Colon Cancer: An Update and Future Directions

Abstract

James LewisView Large Image Figure ViewerDownload Hi-res image Download (PPT)Timothy C. WangView Large Image Figure ViewerDownload Hi-res image Download (PPT)Anil K. RustgiView Large Image Figure ViewerDownload Hi-res image Download (PPT)Colorectal cancer represents one of the most common cancers in the United States and worldwide. Data from 2009 in the United States underscore that primary prevention (eg, screening and surveillance), and presumably secondary prevention, are making significant inroads. The estimated new cases and deaths from colon and rectal cancer in the United States in 2009 were as follows: 106,100 cases of colon cancer, 40,870 cases of rectal cancer, and 49,920 deaths from colon and rectal cancer combined.1National Cancer InstituteColon and rectal cancer.http://www.cancer.gov/cancertopics/types/colon-and-rectalGoogle ScholarOver the past several decades, prevention of colon cancer has become a much larger, and at times controversial, public health issue. The issue was driven initially by evidence that serial fecal occult blood testing and sigmoidoscopy have the potential to reduce colon cancer–related mortality. Strategies for prevention have evolved over the past 10 to 15 years, now including the use of highly sensitive fecal occult blood tests, fecal immunologic tests, fecal DNA tests, colonoscopy, capsule endoscopy, and computed tomographic colonography. Two articles in this issue address the public health issues related to prevention of colon cancer: Drs Ziad Gellad and Dawn Provenzale (pages 2177–2190) of Duke University Medical Center and the Durham VA Medical Center focus on the burden of disease and the evolving secular trends, and Dr David Lieberman (pages 2115–2126) of Oregon Health & Science University reviews the available data on screening and surveillance strategies. Combined, these 2 review articles provide a clear picture of the current status of colon cancer epidemiology and prevention methods.Of the many preneoplastic and neoplastic conditions in humans, nowhere is the ability to prevent disease as profound as it is in colorectal polyps and cancer. To that end, Drs Andrew Chan and Edward Giovannuci (pages 2029–2043) of Massachusetts General Hospital and Harvard School of Public Health, respectively, evaluate the evidence for modifications in diet and lifestyle as venues for reducing the risk of colorectal cancer and providing a platform for complementary approaches to screening for colorectal cancer. Because we know that adenomatous polyps represent the main precursor lesions to colorectal cancer, the investigation of hereditary and familial colorectal cancer as well as sporadic colorectal cancer has served as a paradigm for not only this cancer but almost all cancers in general from molecular genetics, elucidation of new pathways, identification of important subsets of cells (eg, cancer stem cells), molecular detection, endoscopic imaging, risk stratification, and targeted therapeutics.Drs Kory Jasperson, Thérèse Tuohy, Deborah Neklason, and Randall Burt (pages 2044–2058) of the University of Utah elucidate the colorectal cancer syndromes, with particular attention to their genetics and management, and present timely appraisals of the common familial colorectal cancers with current genetic advances and screening guidelines. The molecular pathways that are operative in the evolution of polyps to sporadic colorectal cancer are several, but 4 such pathways merit particular attention, namely chromosomal instability (CIN), microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), and the serrated pathway. Drs Mario Pino and Daniel Chung (pages 2059–2072) of Massachusetts General Hospital review that CIN is the most common pathway for colorectal cancer. CIN involves chromosomal karyotypic abnormalities as well as pivotal mutations in specific oncogenes (eg, Ki-ras) and tumor suppressor genes (APC, p53, SMAD4). Drs C. Richard Boland and Ajay Goel (pages 2073–2087) of Baylor University Medical Center (Dallas) review MSI, which is a hypermutable phenotype due to the loss of DNA mismatch repair activity, a cardinal feature of Lynch syndrome but present also in a subset of sporadic colorectal cancer, the latter due to the hypermethylation of the MLH1 gene promoter and found interestingly in tumors with CIMP. Finally, Drs Barbara Leggett and Vicki Whitehall (pages 2088–2100) of Royal Brisbane and Women's Hospital provide a compelling update on the serrated neoplastic pathway, which involves the transformation of sessile serrated