNA sequence that are believed to cause cancer," said Christine Lian, MD, a physician scientist in the Department of Pathology at BWH and one of the lead authors. "So having discovered that we can reverse tumor cell growth by potentially repairing a biochemical defect that exists -- not within the sequence -- but just outside of it on the DNA structure, provides a promising new melanoma treatment approach for the medical community to explore."

Because cancer is traditionally regarded as a genetic disease involving permanent defects that directly affects the DNA sequence, this new finding of a potentially reversible abnormality that surrounds the DNA (thus termed epigenetic) is a hot topic in cancer research, according to the researchers.

In the United States, melanoma is the fifth most common type of new cancer diagnosis in men and the seventh most common type in women. The National Cancer Institute estimates that in 2012 there will be 76,250 new cases and 9,180 deaths in the United States due to melanoma.

The Shi laboratory pioneers studies in both basic chromatin biology and translational epigenetic research at the Endocrine Division, BWH Department of Medicine, and collaborates with Dr. Murphy's laboratory that focuses on melanoma biology in the Program for Dermatopathology, BWH Department of Pathology. This pre-clinical study, which shows a key role for epigenetics in melanoma development and progression, also enlisted the support of an international team of investigators.

The findings will provide insight for future functional, pre-clinical studies of 5-hmC in cancer biology.

Geneticists Verify Cholesterol-Cancer Link

— University of Rochester Medical Center scientists discovered new genetic evidence linking cholesterol and cancer, raising the possibility that cholesterol medications could be useful in the future for cancer prevention or to augment existing cancer treatment.

The data, published in the online journal Cell Reports, support several recent population-based studies that suggest individuals who take cholesterol-lowering drugs may have a reduced risk of cancer, and, conversely that individuals with the highest levels of cholesterol seem to have an elevated risk of cancer.

The cancer-cholesterol question has been debated since the early 20^thcentury, and along with it doctors and scientists have observed various trends and associations. However, until now genetic evidence directly linking cholesterol and malignancy has been lacking, said senior author Hartmut (Hucky) Land, Ph.D., Robert and Dorothy Markin Professor and chair, Department of Biomedical Genetics, and director of research and co-director of the James P. Wilmot Cancer Center at URMC.

Cholesterol is a fat-like substance supplied in foods and made in cells throughout the body. Too much cholesterol is bad for the heart and vascular system. It is typically measured as serum cholesterol by routine blood tests.

Unlike serum cholesterol that is bound to proteins, however, cholesterol also hides inside cells. While locked inside cell membranes before it is eventually exported, cholesterol has an impact on cell growth and survival. A gene, known as ABCA1, is at the crossroads of the process that shuttles intracellular cholesterol outbound.

Several years ago while conducting unrelated experiments that were published in the journal Nature, Land and colleagues first noticed the importance of ABCA1. At that time, they identified a network of approximately 100 so-called "cooperation response genes" that mediate the action of cancer genes. ABCA1 was found among these genes and is frequently turned off in presence of other mutant cancer genes.

In the latest investigation, Land and co-author Bradley Smith, Ph.D., a post-doctoral fellow in the Land lab, wanted to further understand the role of ABCA1 and cholesterol in cancer. They found that defective cholesterol exportation appears to be a key component in a variety of cancers.

The proper function of ABCA1 is critical for sensing of cell stress. If ABCA1 function is lost in cancer cells, cholesterol is allowed to build up in the cells' mitochondria, or energy centers, making their membranes more rigid. This in turn inhibits the function of cell-death triggers that normally become activated in response to cell stresses, as for example cancer gene activation. Therefore, when functioning properly, ABCA1 has anti-cancer activity -- in the sense that by keeping mitochondrial cholesterol low it protects the functioning of cellular stress response systems and acts as a barrier to tumor formation and progression.

Smith and Land also demonstrated that some of the relatively rare ABCA1 mutations found in human colon cancers by other investigators disabled the gene's ability to export cholesterol. And by re-establishing the cholesterol export function in human colon cancer cells, they inhibited the cells' ability to grow as cancers when grafted onto mice.

