Chronic inflammation is known to be a cancer promoter. Patients with pancreatitis, either chronic or hereditary, have a higher risk of developing pancreatic cancer in their lifetime than the rest of the population. Recently, a seminal paper suggested that mast cells (immune cells that mediate inflammatory and allergic responses), may be the link between inflammation and the development of some forms of pancreatic cancer (Soucek 2007). This study provides strong evidence that mast cells are essential for the initiation and promotion of pancreatic cancer through their ability to promote angiogenesis. This key study, in addition to earlier data, has resulted in a plausible model connecting inflammation with tumor formation and metastasis: Pancreatic cancer cells secrete CCL2, a chemokine that attracts mast cells to the pancreas. Once there, mast cells degranulate releasing growth and angiogenic factors that are thought to induce tumorigenesis and promote tumor growth and metastases. While this study validates inhibitors of mast cells as potential chemopreventatives of pancreatic cancer, there are no effective clinically available mast cell inhibitors. Thus the discovery of novel inhibitors of mast cell migration or degranulation could provide novel therapeutics for the prevention and treatment of pancreatic cancer. The overall objective of the proposed research project is to identify bioactive marine natural products that inhibit mast cell migration and degranulation as potential novel chemo- preventatives of pancreatic cancer.
The Specific Aims of the proposed research are to: 1)assay materials (pure compounds and peak library materials) from the HBOI marine specimen collection to identify those with the ability to decrease levels of the chemokine CCL2 secreted by Panc-1 cells;2)to assay materials (pure compounds and peak library materials) from the HBOI marine specimen collection to identify those with the ability to inhibit mast cell degranulation;and to 3) validate hits found through the screening assays by functional angiogenesis and migration in vitro assays. The approach for aim 1 is to use an ELISA to measure the secretion of CCL2 by Panc-1 pancreatic adenocarcinoma cells in the presence or absence of marine-derived materials. Those materials that reduce CCL2 secretion by 50% or more will be considered hits and will be validated through a migration assay. Since CCL2 attracts mast cells, materials identified in the ELISA should reduce the migration of mast cells (Aim 3).
For aim 2, mast cells will be cultured in the presence or absence of marine-derived materials to determine the ability of the materials to inhibit mast cell degranulation. Those materials that reduce 50% or more degranulation, will be validated by assessing their ability to reduce angiogenesis in vitro (Aim3). This research is expected to identify novel inhibitors of mast cell migration and degranulation useful in both preventing the formation of new pancreatic tumors and the metastasis of tumors already present facilitated by the microenvironment elicited by inflammation.
This project will identify bioactive marine natural products that inhibit mast cell migration and degranulation as potential novel chemo-preventatives of pancreatic cancer.
