New drug target for squamous cell carcinoma

ScienceDaily (May 19, 2011) — Researchers at Fred Hutchinson Cancer Research Center have discovered a -- the second most common form of skin cancer. Scientists in the laboratory of Valeri Vasioukhin, Ph.D., have found that a protein called alpha-catenin acts as a tumor suppressor and they also have unlocked the mechanism by which this protein controls cell proliferation.

See Also:Health & MedicineLung CancerBrain TumorOvarian CancerDiseases and ConditionsCancerSkin CancerReferenceTumor suppressor geneTumorHeat shock proteinMetastasis

The findings by Vasioukhin and colleagues will be published May 24 in Science Signaling.

For the study, the researchers studied mice that were bred to lack a copy of the gene that makes the protein alpha-catenin in hair follicle stem cells. The researchers found that these mice developed a type of skin cancer called squamous cell carcinoma.

"The fact that alpha-catenin-deficient mice developed skin cancer led us to conclude that the loss of this protein is an important event in cancer development, and that alpha-catenin functions as a tumor suppressor," said Vasioukhin, an associate member of the Hutchinson Center's Human Biology Division. "We also found that unlike normal cells, alpha-catenin-mutant cells cannot stop dividing when they become very crowded in the Petri dish -- this characteristic is one of the hallmarks of cancer cells."

The researchers also teased out the mechanisms by which the protein suppresses tumor growth. They found that alpha-catenin controls the activity of a protein called Yap1, which, if activated, can cause cancer.

"We found that alpha-catenin controls cell proliferation by regulating Yap1, which is active in cells missing alpha-catenin. Therefore, Yap1 is likely to be an excellent target for the treatment of patients with squamous cell carcinoma," Vasioukhin said.

More than 700,000 new cases of squamous cell carcinoma are diagnosed each year. This form of skin cancer arises in the cells that make up most of the skin's upper layers (epidermis). Squamous cell malignancies may arise in many areas of the body including the mucous membranes and genitals, but are most common in areas frequently exposed to the sun, such as the rim of the ear, lower lip, face, scalp, neck, hands, arms and legs.

The National Cancer Institute funded this research, which was also supported in part by a Chromosome and Metabolism and Cancer Training Grant from the National Institutes of Health. In addition to researchers in the Hutchinson Center's Human Biology Division, co-authors included investigators from Dermatopathology Northwest in Bellevue, Wash.; Harvard University; and the University of Pennsylvania Medical School.

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Possible new target for sarcoma treatment and prevention

ScienceDaily (May 23, 2011) — Researchers from Mount Sinai School of Medicine have discovered a protein signaling pathway that becomes hyperactivated in human sarcoma cells, suggesting that medications to inhibit this pathway may be effective in the treatment of human sarcomas. The research is published in the current issue of the journal Cancer Cell.

See Also:Health & MedicineStem CellsLymphomaBrain TumorCancerLeukemiaSkin CancerReferenceTumor suppressor geneTumorMetastasisHeat shock protein

A team of researchers led by Stuart Aaronson, MD, Jack and Jane B. Aron Professor and Chairman of the Department of Oncological Sciences at Mount Sinai School of Medicine, compared normal human mesenchymal stem cells to human sarcoma cells and found that the sarcoma cells displayed hyperactive signaling along the Wnt pathway -- a complex network of proteins that interact with each other in a highly ordered manner to regulate numerous biological functions of various species.

The hyperactive Wnt signaling increased the growth of several subtypes of human sarcoma cells by increasing the expression of CDC25A, a gene previously shown to be deregulated in various types of cancer. Increased protein levels of CDC25A enhances the rate of cell proliferation, and cancer cells often exhibit very high CDC25A protein levels compared to normal cells.

"The prevalence of Wnt signaling hyperactivity in human sarcoma cells gives researchers a potential new target as they develop medications to target human sarcoma," said Dr. Aaronson.

"Since several cancer types show increased CDC25A levels, it is regarded as a good target to generate therapeutic agents to dampen its functions and thus will be an important candidate in future drug development," said Sapna Vijayakumar, PhD, Instructor of Oncological Sciences, Mount Sinai School of Medicine, who was the first author of the study.

