Public release date: 10-Jan-2011 [ | E-mail | Share ] Contact: Karen Journal of Clinical Investigation

EDITOR’S PICK Cancer cell survival is not miR-ly dependent on p53

Squamous cell carcinoma (SCC) is a common type of skin cancer and remains one of the most resistant to available chemotherapies. many cancer therapeutic strategies are directed at restoring the function of the tumor suppressor gene p53, because when active, cells are more sensitive to the DNA damage induced by chemotherapy. other proteins related to p53, including p63 and p73, have also been implicated in cancer and cell sensitivity to chemotherapy. Both p63 and p73 are overexpressed in SCC, and are thought to play a role in chemoresistance. in new research, Leif Ellisen and colleagues at Mass General Hospital in Boston investigated the relationship between p63 and p73 in human and mouse SCC cells. They found that p63 negatively regulates the expression of a number of microRNAs (miRs), and that some of these miRs target p73 for inhibition. one of these, dubbed miR-193a, was also positively regulated by p73, suggesting a feedback loop that might promote chemoresistance in these cells. in a mouse model of SCC, the researchers found that inhibiting miR-193a decreased tumor growth and made the cells more sensitive to the chemotherapeutic agent cisplatin. The researchers believe that these findings identify a pro-survival mechanism in SCC, and may highlight new therapeutic targets in the fight against cancer.

TITLE: a microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma

AUTHOR CONTACT: Leif Ellisen Massachusetts General Hospital Cancer Center, Boston, MA, USA Phone: (617)726-4315; Fax: (617)726-8623; E-mail: harvard.edu

View this article at: jci.org/articles/view/43897?key=34ca4a64f929de6d5fea

EDITOR’S PICK Transforming skin cells into cartilage

Hyaline cartilage, composed primarily of chondrocytes in an extensive extracellular matrix, makes up the embryonic skeleton and persists in adults at the ends of bones, where it provides shock absorption and lubrication of joints. Hyaline cartilage injury often results in the formation of the scar tissue fibrocartilage or even new bone formation leading to growth impairment or osteoarthritis. however, regeneration of cartilage might be possible if researchers can develop a method to generate new chondrocytes. in this paper, Noriyuki Tsumaki and his team at the Osaka University Graduate School of Medicine, used fibroblasts isolated from adult mouse skin, and expressed proteins that have previously been used to induce pluripotency along with a factor that promotes a chondrocyte fate. This produced cells with traits that resembled chondrocytes and produced cartilage when injected into mice. The researchers believe this may be an important step toward a therapy that will allow the repair of cartilage injury using a patient’s own skin cells.

TITLE: Generation of hyaline cartilaginous tissue from mouse adult dermal fibroblast culture by defined factors

AUTHOR CONTACT: Noriyuki Tsumaki Osaka University Graduate School of Medicine, Suita, UNK, JPN Phone: +81-6-6879-3552; Fax: +81-6-6879-3559; E-mail: osaka-u.ac.jp

View this article at: jci.org/articles/view/44605?key=631d5aff983c237cf1dc

METABOLISM Glucose homeostasis: the collagen connection

Collagen is the major component of connective tissue, and is made up of three peptide chains (subunits) twisted together to generate fibers with strength and flexibility. Collagen V usually consists of α1(V)2α2(V) subunits, but also occurs in some tissues such as white adipose, pancreatic islets, and skeletal muscle as the poorly characterized α1(V) α2(V) α3(V) heterotrimer. in this paper, Daniel Greenspan and colleagues at the University of Wisconsin, Madison, generated mice that lacked the gene that codes for α3(V). These mice had reduced dermal fat but developed diabetes-like symptoms, exhibiting glucose intolerance, decreased numbers of pancreatic islets, hyperglycemia, and insulin resistance. The authors believe that these results show that collagen and connective tissue are critical in the proper function of cells that control metabolism, including pancreatic islets, fat cells, and skeletal muscle.

TITLE: α3(V) Collagen is critical for glucose homeostasis in mice due to effects in pancreatic islets and peripheral tissues

AUTHOR CONTACT: Daniel Greenspan University of Wisconsin, Madison, WI, USA Phone: 608 262-4676; Fax: 608 262-6691; E-mail:

View this article at: jci.org/articles/view/45096?key=e03bb108c3b2db4ece1d

ONCOLOGY a new method for detecting cancer cells

Detecting and quantifying the cancer cells that remain after treatment or that have migrated to new malignant sites is a powerful predictor of patient survival. however, there are few diagnostic strategies that allow the identification of small numbers of these cancer cells, particularly in patients with solid tumors. in this paper, Axel Weber, Holger Christiansen and colleagues at the Children’s Hospital in Lepzig, Germany, addressed this problem by taking advantage of the unique molecular signatures within the cancer cells: characteristic duplications of genomic regions called amplicons. The group used Human neuroblastoma cells with a known amplification of the MYCN locus, and developed a strategy to identify those amplicons in cancer cells within a mixed population. They have thus developed a tool that might be adapted to other cancers to specifically and sensitively detect tumor cells remnant in the bone marrow, blood, or other sites after treatment.