The URMC study, therefore, is the first to directly show how ABCA1 loss-of-function and cholesterol may play a role in cancer. "Scientifically it is very satisfying to have data that support longstanding ideas about cholesterol in the context of cancer," Land said. "Our paper provides a rationale for cholesterol targeting as a potentially fruitful approach to cancer intervention or prevention strategies."

Millions of Americans take cholesterol-lowering drugs or statins, as prescribed by physicians. Clinical trials also are evaluating statins as a tool against cancer, and some previous studies suggest that when used in combination with chemotherapy, statins might make chemotherapy more effective by sensitizing certain cancer cells to chemotherapy-induced cell death.

Land, however, urges caution and further study. Doctors do not know the appropriate statin dose for cancer prevention or treatment of cancer-related conditions. Side effects cannot be ignored either, and little research has distinguished between the responses among people who take statins.

"The link between cholesterol and cancer is clear," Land said, "but it's premature to say that statins are the answer."

The National Institutes of Health grants CA90663, CA120317 and CA138249 funded the research.

In Lung Cancer, Smokers Have 10 Times More Genetic Damage Than Never-Smokers

— Lung cancer patients with a history of smoking have 10 times more genetic mutations in their tumors than those with the disease who have never smoked, according to a new study from Washington University School of Medicine in St. Louis.

"None of us were surprised that the genomes of smokers had more mutations than the genomes of never-smokers with lung cancer," says senior author Richard K. Wilson, PhD, director of The Genome Institute at Washington University. "But it was surprising to see 10-fold more mutations. It does reinforce the old message -- don't smoke."

The study appears online Sept. 13 inCell.

Overall, the analysis identified about 3,700 mutations across all 17 patients with non-small cell lung cancer, the most common type. Twelve patients had a history of smoking and five did not. In each patient who never smoked, the researchers found at least one mutated gene that can be targeted with drugs currently on the market for other diseases or available through clinical trials. Across all patients, they identified 54 mutated genes already associated with existing drugs.

"Whether these drugs will actually work in patients with these DNA alterations still needs to be studied," says first author Ramaswamy Govindan, MD, an oncologist who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University. "But papers like this open up the landscape to understand what's happening. Now we need to drill deeper and do studies to understand how these mutations cause and promote cancer, and how they can be targeted for therapy."

Lung cancer is divided into two types -- small cell and non-small cell, the latter accounting for about 85 percent of all cases. Within non-small cell lung cancer are three further classifications. This current analysis included two of them. Sixteen patients had adenocarcinoma and one had large-cell carcinoma.

Govindan and Wilson also were involved in a larger genomic study of 178 patients with the third type, squamous cell carcinoma, recently reported in Nature. That study was part of The Cancer Genome Atlas project, a national effort to describe the genetics of common cancers.

"Over the next year or so, we will have studied nearly 1,000 genomes of patients with lung cancer, as part of The Cancer Genome Atlas," says Govindan, who serves as a national co-chair of the lung cancer group. "So we are moving in the right direction -- toward future clinical trials that will focus on the specific molecular biology of the patient's cancer."

Indeed, based on the emerging body of genetic research demonstrating common mutations across disparate cancer types, Wilson speculates that the field may reach a point where doctors can label and treat a tumor based on the genes that are mutated rather than the affected organ. Instead of "lung cancer," for example, they might call it "EGFR cancer," after the mutated gene driving tumor growth. Mutations in EGFRhave been found in multiple cancers, including lung, colon and breast.

This labeling is relevant, Wilson says, because today targeted therapies are approved based on the diseased organ or tissue. Herceptin®, for example, is essentially a breast cancer drug. But he has seen lung cancer patients with mutations in the same gene that Herceptin targets.

"For example, if genome sequencing revealed that a lung cancer patient has a mutation known to be sensitive to a drug that works in breast tumors with the same genetic alteration, you may want to use that agent in those lung cancer patients, ideally as part of a clinical trial," he says. "In the coming years, we hope to be treating cancer based more on the altered genetic make-up of the tumor than by the tissue of origin."

