Research Scientist II
Digestive Disease Research Center (DDRC)
1901 S 1st Street
Temple, Texas 76504
Education and Post-Graduate Training
- PhD, 2010, Texas A&M University Health Sciences College
- BS, Biology, 1990, Sul Ross State University
The focus of my research involves the interplay between histamine, bile acids, cholangiocytes (cells lining the bile ducts) and mast cells during models of regeneration and diseased states like cholangiocarcinoma (biliary cancer) and pancreatic cancer. It is has been shown that bile acids are able to regulate mast cell mediator release including the release of histamine. Further, it is known that mast cells numbers increase during hepatic pathologies including cirrhosis and cancer. We have shown that histamine and the histamine receptors play a critical role in the regulation of both hyperplastic and neoplastic transformation of cholangiocytes.
Specifically, my research projects include:
This project will investigate the role of cholangiocytes (cells that line the bile ducts) during liver regeneration after maneuvers like partial hepatectomy, resection and liver transplantation. The liver is the only organ that is capable of replicating after injury. With as little as 25% of the liver intact, cell types like hepatocytes and cholangiocytes begin to replicate and proliferate replenishing the biliary tree and liver. Along with cellular proliferation, there is an increase in demand for nutrients that is supplied by the peribiliary plexus. This anatomical structure plays a key role in the rebuilding of the liver by releasing factors like vascular endothelial growth factor (VEGF). Preliminary data suggests that the histamine receptors may play a key role in the regeneration of the liver and that activation of these receptors can accelerate or decelerate the regrowth of the biliary tree. To further investigate this, I will examine the effects of anti-histamine treatment on liver regeneration after partial hepatectomy or resection along with evaluation of the signaling pathways that may be involved in this process. Mast cells have been shown to play a detrimental role in liver regeneration by increasing the inflammatory environment and treatment with specific bile acids may decrease unwanted mediator (namely histamine) release after injury.
Cholangiocarcinoma and Pancreatic cancer
Here I will focus on the role of blocking the enzyme responsible for histamine metabolism, histidine decarboxylase. Histamine has been found to have a trophic effect on cholangiocarcinoma growth via increasing VEGF expressing thus supporting an angiogenic environment. Along with blocking HDC, the histamine receptors have also been found to have an impact on cholangiocarcinoma growth and development.
Another aspect that I will investigate is the role of the specific H4 histamine receptor agonist, clobenpropit, on cholangiocarcinoma growth and more importantly, metastatic potential. Preliminary data shows that this receptor, when activated, is able to inhibit growth and invasion potential in cholangiocarcinoma cells in vitro. Further, this agonist plays a key role in epithelial to mesenchymal transition (EMT) whereby a virtually normal cell begins to take on more mesenchymal traits expressing pro-carcinogenic factors. EMT also involves breakdown of the extracellular matrix allowing tumorigenic cells to spread into other organs. Clobenpropit appears to be able to inhibit these processes and may be an excellent candidate for therapy for this devastating disease.
Using a similar approach to the studies involving cholangiocarcinoma, this project will focus on the mechanisms of pancreatic cancer. Specifically, I plan to investigate the effects of histamine, histamine receptors and histamine synthesis on pancreatic cancer growth. Like cholangiocarcinoma, pancreatic carcinoma is difficult to diagnose and survival rates are dramatically low. The pancreatic duct is in extremely close proximity to the common bile duct making this cancer difficult to find and treat.
Vitamin D intake has been shown to decrease pancreatic tumor growth although the mechanisms behind this are unclear. Another area of my research will investigate the mechanisms underlying Vitamin D regulation of both pancreatic and cholangiocarcinoma growth. The enzyme that is responsible for Vitamin D synthesis has been found to be upregulated in lung cancer and may play a role in blocking the protective effect of Vitamin D during carcinogenesis. We will evaluate the expression and role of this enzyme and others related to Vitamin D production in cell cultures, animal models and human tumor samples.
