ADAM10 Proteases and Pancreatic Cancer.
Pancreatic ductal adenocarcinoma is the 4th leading cause of cancer-related
deaths in the United States and is expected to rise to the second rank by 2020.
The survival rate of PDAC is estimated at less than 5% and the high mortality rate is
attributed to the asymptomatic progression and aggressive nature of the tumor, which
exhibit locally advanced or
metastatic disease at the time of diagnosis.
The nucleoside analog Gemcitabine is the standard therapy used for treatment of
PDAC but it shows only marginal therapeutic benefit. The limited accessibility of the drugs
to the tumors is one of the major issues with PDAC, given the dense,
highly fibrotic nature of the stroma. Tumor stroma comprises of Extracellular
matrix proteins, growth factors
such as fibronectin and collagen, stromal fibroblasts, stellate cells, immune cells, and blood vessels.
The strong desmoplastic tumor stroma inhibits transvascular transport of drugs to the
tumors, and therefore the tumors continue to grow and metastasize. Though the
newly developed
combinatorial therapies such as Nab-Paclitaxel and
FOLFIRINOX have shown significant
improvement in survival in patients with metastatic cancer,
they are associated with severe toxicity issues, and therefore
additional strategies are being
developed to effectively treat PDAC.
Several transmembrane proteins that are involved in cell adhesion are cleaved by
matrix degrading enzymes like matrix metalloproteinases,
allowing detachment, migration and metastasis of
cancer cells.
Among the proteases, A Disintegrin And Metalloprotease family member
ADAM10 has recently gained considerable attention for its role in tumor
progression and metastasis.
Pancreas Open J. 2016; 1(2): e8-e10. doi: 10.17140/POJ-1-e003