Normal Wnt functioning is critical for maintaining tissue homeostasis. Hyperactive (deregulated) Wnt signaling is reported to be one of the early causes of colon cancer, and it is also implicated in several other cancer types.

In many instances, hyperactive Wnt signaling increases the expression of certain genes that cause the cell to proliferate faster than normal. This uncontrolled proliferation, often accompanied by additional changes in gene or genes independent of Wnt signaling, can transform a normal cell into a cancerous one.

Sarcomas comprise about one percent of all adult cancers, but about 15 percent of all childhood cancers. There are many sarcoma "subtypes" that can arise from a variety of connective tissue structures, including nerves, muscles, joints, bone, fat, and blood vessels. The most frequent location for sarcomas are the limbs, where the majority of the body's connective tissue is located. About 20 percent of sarcomas are curable by surgery, while 30 percent can be cured by surgery with chemotherapy and/or radiation. About 12,000 new cases are diagnosed in the US each year and about 5,000 people die each year from sarcoma.

Sarcomas are subtyped based on where they occur in the body (in the bone, they are called osteosarcoma, in the smooth muscle they are leiomyosarcoma, in the cartilage they are chondrosarcoma, and so on). Studies suggest that even though sarcomas can occur in any part of the body, they commonly arise from the transformation of mesenchymal stem cells.

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Scientists find new drug target in breast cancer

ScienceDaily (May 22, 2011) — Researchers have identified a new protein involved in the development of drug resistance in breast cancer which could be a target for new treatments, they report May 22 in the journal Nature Medicine.

See Also:Health & MedicineBreast CancerCancerWomen's HealthLung CancerColon CancerProstate CancerReferenceBreast cancerBreast reconstructionHormone replacement therapyMetastasis

In a mouse model of breast cancer, blocking production of the protein using genetic techniques caused tumours to shrink. The scientists are now looking for new drugs which could achieve a similar effect.

Breast cancer is the most common cancer in the UK, affecting about 46,000 women each year. More than two thirds of breast tumours contain oestrogen receptors, meaning that they require the hormone oestrogen to grow and they can be treated with anti-oestrogen drugs such as tamoxifen. However, many patients develop resistance to these treatments so that the drugs eventually cease to be effective.

In the study, researchers from Imperial College London found that blocking a protein called LMTK3 in human cancer cells that were resistant to tamoxifen made the cells more responsive to the drug. In a mouse model of the disease, using genetic techniques to block the production of LMTK3 led to a significant decrease in the size of breast tumours.

The researchers also measured levels of LMTK3 in tissue samples taken from women with breast cancer. They found that women who had higher levels of LMTK3 in their tumours tended to live less long and were less likely to respond to hormone therapy. In addition, they found that particular mutations in the gene coding for LMTK3 also correlated with how long a patient would survive.

"Anti-oestrogen drugs have been very successful at allowing women with breast cancer to live longer, but resistance to these drugs is a common problem," said Professor Justin Stebbing, from the Department of Surgery and Cancer at Imperial College London, the study's senior author. "Our results suggest that the action of LMTK3 on the oestrogen receptor has a crucial role in the development of drug resistance.

"We're now looking for drugs that can block the effect of LMTK3, which we could hopefully give to patients to prevent them from becoming resistant to hormone therapy. It will probably take at least five to ten years to develop new treatments that are safe to be used in humans."

Evidence from the laboratory suggests that resistance to hormone therapy might occur when the oestrogen receptor is modified by enzymes called kinases. The team identified LMTK3 as a potential treatment target by screening for kinases that affect how cancer cells respond to oestrogen.

The researchers also compared DNA sequences in the gene coding for LMTK3 in humans and chimpanzees, because chimpanzees are not susceptible to oestrogen receptor positive breast cancer. They found that substantial differences have evolved in these sequences between the two species.

"It's quite intriguing that humans and chimps have evolved these differences in the LMTK3 gene, since related genes are very similar between the two species," said Dr Georgios Giamas, who designed and led the study, from the Department of Surgery and Cancer at Imperial College London.

"We could speculate that evolutionary changes in this gene might have given humans some unknown advantage, but also have made us more susceptible to breast cancer."

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