The role of bile acids and mast cells will also be evaluated in cholangiocarcinoma and pancreatic carcinoma regulation. It is likely that mast cells are activated during both of these diseases releasing unwanted components into the tumor microenvironment. Treatment with bile acids that are able to decrease mast cell mediator release may also aide in decreasing the growth of these cancers.
1. Francis H and Meininger CJ A review of mast cells and liver disease: What have we learned? Dig Liver Dis. 2010 Apr 2 [Epub ahead of print]
2. Francis H, Onori P, Gaudio E, Franchitto A, DeMorrow S, Venter J, Kopriva S, Carpino G, Mancinelli R, White M, Meng F, Vetuschi A, Sferra R, Alpini G. H3 histamine receptor-mediated activation of protein kinase Calpha inhibits the growth of cholangiocarcinoma in vitro and in vivo. Mol Cancer Res . 2009 Oct;7(10):1704-13. Epub 2009 Oct 13
3. R Mancinelli, P Onori, E Gaudio, A Franchitto, G Carpino, Y Ueno, D Alvaro, LP Annarale, S DeMorrow and H Francis. Taurocholate feeding to bile duct ligated rats prevents caffeic-acid –induced bile duct damage by changes in cholangiocyte VEGF expression. Exp Biol Med (Maywood). 2009 Apr;234(4):462-74. Epub 2009 Feb 20.
4. H Francis, S Glaser, S DeMorrow, J Venter, Y Ueno, M Marzioni, S Vaculin, B Vaculin, and G Alpini. Small murine cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP 3 /CAMK I/CREB pathway. Am J Physiol 295:C499-C513, 2008.
5. P Onori, S DeMorrow, E Gaudio, A Franchitto, R Mancinelli, J Venter, S Kopriva, Y Ueno, D Alvaro, J Savage, G Alpini and H Francis. Caffeic acid phenethyl ester decreases cholangiocarcinoma growth by inhibition of NF-kappaB and induction of apoptosis. Int J Cancer. 2009 Jan 21.
6. S DeMorrow, H Francis, E Gaudio, Y Ueno, J Venter, P Onori, A Franchitto, B Vaculin, S Vaculin, and G Alpini. Anandamide inhibits cholangiocyte hyperplastic proliferation via activation of thioredoxin 1/redox factor 1 and AP-1 activation. Am J Physiol, 294:G506-519, 2008.
7. H Francis, G LeSage, S DeMorrow, D Alvaro, Y Ueno, J Venter, S Glaser, MG Mancino, L Marucci, A Benedetti, and G Alpini. The a-2 adrenergic receptor agonist, UK 14,304, inhibits secretin-stimulated ductal secretion by impairing activation of the cAMP system. Am J Physiol Cell Physiol 293:C1252-62, 2007.
8. H Francis, A Franchitto, Y Ueno, S Glaser, S DeMorrow, E Gaudio, D Alvaro, G Fava, M Marzioni, J Venter, BT Vaculin, and G Alpini. H3 histamine receptor agonist inhibits cholangiocyte growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2 /ELK-1 pathway. Lab Invest 87: 473-87, 2007.
9. M Marzioni , H Francis, A Benedetti, Y Ueno, G Fava, J Venter, R Reichenbach, G Alpini, and Glaser. Ca 2+ -dependent cytoprotective effects of urso- and tauroursodeoxycholic acid on the biliary epithelium in a rat model of cholestasis and loss of bile ducts. Am J Pathol 168:398-409, 2006.
10. H Francis, S Glaser, Y Ueno, G LeSage, L Marucci, A Benedetti, S Taffetani, M Marzioni, D Alvaro, J Venter, R Reichenbach, G Fava, J L Phinizy, and G Alpini. cAMP stimulates the secretory and proliferative capacity of the rat intrahepatic biliary epithelium through changes in the PKA/Src/MEK/ERK1/2 pathway. J Hepatol 41:528-537, 2004.