Gallbladder and Bile Duct Cancer

2002 News Archive

A New Lab for Biliary Tract Cancers at Johns Hopkins

Overview
Biliary tract cancers encompass cancers of the gallbladder and bile ducts. The diagnosis of biliary tract cancers is often difficult since tumors may reach a large size before symptoms are present, and serum markers are currently not available for screening. In addition, there is no "gene test" to determine who is at risk for these cancers. Therefore, in order to fight these cancers, we need to understand the biology of these tumors better and use this knowledge to develop new methods for screening, early detection, and treatment for patients suffering from this disease.

The goal of our lab is to identify genes and proteins that are abnormally expressed in biliary tract cancers. Once we have identified these "candidate genes" that are responsible for transforming normal bile duct cells into cancer cells, we can use this information to determine how we can prevent biliary cancers, and identify new strategies for diagnosis and treatment.

For example, certain subgroups of individuals are at high risk for developing biliary cancers; in this country the single most important risk factor is the presence of an uncommon disease called primary sclerosing cholangitis. Patients with this condition have a one in three chance of developing bile duct cancers within 10 years. We plan to use information gained from our molecular studies in biliary cancers to develop novel screening and early detection techniques for this at-risk group of patients.

Research
We are using state-of-the-art "gene chip" technology to study changes in gene expression between normal samples and biliary cancer specimens. Using specialized chips, we can detect genes that are up- or down-regulated in cancer specimens compared to normal. Secondly, we are using biliary cancer cells in tissue culture to manipulate genes in order to identify the functional changes important in biliary tumor cell growth and invasion. Finally, we are growing human biliary tumors in mice (a technique called "xenografting") in order to develop a model where we can test novel treatment strategies for biliary cancer using an animal model.

Our ultimate goal is to utilize the basic knowledge we gain through our molecular studies to develop new methods of screening and treatment for patients with biliary tract cancers. In addition, the findings from biliary tract cancer studies may help people with other cancers, since often the pathways of tumor development are often similar between different cancer types.

People
Anirban Maitra, MD is the Principal Investigator of the new biliary tract cancer lab and an Instructor of Pathology and Genetic Medicine at The Johns Hopkins University School of Medicine. Dr. Maitra graduated from the All India Institute of Medical Sciences in New Delhi, India. He completed his residency and fellowship training in Anatomic Pathology at the University of Texas Southwestern Medical Center in Dallas, followed by a fellowship in Gastrointestinal and Liver Pathology at The Johns Hopkins University School of Medicine. Dr. Maitra has authored numerous papers in the field of pancreatic and biliary cancer research, and is an Associate Editor for the peer-reviewed journal Current Molecular Medicine.

Donna Hansel, MD/PhD is a fellow in the division of Gastrointestinal Pathology at The Johns Hopkins University School of Medicine. Dr. Hansel received her MD/PhD from The Johns Hopkins University School of Medicine and has trained in anatomic pathology at the Josephine Nefkins Instituut, Erasmus Universiteit, Rotterdam, The Netherlands. Dr. Hansel is interested a career in basic research in gastrointestinal malignancies.

Ayman Rahman, BA is the research assistant for the new biliary tract cancer lab and is responsible for harvesting tissue for creating biliary tumor xenografts. He received his degree in biology from the University of Virginia. Ayman is an expert in immunohistochemistry and in situ hybridization techniques.

Pedram Argani, MD is an Assistant Professor of Pathology at The Johns Hopkins University School of Medicine and an attending pathologist at The Johns Hopkins Hospital. Dr. Argani is a graduate of the University of Pennsylvania School of Medicine and received his pathology training at the Hospital of the University of Pennsylvania. He also completed fellowships in Oncologic Pathology and Molecular Pathology at Memorial Sloan-Kettering Cancer Center in New York. Dr. Argani is Director of the Immunopathology Laboratory of The Johns Hopkins Hospital. He has a special diagnostic interest in biliary cancer pathology. He has created the first biliary cancer tissue microarrays, which facilitates the high-throughput molecular analysis of abnormal proteins expressed by biliary cancers. He has also published on biliary tract cancers in the internationally-recognized journal Cancer.

