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Abstract

Progression of Barrett’s Esophagus with Associated NSAIDs and Statin UseIt has been estimated that 10% of patients with gastroesophageal reflux develop Barrett's esophagus. Barrett's esophagus is a premalignant epithelial that increases the risk of developing adenocarcinoma by 30- to 125-fold, with a yearly incidence of approximately 0.5%. Approaches employed to reduce the risk of developing adenocarcinoma include regular surveillance and/or ablation of the Barrett's epithelia. An observational study recently published in this journal of Veterans Administration patients supported an effect by nonsteroidal anti-inflammatory drugs (NSAIDs) and statins in reducing the development of adenocarcinoma in patients with Barrett's esophagus (Gastroenterology 2010;138:2260–2266).In this issue of Gastroenterology, Kastelein et al report on an observational study in The Netherlands that followed 570 patients with Barrett's esophagus for the development of either high-grade dysplasia or adenocarcinoma. Over a median follow-up of 4.5 years, 38 cases of high-grade dysplasia or adenocarcinoma developed among the Barrett's esophagus patients. The authors then evaluated the entire cohort for the use of NSAIDs and statins, either alone or in combination.Using a multivariate model that adjusted for age, gender, Barrett's esophagus length, baseline histology, and other medications, the authors found that the development of high-grade dysplasia or adenocarcinoma is significantly reduced in patients who used NSAIDs (hazard ratio [HR], 0.47; 95% confidence interval, 0.24–0.93) or statins (HR, 0.46) alone. Only the use of nonselective, and not cyclo-oxygenase-2 selective, NSAIDs demonstrated a significant lower risk. For the statins, lower risk was observed only for men older than 60 years of age.When a multivariate model was applied to patients who used both NSAIDs and statins, an additive effect in reducing the risk of progression of Barrett's esophagus to high-grade dysplasia or adenocarcinoma was observed (Figure 1). This study adds to the growing evidence that the progression of Barrett's esophagus may be pharmacologically influenced.See page 2000.Screening for Esophageal Varices in ChildrenUpper gastrointestinal endoscopy is the gold standard for screening for esophageal varices and is a key component of guidelines used in the care and management of adults with cirrhosis. However, this screening method is invasive, can be associated with adverse events, and is expensive, particularly if it needs to be repeated every two to three years. This has led to a search for noninvasive alternatives to the screening of high risk varices. The need for such noninvasive screening methods is all the more urgent in the pediatric patient population. In this issue of Gastroenterology, Gana et al report the findings of a prospective study involving 8 centers throughout the world of noninvasive tests in >100 children with portal hypertension. The 4 noninvasive tests studied were a clinical prediction rule (CPR), previously validated in a retrospective study, that is calculated from the platelet count, a spleen length (measured by ultrasonography) standard deviation (z)-score (SSAZ) and the albumin concentration, the ratio of platelet count and spleen length z-score (P/SSAZ), platelet count alone, and spleen length alone (SSAZ). In multivariate analysis, the CPR was an independent predictor of varices. In receiver operator characteristic curve analysis, the best predictors of esophageal varices of any size, in decreasing order, were the P/SSAZ, the CPR, the platelet count alone, the SSAZ, and the albumin concentration (Figure 2). The best predictors of large esophageal varices, in decreasing order, were platelet count, P/SSAZ, and the CPR. In the 16 children who underwent repeat endoscopy during the study period, the change in the CPR correlated with the observed changes in varices. These results demonstrate that noninvasive tests, in particular the CPR and the platelet count, may be able to predict the presence of esophageal varices in children with portal hypertension and obviate the need for endoscopic screening in many.Figure 2Receiver operator characteristic curve to differentiate the presence versus the absence of esophageal varices.View Large Image Figure ViewerDownload Hi-res image Download (PPT)See page 2009.Dependence Receptors and Colorectal CancerDependence receptors exhibit proapoptotic activity in the absence of their respective ligand. Receptors for netrin-1, a laminin-related protein, are prototypical of this recently described family of receptors. Binding of netrin-1 to its 2 major receptors, UNC5H and DCC (Deleted in Colorectal Cancer), by inhibiting apoptosis, has been shown to regulate endothelial and epithelial cell survival and promote tumor development. Up-regulation of netrin-1 inhibits tumor cell death in vitro and is associated, as is the inactivation of UNC5C, with the development and progression of intestinal tumors in animal models, consistent with a role for UNC5C as a tumor suppressor. In this issue of Gastroenterology, Coissieux et al investigate the role of germline mutations in the human UNC5C gene in colorectal carcinogenesis in 3 independent cohorts from France, Finland, and the United States. Four distinct and previously unreported missense mutations in UNC5C were identified. In the French cohort, the single missense mutation, A628K, located in exon 11 that codes for an intracellular domain involved in the proapoptotic activity of UNC5C, significantly predisposed patients to colorectal cancer. A similar trend was observed in the US cohort, although the difference between probands and controls did not reach significance. In addition, the A628K mutation co-segregated with colorectal cancer in 3 French families. Loss of proapoptotic activity of the UNC5C A628K variant was confirmed in transfected human embryonic kidney (HEK293T) cells by assays of apoptosis, including caspase-3 activity assay (Figure 3) and TUNEL staining. These findings suggest that the germline