adenomas and traditional serrated adenomas to colorectal cancer with the importance of B-raf mutations and MSI.This issue provides also an integrated approach to newly emerging topics in the context of colorectal cancer and potential applications to therapy. In the past several years, the role of inflammation has been emphasized as critical in the tumor microenvironment. The review by Drs Janoš Terzić, Sergei Grivennikov, Eliad Karin, and Michael Karin (pages 2101–2114) of the University of California, San Diego, build on the long-standing link between inflammatory bowel disease and the development of colitis-associated cancer, which differs from sporadic colorectal cancer in the genetic pathways leading to malignancy. They delineate the pro-tumorigenic role for the immune system in colitis-associated cancer and the specific contributions by the nuclear factor κB/IKKβ, interleukin-6, and STAT3 in promoting carcinogenesis (eg, invasion) and metastasis. Newer anti-inflammatory approaches, including biologics targeting specific cytokines and small molecules that modulate immune responses, may be used to treat and prevent inflammation-associated colon cancer.Drs Matilde Todaro, Maria Giovanna Francipane, Jan Paul Medema (Academic Medical Center, The Netherlands), and Giorgio Stassi (pages 2151–2162) of the University of Palermo bring the latest concepts of cancer stem cells to the field of colorectal cancer. They summarize recent advances in the cancer stem cell model, the limitations of the theory, and how a cancer stem cell model could account for past failures in cancer therapy. The authors report on our latest understanding of molecular markers for the adult colonic stem cell that likely gives rise to colon cancer stem cells, as well as the relative contribution of the stem cell niche. A perspective is given to the proposed issue of markers for colon cancer stem cells, which include not only CD133/prominin but a number of others as well. Potential therapies that are targeted more specifically for colon cancer stem cells are discussed. The reader is referred to other reviews in Gastroenterology on normal intestinal stem cells for comparison.2Barker N, Clevers H. Lgr5 and Lgr6 as adult stem cell markers. Gastroenterology (in press).Google Scholar, 3Snippert H.J. van Es J.H. van den Born M. et al.Prominin-1/CD133 marks stem cells and early progenitors in mouse small intestine.Gastroenterology. 2009; 136: 2187-2194. e1Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 4Scoville D.H. Sato T. He X.C. et al.Current view: intestinal stem cells and signaling.Gastroenterology. 2008; 134: 849-864Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar, 5Barker N. Clevers H. Tracking down the stem cells of the intestine: strategies to identify adult stem cells.Gastroenterology. 2007; 133: 1755-1760Abstract Full Text Full Text PDF PubMed Scopus (122) Google ScholarAlthough surgery has been the mainstay of therapy for colorectal cancers, and with the incorporation of either neoadjuvant chemoradiation therapy for specific stages of rectal cancer or adjuvant chemotherapy for stage III colon cancer, it is clear that targeted therapeutics offer much hope in ameliorating the poor outcomes with advanced colorectal cancer. Some of this may involve patient risk stratification dependent on the particular genomic, transcriptome, and/or proteomic signatures of colorectal cancers. Drs Thomas Winder and Heinz–Josef Lenz (pages 2163–2176) of the University of Southern California provide a current update on how vascular endothelial growth factor and epidermal growth factor signaling pathways have become preferred targets for therapy in colorectal cancer. Perhaps combinatorial approaches with anti-inflammatory biologics and cancer stem cell targeting, mentioned previously, might augment further patient survival in the future.It is clear that early detection of adenomatous polyps and other at-risk polyps, and of colorectal cancer, is imperative. Strategies involve molecular detection (eg, next-generation stool-based tests), as covered by Dr David Ahlquist (pages 2127–2139) of the Mayo Clinic (Rochester), and high-magnification endoscopic tools (eg, optical magnification, confocal endomicroscopy), as elucidated by Drs Michael Wallace of the Mayo Clinic (Jacksonville) and Ralf Kiesslich (pages 2140–2150) of the University of Mainz. When combined potentially with conventional screening and surveillance approaches, the future is very bright for the prevention, detection, prognosis/risk stratification, and treatment of patients afflicted with