Connie Knapik provides assistance with manuscript preparation and lab organization.

Support our Research
Since the molecular biology of biliary cancers has been studied for only a short period of time, there is little organized funding available to support innovative research in this area. In order to move forward in our understanding of these cancers, we need support from many arenas, including both federal funding and private donations. You can make a difference with your contribution to this cause! If you would like to contribute to our understanding of biliary tract cancers, please address your donations to:

~September 2002

Creation of Gallbladder and Bile Duct Cancer Tissue Microarrays

Through the use of high throughput genetic technologies, such as cDNA microarrays and serial analysis of gene expression (SAGE), numerous new markers of cancer have been identified. This has been particularly true for cancer of the pancreas (see the What's New section on the pancreas cancer Website). With the discovery of so many novel markers of disease and targets for potential therapy, there needs to be a way to quickly screen a large number of cancers for their expression of these new markers. Tissue microarray technology allows for such high-volume screening. In tissue microarrays, numerous cores (spots) of a large number of different tumors are placed into a single paraffin tissue block. This block can yield up to 300 or so slides, each containing samples of multiple (up to 300) tumors, which can be analyzed using a variety of technologies including immunohistochemistry for protein expression, in situ hybridization for RNA expression, and florescence in situ hybridization for DNA copy number. The pathology department of The Johns Hopkins Hospital has created a tissue microarray facility, which allows for construction of microarrays from tumors of any organ system. Such arrays have been constructed for prostatic and pancreatic adenocarcinomas, and preliminary results with these arrays have shown that tissue arrays can greatly speed the analysis of new cancer markers.

This past month, we have just completed the construction of, to our knowledge, the first gallbladder and bile duct carcinoma tissue microarray (See Figure below). This microarray contains spots of 40 different gallbladder and bile duct carcinomas, along with five normal gallbladder specimens and nine normal unrelated tissues as controls. We have made duplicate blocks such that each tumor is represented in four spots on the two blocks. These blocks will allow us to rapidly screen gallbladder and bile duct carcinomas for novel tumor markers that we identify through analysis of gene expression using gene chips. Preliminarily, we can report that these arrays have proven quite useful for evaluating markers identified in pancreatic cancers in gallbladder and bile duct carcinomas, and hold promise for identifying new ways to make the diagnosis earlier and potentially identify targets for rational therapy.

Our research team is greatly indebted to the friends and family of Margaret Lee for their generous donation, which funded the creation of these tissue microarrays. Because biliary tract cancers are not common, it is difficult to obtain government funding for this sort of study. Because of the Lee's generous gift, we were able to rapidly create these tissue microarrays to spur a new wave of biliary tract cancer research at Johns Hopkins. The patients and families who will benefit from the discoveries that result from these arrays, as well as the investigators themselves, are greatly indebted to the Lee family for their generosity.

~February 2002

Immunohistochemical Analysis of Cyclooxygenase Enzymes in the Sequential Pathogenisis of Gallbladder Carcinoma

It is known that gallbladder carcinoma is associated with gallstones (cholelithiasis), and chronic inflammation. Recently, it has been discovered that the proinflammatory enzymes cyclooxygenase (COX1 and COX2) are overexpressed in a variety of human cancers, and may contribute to their formation. Analysis of COX expression in gallbladder carcinoma, which is associated with inflammation, has not yet been studied.

In this study, Dr. Maitra and colleagues at Johns Hopkins, University of Texas Southwestern Medical Center, and Catholic University in Chile studied a series of gallbladder carcinomas for expression of COX1 and COX2. The study showed that COX1 and COX2 were overexpressed in gallbladder carcinoma as compared to normal epithelium. In fact, the level of expression increased progressively from normal epithelium to low-grade dysplasia, to carcinoma in situ to invasive gallbladder carcinoma.

These studies demonstrate that COX overexpression is associated with tumor progression in gallbladder carcinoma. Since COX inhibitors are well characterized and well tolerated medications, these findings raise the possibility that COX2 and COX1 may be targets for prevention of gallbladder carcinoma.

A Maitra, II Wistuba, JF Miquel, RH Hruban, P Argani, R Ashfaq.
Modern Pathology 2002; 15: 137A (abstract 571)


~January 2002