Lack of Oxygen in Cancer Cells Leads to Growth and Metastasis

— It seems as if a tumor deprived of oxygen would shrink. However, numerous studies have shown that tumor hypoxia, in which portions of the tumor have significantly low oxygen concentrations, is in fact linked with more aggressive tumor behavior and poorer prognosis. It's as if rather than succumbing to gently hypoxic conditions, the lack of oxygen commonly created as a tumor outgrows its blood supply signals a tumor to grow and metastasize in search of new oxygen sources -- for example, hypoxic bladder cancers are likely to metastasize to the lungs, which is frequently deadly.

A University of Colorado Cancer Center study recently published in the journal Cancer Research details a mechanism by which these hypoxic conditions create aggressive cancer, with possible treatment implications for cancers including breast, ovarian, colorectal, pancreatic, prostate, bladder and other cancers.

"We've known that the protein HIF-1a is overexpressed in hypoxic tumors. And we've known that the cancer stem cell marker CD24 is overexpressed in many tumors. This study shows a link between the two -- the HIF-1a of hypoxia creates the overexpression of CD24. And it's this CD24 that creates a tumor's aggressive characteristics of growth and metastasis," says Dan Theodorescu, MD, PhD, director of the University of Colorado Cancer Center and the paper's senior author.

Outgrowing the blood supply leads to tumor hypoxia, which leads to overexpression of HIF-1a, which signals the production of CD24, which makes tumors grow and metastasize. In addition to aggression, CD24 has also been shown to confer resistance to chemotherapy, allowing this small population of cells to regrow the tumor once chemotherapy ends, leading to relapse and disease progression.

"Now imagine we target CD24," Theodorescu says. "Either by removing a cell's ability to make CD24 or by killing cells marked by this protein, it's likely we could disarm this most dangerous population of cells."

Theodorescu and colleagues showed this by adjusting levels of HIF-1a and CD24 in cancer cell samples and animal models. With HIF-1a low and yet CD24 artificially high, cells retained the ability to grow and metastasize. With CD24 low and yet HIF-1a artificially high, cell survival and proliferation decreased.

"It seems CD24 overexpression in hypoxic cells drives growth and metastasis in these hypoxic tumors," Theodorescu says. "Now we have a rational target: CD24 for these hypoxic tumors."

Chemists Develop Nose-Like Array to 'Smell' Cancer

— In the fight against cancer, knowing the enemy's exact identity is crucial for diagnosis and treatment, especially in metastatic cancers, those that spread between organs and tissues. Now chemists led by Vincent Rotello at the University of Massachusetts Amherst have developed a rapid, sensitive way to detect microscopic levels of many different metastatic cell types in living tissue.

Findings appear in the current issue of the journal ACS Nano.

In a pre-clinical non-small-cell lung cancer metastasis model in mice developed by Frank Jirik and colleagues at the University of Calgary, Rotello's team at UMass Amherst use a sensor array system of gold nanoparticles and proteins to "smell" different cancer types in much the same way our noses identify and remember different odors. The new work builds on Rotello and colleagues' earlier development of a "chemical nose" array of nanoparticles and polymers able to differentiate between normal cells and cancerous ones.

Rotello explains, "With this tool, we can now actually detect and identify metastasized tumor cells in living animal tissue rapidly and effectively using the 'nose' strategy. We were the first group to use this approach in cells, which is relatively straightforward. Now we've done it in tissues and organs, which are very much more complex. With this advance, we're much closer to the promise of a general diagnostic test."

Until now the standard method for precisely identifying cancer cells used a biological receptor approach, a protein binding to a cancer cell wall. Its major drawback is that one must know the appropriate receptor beforehand. Rotello and colleagues' breakthrough is to use an array of gold nanoparticle sensors plus green fluorescent protein (GFP) that activates in response to patterns in the proteins found in cancer cells within minutes, assigning a unique signature to each cancer.