sporadic colorectal cancer and those patients with hereditary and familial forms of colorectal cancer. Colorectal cancer represents one of the most common cancers in the United States and worldwide. Data from 2009 in the United States underscore that primary prevention (eg, screening and surveillance), and presumably secondary prevention, are making significant inroads. The estimated new cases and deaths from colon and rectal cancer in the United States in 2009 were as follows: 106,100 cases of colon cancer, 40,870 cases of rectal cancer, and 49,920 deaths from colon and rectal cancer combined.1National Cancer InstituteColon and rectal cancer.http://www.cancer.gov/cancertopics/types/colon-and-rectalGoogle Scholar Over the past several decades, prevention of colon cancer has become a much larger, and at times controversial, public health issue. The issue was driven initially by evidence that serial fecal occult blood testing and sigmoidoscopy have the potential to reduce colon cancer–related mortality. Strategies for prevention have evolved over the past 10 to 15 years, now including the use of highly sensitive fecal occult blood tests, fecal immunologic tests, fecal DNA tests, colonoscopy, capsule endoscopy, and computed tomographic colonography. Two articles in this issue address the public health issues related to prevention of colon cancer: Drs Ziad Gellad and Dawn Provenzale (pages 2177–2190) of Duke University Medical Center and the Durham VA Medical Center focus on the burden of disease and the evolving secular trends, and Dr David Lieberman (pages 2115–2126) of Oregon Health & Science University reviews the available data on screening and surveillance strategies. Combined, these 2 review articles provide a clear picture of the current status of colon cancer epidemiology and prevention methods. Of the many preneoplastic and neoplastic conditions in humans, nowhere is the ability to prevent disease as profound as it is in colorectal polyps and cancer. To that end, Drs Andrew Chan and Edward Giovannuci (pages 2029–2043) of Massachusetts General Hospital and Harvard School of Public Health, respectively, evaluate the evidence for modifications in diet and lifestyle as venues for reducing the risk of colorectal cancer and providing a platform for complementary approaches to screening for colorectal cancer. Because we know that adenomatous polyps represent the main precursor lesions to colorectal cancer, the investigation of hereditary and familial colorectal cancer as well as sporadic colorectal cancer has served as a paradigm for not only this cancer but almost all cancers in general from molecular genetics, elucidation of new pathways, identification of important subsets of cells (eg, cancer stem cells), molecular detection, endoscopic imaging, risk stratification, and targeted therapeutics. Drs Kory Jasperson, Thérèse Tuohy, Deborah Neklason, and Randall Burt (pages 2044–2058) of the University of Utah elucidate the colorectal cancer syndromes, with particular attention to their genetics and management, and present timely appraisals of the common familial colorectal cancers with current genetic advances and screening guidelines. The molecular pathways that are operative in the evolution of polyps to sporadic colorectal cancer are several, but 4 such pathways merit particular attention, namely chromosomal instability (CIN), microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), and the serrated pathway. Drs Mario Pino and Daniel Chung (pages 2059–2072) of Massachusetts General Hospital review that CIN is the most common pathway for colorectal cancer. CIN involves chromosomal karyotypic abnormalities as well as pivotal mutations in specific oncogenes (eg, Ki-ras) and tumor suppressor genes (APC, p53, SMAD4). Drs C. Richard Boland and Ajay Goel (pages 2073–2087) of Baylor University Medical Center (Dallas) review MSI, which is a hypermutable phenotype due to the loss of DNA mismatch repair activity, a cardinal feature of Lynch syndrome but present also in a subset of sporadic colorectal cancer, the latter due to the hypermethylation of the MLH1 gene promoter and found interestingly in tumors with CIMP. Finally, Drs Barbara Leggett and Vicki Whitehall (pages 2088–2100) of Royal Brisbane and Women's Hospital provide a compelling update on the serrated neoplastic pathway, which involves the transformation of sessile serrated adenomas and traditional serrated adenomas to colorectal cancer with the importance of B-raf mutations and MSI. This issue provides also an integrated approach to newly emerging topics