Arrows point to cells within human colon cancer samples producing a protein called CD133, which served as a marker for identifying cells that initiate colon cancer. Markers such as this one may be helpful for targeting future therapeutic approaches. Image courtesy of Dr. Ruggero De Maria. Reprinted by permission from MacMillan Publishers Ltd: Nature, 445:111-115, copyright 2008. 0 Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Cancers of the Digestive System SUMMARY OF RESEARCH GOALS Recognizing the substantial public health impact of digestive system cancers, the Commission recommends several research goals targeted at improving the detection, prevention, and treatment of these diseases. Research is needed to develop more efficient screening tools to predict and detect digestive tract cancers and pre-malignant conditions that frequently progress to cancer. These efforts would be bolstered by identifying health disparities that influence an individual’s susceptibility to digestive system cancers or their response to treatment. Understanding the underlying mechanisms common to all digestive cancers and identifying biomarkers to detect disease or predict response to treatment would accelerate the search for safe, effective therapies. In order to develop targeted strategies for cancer detection, prevention, and treatment, it is critical that researchers identify the genetic risk factors that predispose an individual to a specific form of digestivecancer, such as esophageal cancer, pancreatic cancer, gastric cancer, colorectal cancer, or certain rare gastrointestinal (GI) cancers. Together, these research goals aim to improve the health and lives of people at risk for or living with digestive cancers. Cancers of the Digestive System INTRODUCTION AND BACKGROUND In the early 1900s, cancer of the distal stomach was the leading cause of death from cancer The digestive system, including the gut, in the U.S. Seventy years later, gastric cancer pancreas, liver, and biliary tree, is the site of prevalence has declined to represent the 13th more cancers and the source of more cancer leading cause of death from cancer in the mortality than any other organ system in the U.S., but it is still ranked second worldwide. body. More than 270,000 Americans develop Improvements in food storage and public a cancer of the GI tract each year, and half of sanitation are considered the major reasons these patients will die from the cancers for the decline in these statistics, suggesting (Table 2). that this disease can be prevented. In 1994, the World Health Organization designated The burden of digestive cancers on the Helicobacter pylori as a definite carcinogen, American population is considerable in based on the epidemiologic evidence linking terms of numbers of new cases, deaths, and the chronic gastric inflammation induced by economic costs for diagnosis and treatment. H. pylori to cellular transformation in Research directed at understanding the causes the stomach. of the digestive cancers will help reduce their incidence, prevent deaths, and lower Esophageal cancers represent an enormous healthcare costs. burden of morbidity and mortality worldwide. In 2002, there were an estimated 462,117 new Of the digestive cancers, colorectal cancer is cases and 385,892 deaths from esophageal the most prevalent, with a lifetime risk in the cancer worldwide, making it the eighth and U.S. of 5-6 percent. Colorectal cancer is unique sixth leading causes of cancer and cancer among cancers because it is highly amenable mortality, respectively. Developing strategies to screening programs that can reduce to reduce the mortality of esophageal cancer cancer mortality by early detection and, more is complicated by the fact that the two major importantly, reduce the incidence of invasive histologic subtypes (squamous cell carcinoma cancer by removing pre-malignant lesions. and adenocarcinoma) show marked regional Colorectal cancer incidence and mortality have variation in incidence, differ substantially been falling over the past 2 decades for reasons in etiology, and arise in different tissues. that are not fully explained. High mortality is one of the main shared characteristics of the two histologic subtypes. Table 2. Incidence and Mortality of GI Cancers in the U.S. (2008 estimated) Overall Male Female Annual # of Deaths Cancer Site Incidence Incidence Incidence Deaths Divided by Incidence (%) Esophagus 16,470 12,970 3,500 14,280 87% Stomach 21,500 13,190 8,310 10,880 51% Small intestine 6,110 3,200 2,910 1,110 18% Pancreas 37,680 18,770 18,910 34,290 91% Liver and intrahepatic duct 21,370 15,190 6,180 18,410 86% Gallbladder and biliary ducts 9,520 4,500 5,020 3,340 35% Colon and rectum 148,810 77,250 71,560 49,960 34% Anus and anorectum 5,070 2,020 3,050 680 13% Other digestive organs 4,760 1,470 3,290 2,180 46% TOTALS ,0 ,0 ,0 ,0 0% Opportunities and Challenges in Digestive Diseases Research: Recommendations of the National Commission on Digestive Diseases Esophageal adenocarcinomas have been Research on digestive cancers has been generally reported to