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News From The Journal Of Clinical Investigation: Aug. 1, 2012

ONCOLOGY
Chemokine pathway suppresses

Chemokines are signals in the body that act as beacons, calling out to migrating cells, such as white blood cells, guiding them to where they are needed. One chemokine in particular, chemokine 25 (CCL25), binds to chemokine Receptor 9 (CCR9), forming a signaling pathway that is important in the small intestine and colon, where it regulates immune response and decreases cell death. Drs. Steven Lipkin, Xiling Shen, and colleagues at Cornell University have discovered that the CCL25-CCR9 pathway also has an unexpected role – inhibiting colon metastasis and invasion. They found that CCR9 was highly abundant in early stage colon derived from human cancer but surprisingly lacking in invasive and , suggesting a role for this receptor in reducing the spread of colon cancer. By blocking this pathway in early stage , they showed that tumor formation within the small intestine/colon of mice was inhibited, but metastasis and invasion were increased. Furthermore, they found that activation of a second pathway called NOTCH, known to stimulate metastasis and invasion, promotes the degradation of CCR9, thus inhibiting the actions of its binding partner CCL25. This discovery sheds light on how colon cancer progresses and metastasizes.

TITLE: Chemokine 25-induced signaling suppresses colon cancer invasion and metastasis

http://www.jci.org/articles/view/62110?key=ec3038b0ac205857d679

ENDOCRINOLOGY
retooled to combat excess hormone production

In acromegaly, excess production of triggers aberrant growth of body tissues . Researchers at the University of Geneva in Switzerland sought to develop new therapeutic approaches for treating acromegaly. Led by Dr. Emmanuel Somm, the team modified a Botulinum neurotoxin to specifically target pituitary somatotroph cells that secrete . When given to rats, the recombinant protein reduced synthesis and secretion. Reflecting this change, the body weight gain, body length, organ weight, and bone mass acquisition were all decreased in treated animals. These results provide promising preclinical data to support that engineered Botulinum neurotoxin to can be retargeted to non-neural cells to selectively inhibit hormone secretion.

TITLE: A botulinum toxin-derived targeted secretion inhibitor downregulates the GH/IGF1 axis

http://www.jci.org/articles/view/63232?key=2524aed3b01dc0c147b8

IMMUNOLOGY
Gene deficiency increases risk for human papillomavirus infection

Epidermodysplasia verruciformis (EV) is a rare skin disorder caused by an increased susceptibility to a specific group of related human papillomaviruses. The majority of cases of this congenital disorder are associated with mutations either the gene EVER1 or EVER2. However, the underlying cause in the remaining patients is unclear. Dr. Emmanuelle Jouanguy and researchers at INSERM in Paris now report on two patients with an immune deficiency and various infectious diseases, including persistent EV-associated human papillomavirus infections. The Jouanguy team found that the patients both had loss-of-function of the RHOH gene, which encodes an atypical Rho GTPase that is primarily expressed in developing blood and immune cells. The patients lacked specific populations of T cells, and those T cell present had impaired T cell receptor signaling. The team went on to model the same genetic mutation in mice, which had similar T cell defects. Their findings uncover a new genetic risk factor for T cell deficiency and persistent EV-associated human papillomavirus infections in patients.

TITLE: Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections

http://www.jci.org/articles/view/62949?key=e8f5d52df7d9367c509f

ONCOLOGY
Micromanagement impacts cancer spread: miR34-a in cancer metastasis

Once a cancer has spread to other sites in the body, this aggressive, metastatic cancer is extremely refractory to most treatment options. Dr. Jonathan Kurie and coworkers at M.D. Anderson Cancer Center in Houston, Texas wanted to better understand the molecular pathways that underlie metastasis. They examined a known promoter of metastasis, a gene transcription factor known as ZEB1 that regulates the expression of multiple regulatory microRNAs. The team specifically studied which microRNAs regulated by ZEB1 contributed to its metastasis-promoting functions. They found that a major target of ZEB1 is microRNA-34a (miR34-a). Forced expression of miR-34a decreased tumor cell invasion and metastasis in mice, and expression patterns of miR-34a in human lung adenocarcinomas predicted clinical outcome. Their results suggest that pharmaceuticals targeting miR-34a may merit exploration as a therapeutic agent in lung cancer patients.

TITLE: ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression

http://www.jci.org/articles/view/63608?key=2741a2e21930025f7a44

Source

Journal of Clinical Investigation