Reducing N-Cadherin Increases Survival in Mouse Model of Pancreatic Cancer

Reduction in the activity of a key membrane adhesive protein causes pancreatic cancer cells to lose the ability to metastasize and spread tumors to other sites within the body.

Pancreatic ductal adenocarcinma (PDA) does not typically produce symptoms until after it has metastasized. Late detection leads to a high mortality rate with a five-year survival rate of less than 5%.

Investigators at Thomas Jefferson University (Philadelphia, PA, USA) worked with lines of genetically engineered mice to determine whether modifying PDA cell surface proteins could block the ability of the cancer to spread.

They reported in the December 12, 2011, online edition of the journal Oncogene that mice with reduced N-cadherin expression survived 25% longer than animals expressing two wild-type N-cadherin (Cdh2) alleles.

Cadherins are members of a family of calcium-dependent cell adhesion proteins that preferentially interact in a homophilic manner in cell-cell interactions. They are type I membrane proteins that contribute to the sorting of heterogeneous cell types. The names of different classes indicate the tissues in which they were first found: E-cadherin is present on many types of epithelial cells; N-cadherin is present on nerve, muscle, and lens cells; and P-cadherin is present on placental and epidermal cells. Typically, cadherins have five similar extracellular domains, the outermost three of which have Ca2+-binding sites, and an intracellular C-terminal domain that interacts with the actin cytoskeleton.

“Previous studies demonstrated the importance of this cell surface protein for tumor cell growth,” said senior author Dr. Glenn Radice, associate professor of medicine at Thomas Jefferson University. “However, it was not clear from those studies whether interfering with N-cadherin levels would increase survival of animals genetically engineered to develop highly metastatic pancreatic cancer. Our survival results are very exciting because a drug, known as ADH-1that specifically targets N-cadherin is already in clinical trial for melanoma. The next step is to test this N-cadherin-function blocking drug or a similar compound in the pancreatic cancer mouse model to see if it can prolong survival.”

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