The chemist says, "Smell 'A' generates a pattern in the nose, a unique set of activated receptors, and these are different for every smell we encounter. Smell 'B' has a different pattern. Your brain will instantly recognize each, even if the only time you ever smelled it was 40 years ago. In the same way, we can tune or teach our nanoparticle array to recognize many healthy tissues, so it can immediately recognize something that's even a little bit 'off,' that is, very subtly different from normal. It's like a 'check engine' light, and assigns a different pattern to each 'wrong' tissue. The sensitivity is exquisite, and very powerful."

For this work, the researchers took healthy tissue and mouse tumor samples and trained the nanoparticle-GFP sensor array to recognize them and the GFP to fluoresce in the presence of metastatic tissue. Metastases are differentiated from healthy tissue in a matter of minutes, providing a rapid and very general means of detecting and identifying cancer and potentially other diseases using minimally invasive microbiopsies.

"It's sensitive to really subtle differences," says Rotello. "Even though two cheeses may look the same, our noses can tell a nicely ripe one from a cheese that's a few days past tasting good. In the same way, once we train the sensor array we can identify whether a tissue sample is healthy or not and what kind of cancer it is with very high accuracy. The sensitivity is impressive from a sample of only about 2,000 cells, a microbiopsy that's less invasive for patients."

In addition to the high sensitivity, the authors point out, their sensor is able to differentiate between low (parental) and high (bone, adrenal, and ovary) metastases, as well as between site-specific cells such as breast, liver, lung and prostate cancers.

"Overall, this array-based sensing strategy presents the prospect of unbiased phenotype screening of tissue states arising from genetic variations and differentiation state." Their next step will be to test the new sensor array method in human tissue samples, the researchers say.