TITLE: Detection of human tumor cells by amplicon fusion site polymerase chain reaction (AFS-PCR)

AUTHOR CONTACT: Axel Weber Children?s Hospital, University of Leipzig, Leipzig, , DEU Phone: 0049 163 3793237; Fax: ; E-mail: -leipzig.de

View this article at: jci.org/articles/view/44415?key=125ee2993c1c124f1e48

STEM CELLS Turning unfertilized eggs into stem cells

It is hoped that individuals with inherited disorders such as β-thalassemia, which is caused by mutations in the beta-globin gene, might one day be cured by gene therapy and/or stem cell?based therapeutics. however, there are many obstacles preventing routine clincal use of such approaches. in this paper, John McLaughlin and his team at the Nationwide Children’s Hospital in Columbus, OH have shown that they can overcome some of these hurdles and treat mice with β-thalassemia caused by dominant inheritance of disease-causing mutations. They harvested unfertilized oocytes from affected female mice and used them to generate diploid uniparental zygotes, then alloweded them to develop to the blastocyst stage and derived ES cell lines. Selection of ES cell lines lacking the disease allele provided a source of genetically corrected autologous stem cells that had not been genetically manipulated. These ES cell lines were differentiated in vitro into hematopoietic progenitor/stem cells, which were transplanted into mice with dominantly inherited β-thalassemia, leading to long-term reversion of the disease phenotype. The authors therefore suggest that their genetic correction strategy could potentially be applicable to any dominantly inherited disease. however, several obstacles to clinical use remain that are problematic for all human ES cells, including developing ways to efficiently differentiate the cells into transplantable tissue.

TITLE: Gene therapy by allele selection in a mouse model for beta-thalassemia

AUTHOR CONTACT: John McLaughlin Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA Phone: 614 355 3639; Fax: ; E-mail:

View this article at: jci.org/articles/view/45377?key=5b3c6bee1d4d99ebb498

HEPATOLOGY Waste removal by the liver protects the kidney

in every tissue in the body, homeostasis requires constant breakdown of large biological molecules, and this breakdown process can generate toxic waste products. Waste can be cleared by specialized liver cells called liver sinusoidal endothelial cells (LSECs) that express receptors on their surface to specifically bind to circulating factors and mediate their endocytosis. two of these LSEC receptors, Stabilin-1 and Stabilin-2, have been shown to bind to a number of ligands, but their exact function remains unknown.

In this paper, Cyrill G?raud and his team at the University Medical Center in Mannheim, Germany investigated the roles and functions of Stabilin 1 and 2 by genetically engineering mice that lacked these genes. Mice lacking either one of the genes were normal, but mice lacking both Stabilin 1 and 2 developed kidney dysfunction and liver fibrosis and died prematurely. These findings suggest that Stabilin 1 and 2 are required for normal clearance of one or more circulating factors and the maintenance of tissue homeostasis.

TITLE: Deficiency of liver sinusoidal scavenger receptors stabilin-1 and -2 in mice causes glomerulofibrotic nephropathy via impaired hepatic clearance of noxious blood factors

AUTHOR CONTACT: Cyrill G?raud Department of Dermatology, Venereology and Allergology, University Medical, Mannheim, UNK, DEU Phone: 00496213832048; Fax: ; E-mail:

View this article at: jci.org/articles/view/44740?key=a71e78d65959c8a8bbf3

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Dec 16, 2008 Scott Rupp

Stethoscope and medical form – istock photoA new drug may be effective in fighting bone cancers; however, it needs more study, and eventually, approval from the FDA.

Oregon Health & Science University in Portland announced in December 2008 the results of a study that indicate an experimental drug called CYT387 blocks an enzyme that causes bone marrow cancers. The tests were conducted in mice and human cells.

Researchers from the university reported that they found that CYT387 was very effective against a specific type of cancer cell driven by an enzyme mutation called JAK2-V617F. The drug binds to the V617F mutation in the JAK2 enzyme.

In the mouse model, the drug blocked JAK2-V617F, normalized blood counts and reduced enlarged spleens back to a normal size.

There is a very good chance that the drug will enter clinical trials as early as 2009, said investigator Dr. Michael Deininger.

What is Bone Cancer?

According to Jason C. Eck, DO, MS of MedicineNet.com, bone cancer is caused by a problem with the cells that make bone. The most common bone tumors include osteosarcoma, Ewing’s sarcoma, chondrosarcoma, malignant fibrous histiocytoma, fibrosarcoma, and chordoma.