be increasing in incidence in directed toward understanding the basic biologic many regions of the Western world. Although mechanisms of tumors. Despite major advances esophageal cancers are less common than in this area, the research community is far from lung, breast, prostate, and colon cancers in understanding how digestive cancers form, the U.S., they are nevertheless the seventh grow, and spread. An improved understanding leading cause of cancer death among U.S. is crucial to lowering the incidence of digestive males. Between 1972 and 2002, the incidence cancers in the diverse U.S. population, identi- of esophageal adenocarcinoma in Caucasian fying predictive biomarkers to prevent cancer males increased more than 600 percent, occurrence or recurrence, and developing novel making it the most rapidly increasing cancer and creative approaches toward prevention or in the U.S., as well as in many other regions of treatment strategies. the Western world. This chapter addresses digestive cancers, Pancreatic cancer is the fourth most common except liver cancer (see the chapter on Diseases cause of cancer death in the U.S., with an of the Liver and Biliary System), with a focus annual incidence of 11.4 per 100,000 men on the four most common digestive cancers: and women. Based on rates from 2002 to colorectal, esophageal, gastric, and pancreatic. 2004, 1.31 percent of men and women (1 in Rarer GI cancers (e.g., cancers affecting the 76) born today may be diagnosed with cancer small intestine, anus, gastrointestinal stromal of the pancreas at some time during their tumors (GIST), gastrointestinal lymphomas, lifetime. Ninety-five percent or more of the and carcinoids) are discussed in aggregate. The deaths from pancreatic malignancy are due chapter outlines a set of research goals that to ductal carcinomas, the most common and should improve our overall understanding of highly metastatic form. Less common tumor basic mechanisms that are relevant to cancer types can occur in the pancreas, but are often etiology and prevention, as well as specific goals less lethal or even benign. The less frequent that are directed at individual cancer types. mesenchymal, hematopoietic, and endocrine tumors often share greater similarity with tumors occurring in other organs than with RECENT RESEARCH ADVANCES the pancreas-specific tumors. Pancreatic cancer is usually not diagnosed until after the Genetic instability as an underlying disease has been manifested through clinical mechanism of cancer symptoms; as a result, only 20 percent are considered appropriate for surgical resection A fundamental principle underlying the of the original tumor at the time of diagnosis. formation of digestive cancers is the sequential Even those patients whose cancer is deemed acquisition of alterations in specific genes. surgically resectable usually have local lymph These alterations lead to genetic instability node spread at the time of surgery, and nearly that fuels the growth of cancer cells. A fraction all have micro-metastatic disease that is of cancers exhibits a form of genetic instability simply undetected at presentation. The overall called microsatellite instability, which is often 5-year survival rate for pancreatic ductal characterized by DNA mismatch repair (MMR) cancer is less than 5 percent. enzyme deficiency. Loss of MMR functions renders tumor cells susceptible to the acquisition Cancers of the Digestive System of somatic mutations throughout the genome. stem cells, a property known as self-renewal, A more common form of genetic instability and they can produce cells that differentiate. is chromosomal instability, which is usually Recent studies support the concept that cells manifested by aneuploidy (a change in the with properties of stem cells are integral to number of chromosomes). For example, multiple the development and perpetuation of human studies have established that esophageal digestive cancers. Eradication of the stem adenocarcinoma develops in association with cell component of a tumor may be essential chromosomal instability, which generates to achieve stable, long-term remission or cure non-random loss of heterozygosity involving of cancer. Advances in the knowledge of the chromosomes 9p, 17p, 5q, and 18q, as well as properties of stem cells have made the specific tetraploidy (another form of altered chromosomal targeting and eradication of cancer stem cells a number) and aneuploidy. Additionally, telomere topic of considerable interest. The concept that dysfunction has been shown to contribute to the GI cancers arise from hematopoietic precursor onset of genetic instability in somatic cells. cells is a theme that was initially shown in the liver. The identification of bone marrow- Epigenetic silencing of gene expression as derived cancer stem cells in gastric cancer is a mechanism in cancer formation the first evidence that a luminal organ may show this property. Chromosomal alterations or modifications have been associated with all stages of digestive Cellular receptors and related signaling tumor formation and progression.