Enzyme Identified That Promotes Aggressive Forms of Pancreatic Cancer

Cancer researchers have identified an enzyme that seems to cause pancreatic tumors to act in a much more aggressive – and therefore lethal – fashion.

Pancreatic cancer is not uniformly aggressive, and some patients have a relatively better outcome. Why this should be, has been the subject of research carried out at the Mayo Clinic (Jacksonville, FL, USA). The investigators were particularly interested in understanding why pancreatic cancer cells produce matrix metalloproteinases (MMPs), since most MMPs are made by cells that surround and support a tumor, not by the tumor itself. Enzymes of the MMP family are involved in the breakdown of extracellular matrix and during tissue remodeling in normal physiological processes such as embryonic development and reproduction, as well as in disease processes such as arthritis and tumor metastasis.

The investigators reported in the May 21, 2014, online edition of the journal Molecular Cancer Research that matrix metalloproteinase-3 (MMP3) was found to be associated with the expression of the enzyme Rac1b, a tumorigenic splice isoform of Rac1, in all stages of pancreatic cancer.

Rac1, also known as Ras-related C3 botulinum toxin substrate 1, is a protein encoded by the RAC1 gene. This gene can produce a variety of alternatively spliced versions of the Rac1 protein, which appear to carry out different functions. Rac1 is thought to play a significant role in the development of various cancers, including melanoma and non-small-cell lung cancer. As a result, it is now considered a therapeutic target for these diseases. Rac1 is a small (approximately 21 kDa) signaling G-protein (more specifically a GTPase), and is a regulator of many cellular processes, including the cell cycle, cell-cell adhesion, motility (through the actin network), and of epithelial differentiation (proposed to be necessary for maintaining epidermal stem cells).

The investigators used a large cohort of human pancreatic cancer tissue biopsy specimens to determine that both MMP3 and Rac1b were expressed in pancreatic cancer cells, that the expression levels of the two markers were highly correlated and that the subcellular distribution of Rac1b in pancreatic cancer was significantly associated with patient outcome.

Co-expression of MMP3 with activated KRAS in pancreatic acinar cells was found to stimulate cancer cell formation and immune cell infiltration in transgenic mouse models, thus priming the stromal microenvironment for early tumor development. Furthermore, exposure of cultured pancreatic cancer cells to recombinant MMP3 stimulated expression of Rac1b, increased cellular invasiveness, and activated tumorigenic transcriptional profiles.

“The implication from our research is that Rac1b is activating unique pathways in pancreatic tumors that make this cancer aggressive. If we can therapeutically target that pathway, we may be able to have an impact on this very difficult-to-treat disease,” said senior author Dr. Derek Radisky, a Mayo Clinic researcher.

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