Osteosarcoma is the most common primary malignant bone cancer. It most commonly affects males between 10 and 25-years-old. It often occurs in the long bones of the arms and legs at areas of rapid growth around the knees and shoulders of children. This type of cancer is often very aggressive with risk of spread to the lungs. The five-year survival rate is about 65 percent.

Ewing’s sarcoma is the most aggressive bone tumor and affects younger people between 4 to 15-years of age. It is more common in males and is very rare in people over 30 years old. It most commonly occurs in the middle of the long bones of the arms and legs. The three-year survival rate is about 65 percent, but this rate is much lower if there has been spread to the lungs or other tissues of the body.

Chondrosarcoma is the second most common bone tumor and accounts for about 25 percent of all malignant bone tumors. These tumors arise from the cartilage cells and can either be very aggressive or relatively slow-growing. unlike many other bone tumors, chondrosarcoma is most common in people over 40 years old. Chondrosarcoma most commonly affects the bones of the pelvis and hips. The five-year survival for the aggressive form is about 30 percent, but the survival rate for slow-growing tumors is 90 percent.

Malignant fibrous histiocytoma (MFH) affects the soft tissues including muscle, ligaments, tendons, and fat. It is the most common soft-tissue malignancy in later adult life, usually occurring in people 50-60 years of age. It most commonly affects the extremities and is about twice as common in males as females. MFH also has a wide range of severity. The overall five-year survival rate is about 35 to 65 percent.

Fibrosarcoma is much more rare than the other bone tumors. It is most common in people 35 to 55-years of age. It most commonly affects the soft tissues of the leg behind the knee. It is slightly more common in males than females.

Chordoma is a very rare tumor with an average survival of about six years after diagnosis. It occurs in adults over 30 years of age and is about twice as common in males as females. It most commonly affects either the lower or upper end of the spinal column.

According to Healthline.com, bone marrow is “the tissue that makes blood cells. It is found in the hollow part of most bones.”

What are the Symptoms of Bone Cancer?

Eck says the most common symptom of bone tumors is pain.

“in most cases, the symptoms become more severe with time,” Eck wrote. “Initially, the pain may only be present either at night or with activity and depending on the growth of the tumor, those affected may have symptoms for weeks, months, or years before seeking medical advice.”

In some cases, a mass or lump may be felt either on the bone or in the tissues surrounding the bone. Bones can become weakened by the tumor and lead to a fracture after little or no trauma or just from standing on the affected bone.

• Stethoscope and medical form – istock photo

LONDON – Chemicals in cannabis have been found to stop prostate cancer cells from growing in the laboratory, suggesting that cannabis-based medicines could one day help fight the disease, scientists said Wednesday.

After working initially with human cancer cell lines, Ines Diaz-Laviada and colleagues from the University of Alcala in Madrid also tested one compound on mice and discovered it produced a significant reduction in tumor growth.

Their research, published in the British Journal of Cancer, underlines the growing interest in the medical use of active chemicals called cannabinoids, which are found in marijuana.

Experts, however, stressed that the research was still exploratory and many more years of testing would be needed to work out how to apply the findings to the treatment of cancer in humans.

"this is interesting research which opens a new avenue to explore potential drug targets but it is at a very early stage," said Lesley Walker, director of cancer information at Cancer Research UK, which owns the journal.

"It absolutely isn’t the case that men might be able to fight prostate cancer by smoking cannabis," she added

The cannabinoids tested by the Spanish team are thought to work against prostate cancer because they block a receptor, or molecular doorway, on the surface of tumour cells. this stops them from dividing.

In effect, the cancer cell receptors can recognize and "talk to" chemicals found in cannabis, said Diaz-Laviada.

"these chemicals can stop the division and growth of prostate cancer cells and could become a target for new research into potential drugs to treat prostate cancer," she said.

Her team’s work with two cannabinoids — called methanandamide and JWH-015 — is the first demonstration that such cannabis chemicals prevent cancer cells from multiplying.

Some drug companies are already exploring the possibilities of cannabinoids in cancer, including British-based cannabis medicine specialist GW Pharmaceuticals.

It is collaborating with Japan’s Otsuka on early-stage research into using cannabis extracts to tackle prostate cancer — the most commonly diagnosed cancer in men — as well as breast and brain cancer.

GW has already developed an under-the-tongue spray called Sativex for the relief of some of the symptoms of multiple sclerosis, which it plans to market in Europe with Bayer and Almirall.

Other attempts to exploit the cannibinoid system have met with mixed success. Sanofi-Aventis was forced to withdraw its weight-loss drug Acomplia from the market last year because of links to mental disorders.

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