Cancer - A Synonym of Death

Cancer is not a new dub for the people breathing in the 21st century. It is as recurrent as our day to day usual activities. Every year about a million of new cases of cancer are diagnosed throughout the world. Most people loose their lives because of cancer. Treatment are available but there is still no 100% surety of recovery from cancer. Cancer influences almost every organ of human body transfiguring it into ruins in later stages.
Truly speaking cancer is not a single disease, but a heterogeneous group of disorders that are characterized by the presence of cells that loose control on normal cell division. Cancer cells divide rapidly and continuously resulting in formation of tumours that eventually strike healthy tissues. These tumourous cells travel across healthy cells creating tumours in them. The most frequent cancers include cancers of breast, lung, prostrate, blood, colon, rectum, pancreas, liver etc.
Formation of Tumour
Basically normal cells grow, divide, mature and die in response to a complex set of internal and external signals. A normal cell receives both stimulatory as well as inhibitory signals which are responsible for its growth, division and maturation. In case of a cancer cell, these signals get disrupted, so the cell divides abnormally at a higher rate. After losing normal control, the cancer cell loose its normal shape and forms a distinct mass what we call a 'tumour'. If the cells of a tumour remain localized it is termed a 'benign tumour' but if the cells invade other tissues, the tumour is termed as 'malignant tumour'. Cells that travel to other sites of the body, they form secondary tumours and have undergone 'metastasis'.
Cancer- The Genetic Aspect
Cancer is the culmination of abnormal cell growth so needs attention both publicly as well as scientifically. A number of theories have been put forward regarding cancer but now researchers realize that most if not all cancers arise from the defects in DNA> Previous views recommend the genetic origin of cancer. Many agents like ionizing radiations, chemicals that we come across result in episode of mutations that cause cancer. Some cancers are often syndicated with chromosomal abnormalities, about 90% of people with chronic myeloid leukemia bear a reciprocal trans location between chromosome 22 and chromosome 9> These observations accord clues for the genetic origin of cancer. In 1971 Alfred Knudson proposed a model for defining the genetic basis of cancer. His model id designated as 'Knudson multistep model of cancer', he was studying retinoblastoma- a cancer that develops in only one eye but occasionally appears in both> Knudson's proposal highlights that cancer is a multistep process requiring several mutations, if one or more mutations are inherited additional mutations are also obligatory to disclose a cancer and the cancer will run in families. His model has been confirmed today.
Cancer starts when a single cell is encountered with mutation and results in its abnormal growth. This cell divides and forms a clone of cells each carrying same mutation. An additional mutation that occurs in any of the clone cells may further enhance adroitness of these cells to burgeon and cells with both mutations become dominant. In this process, depicted as clonal evolution, the tumour cells gain more mutations that allow them to become increasingly aggressive in their proliferate aspects. The rate of clonal evolution depends upon the frequency of occurrence of new mutations. The genes that regulate DNA repair have also been found to get mutated in progressive cancer stages and inherited disorders of DNA repair are usually depicted by intensified incidences of cancer. Normally DNA repair mechanisms eliminate many of the mutations but cells with defective DNA repair systems are more likely to remain mutated including the genes that regulate cell division. Many cells are aneuploid and hence accelerate cancer progression.
Are Environmental Factors Also Responsible For Cancer?
Smoking is a good paradigm of environmental factor confronted with cancer strongly. Other environmental factors incorporate certain types of chemicals such as benzene (industrial solvent), benzo [a] pyrene (cigarette smoke), polychlorinated biphenyls (transformers and capacitors). Ultraviolet light, ionizing radiations, viruses are other carcinogens associated with cancer. Most environmental factors cause somatic mutations that quicken cell division.
Genes Contributing Cancer
The signals that regulate cell division fall under two categories: molecules that speed up cell division and others that inhibit it. Because cell division is perturbed by these two factors, cancer can arise from mutations in any of these two factors. Mutations in stimulatory genes are usually dominant and are termed 'oncogenes'. Oncogenes were first identified cancer causing genes discovered by Peyton Rous in 1909. Michael Bishop, Harold Varmus and their colleagues in 1975 discovered that genomes of all normal cells carry DNA sequences that are closely related to viral oncogenes. These cellular genes are termed as protoncogenes. THey are blameworthy for basic cellular functions of normal cells but when mutated they become oncogenes and produce cancer. Many oncogenes have been pinpointed by experiments in which selectted fragments of DNA are added to cells in a culture.
Tumour suppressor genes are more difficultly discerned than oncogenes as they inhibit cancer and are reccessive in action. One of the first tumour suppressor gene to be spotted out was that of retinoblastoma in 1985 by Raymond White and Webster Cavenne.
Alteration In Stucture And Number Of Chromosome Also Cause Cancer
Most tumours possess mutations. It is now clear that mutations in chromosomes appear to be both cause and be a result of cancer. At least three kinds of chromosome rearrangements- deletions, inversions and trans locations may be associated with cancer. Deletions may result in loss of one or more tumour suppressor genes. Inversions and trans locations may result in disruption of functions tumour suppressor genes and generation of fused proteins that may stimulate symptoms of cancer. Fusion proteins are generally formed in myelogenous leukemia, a form of leukemia affecting bone marrow cells. A third process by which cancer may arise due to chromosomal rearrangement is by the transfer of a potential cancer causing gene to a new location where it is activated by regulatory sequences, Burkitt lymphoma is common example.
Viruses Also Cause Cancer
About 95% of the women with cervical cancer are infected with human papiloma viruses (HPVs). Similarly, infection with the virus that causes hepatitis B increases the risk of liver cancer. Epstein-Barr virus causes mononucleosis embracing Burkitt's lymphoma. There are only few retroviruses that cause cancer in humans. Other human cancers are associated with DNA viruses which like retroviruses integrate into the host chromosome but disparate retroviruses donot reverse transcription.
Changes In DNA Methylation Are Often Associated With Cancer
In many cancerous cells the ornamentation of DNA methylation are found to be altered. In some cases, the DNA of cancer cells is over methylated (hypermethylated) or undermethylated (hypomethylated). Hypermethylation is seen to contribute to cancer by silencing the expression of tumour suppressor genes. However, hypomethylation also contributes to cancer requires further research. The role of DNA methylation is interesting because unlike other genetic changes DNA methylation is reversible. These types of reversible genetic alterations are called epigenetic processes.
The treatment of cancer is accessible at present inclusive of chemotherapy, bone marrow transplantation, radiotherapy etc. but the question to be 100% free from cancer still preponderates.