in the context of colorectal cancer and potential applications to therapy. In the past several years, the role of inflammation has been emphasized as critical in the tumor microenvironment. The review by Drs Janoš Terzić, Sergei Grivennikov, Eliad Karin, and Michael Karin (pages 2101–2114) of the University of California, San Diego, build on the long-standing link between inflammatory bowel disease and the development of colitis-associated cancer, which differs from sporadic colorectal cancer in the genetic pathways leading to malignancy. They delineate the pro-tumorigenic role for the immune system in colitis-associated cancer and the specific contributions by the nuclear factor κB/IKKβ, interleukin-6, and STAT3 in promoting carcinogenesis (eg, invasion) and metastasis. Newer anti-inflammatory approaches, including biologics targeting specific cytokines and small molecules that modulate immune responses, may be used to treat and prevent inflammation-associated colon cancer. Drs Matilde Todaro, Maria Giovanna Francipane, Jan Paul Medema (Academic Medical Center, The Netherlands), and Giorgio Stassi (pages 2151–2162) of the University of Palermo bring the latest concepts of cancer stem cells to the field of colorectal cancer. They summarize recent advances in the cancer stem cell model, the limitations of the theory, and how a cancer stem cell model could account for past failures in cancer therapy. The authors report on our latest understanding of molecular markers for the adult colonic stem cell that likely gives rise to colon cancer stem cells, as well as the relative contribution of the stem cell niche. A perspective is given to the proposed issue of markers for colon cancer stem cells, which include not only CD133/prominin but a number of others as well. Potential therapies that are targeted more specifically for colon cancer stem cells are discussed. The reader is referred to other reviews in Gastroenterology on normal intestinal stem cells for comparison.2Barker N, Clevers H. Lgr5 and Lgr6 as adult stem cell markers. Gastroenterology (in press).Google Scholar, 3Snippert H.J. van Es J.H. van den Born M. et al.Prominin-1/CD133 marks stem cells and early progenitors in mouse small intestine.Gastroenterology. 2009; 136: 2187-2194. e1Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 4Scoville D.H. Sato T. He X.C. et al.Current view: intestinal stem cells and signaling.Gastroenterology. 2008; 134: 849-864Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar, 5Barker N. Clevers H. Tracking down the stem cells of the intestine: strategies to identify adult stem cells.Gastroenterology. 2007; 133: 1755-1760Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar Although surgery has been the mainstay of therapy for colorectal cancers, and with the incorporation of either neoadjuvant chemoradiation therapy for specific stages of rectal cancer or adjuvant chemotherapy for stage III colon cancer, it is clear that targeted therapeutics offer much hope in ameliorating the poor outcomes with advanced colorectal cancer. Some of this may involve patient risk stratification dependent on the particular genomic, transcriptome, and/or proteomic signatures of colorectal cancers. Drs Thomas Winder and Heinz–Josef Lenz (pages 2163–2176) of the University of Southern California provide a current update on how vascular endothelial growth factor and epidermal growth factor signaling pathways have become preferred targets for therapy in colorectal cancer. Perhaps combinatorial approaches with anti-inflammatory biologics and cancer stem cell targeting, mentioned previously, might augment further patient survival in the future. It is clear that early detection of adenomatous polyps and other at-risk polyps, and of colorectal cancer, is imperative. Strategies involve molecular detection (eg, next-generation stool-based tests), as covered by Dr David Ahlquist (pages 2127–2139) of the Mayo Clinic (Rochester), and high-magnification endoscopic tools (eg, optical magnification, confocal endomicroscopy), as elucidated by Drs Michael Wallace of the Mayo Clinic (Jacksonville) and Ralf Kiesslich (pages 2140–2150) of the University of Mainz. When combined potentially with conventional screening and surveillance approaches, the future is very bright for the prevention, detection, prognosis/risk stratification, and treatment of patients afflicted with sporadic colorectal cancer and those patients with hereditary and familial forms of colorectal cancer. The editors express their deep gratitude to Brook Simpson in the publication of this issue.