A682K mutation in UNC5C, a gene in the netrin-1–dependence receptor family, by preventing apoptosis, has a role in the development of colorectal cancer in certain populations. Further study for mutations in other genes implicated in this receptor family may provide additional insight into colorectal carcinogenesis.Figure 3Apoptosis quantification by active caspase-3 activity in HEK293T cells transfected with control (Ctrl) vector or constructs containing A628K, M721T, or wild-type (WT) UNC5C allele.View Large Image Figure ViewerDownload Hi-res image Download (PPT)See page 2039.c-Met+ Cancer Stem CellsPancreatic adenocarcinoma remains among the most lethal human cancers. Similar to other tumors, pancreatic cancer has been hypothesized to harbor a small population of cancer stem cells from which the bulk of tumors cells derive. The resistance of cancer stem cells to radiation and the targeting of conventional chemotherapies at the bulk of non–stem cell tumor cells represent potential reasons for the poor outcome of current therapies.Prior studies utilized fluorescence-activated cell sorting to isolate a population of pancreatic cancer cells that expressed the cell surface marker profile CD44+CD24+ESA+. When as few as 100 such cells were injected into an immunodeficient mouse, tumors resulted that closely resembled their human counterpart, and suggested that this enriched cell population harbored cancer stem cells (Cancer Res 2007;67:1030–1037).In this issue of Gastroenterology, Li et al extend their previous studies by characterizing cells isolated using c-Met as a marker. c-Met is a tyrosine kinase receptor expressed by normal stem and progenitor cells. Its only known ligand is hepatocyte growth factor. c-Met is also expressed by cancer cells and promotes cell invasion and metastasis. In the present study, Li et al isolated putative cancer stem cells using only c-Met as a marker for fluorescence-activated cell sorting-mediated isolation. When isolated cells with high c-Met levels were implanted in immunodeficient mice, they produced tumors that grew at a rate similar to cancer cells isolated with the previously used cancer markers CD44 or CD133. In addition, using c-METhigh and CD44 together in tandem to isolate cells significantly increased the rate of tumor formation. The c-METhigh cells could also be grown in vitro as spheroid colonies in nonadherent cultures, a characteristic displayed by cancer stem cells.In addition to c-Met's role as a biomarker for cancer stem cells, the authors also evaluated whether c-Met itself served a functional role (Figure 4). c-Met function was reduced using 2 different approaches, the use of the c-Met specific tyrosine kinase inhibitor, XL184, or shRNA to reduce c-Met expression. Using either approach compromised the formation of spheroid colonies in vitro.Figure 4The effects of XL184 and gemcitabine on orthotopic tumor growth.View Large Image Figure ViewerDownload Hi-res image Download (PPT)c-Met's role in tumor growth was also tested in vivo using human pancreatic adenocarcinomas established in immunodeficient mice. The XL184 c-Met inhibitor reduced tumor growth rate and the development of metastasis. The reduction of tumor growth was reduced even further when XL184 was combined with the commonly used chemotherapeutic agent for pancreatic cancer, gemcitabine.In summary, Li et al have identified c-Met as a marker for pancreatic cancer stem cells. In addition, they have demonstrated that c-Met serves a significant role in tumor growth and metastasis and thus serves as a promising candidate for the development of therapeutic strategies.See page 2218. Progression of Barrett’s Esophagus with Associated NSAIDs and Statin UseIt has been estimated that 10% of patients with gastroesophageal reflux develop Barrett's esophagus. Barrett's esophagus is a premalignant epithelial that increases the risk of developing adenocarcinoma by 30- to 125-fold, with a yearly incidence of approximately 0.5%. Approaches employed to reduce the risk of developing adenocarcinoma include regular surveillance and/or ablation of the Barrett's epithelia. An observational study recently published in this journal of Veterans Administration patients supported an effect by nonsteroidal anti-inflammatory drugs (NSAIDs) and statins in reducing the development of adenocarcinoma in patients with Barrett's esophagus (Gastroenterology 2010;138:2260–2266).In this issue of Gastroenterology, Kastelein et al report on an observational study in The Netherlands that followed 570 patients with Barrett's esophagus for the development of either high-grade dysplasia or adenocarcinoma. Over a median follow-up of 4.5 years, 38 cases of high-grade dysplasia or adenocarcinoma developed among the Barrett's esophagus patients. The authors then evaluated the entire cohort for the use of NSAIDs and statins, either alone or in combination.Using a multivariate model that adjusted for age, gender, Barrett's esophagus length, baseline histology, and other medications, the authors found that the development of high-grade dysplasia or adenocarcinoma is significantly reduced in patients who used NSAIDs (hazard ratio [HR], 0.47; 95% confidence interval, 0.24–0.93) or statins (HR, 0.46) alone. Only the use of nonselective, and not cyclo-oxygenase-2 selective, NSAIDs demonstrated a significant lower risk. For the statins, lower risk was observed only for men older than 60 years of age.When a multivariate model was applied to patients who used both NSAIDs and statins, an additive effect in reducing the risk of progression of Barrett's esophagus to high-grade dysplasia or adenocarcinoma was observed (Figure 1). This study adds to the growing evidence that the progression of Barrett's esophagus may be pharmacologically influenced.See page 2000. It has been estimated that 10% of patients with gastroesophageal reflux develop Barrett's esophagus. Barrett's esophagus is a premalignant epithelial that increases the risk of developing adenocarcinoma by 30- to 125-fold, with a yearly incidence of approximately 0.5%. Approaches employed to reduce the risk of developing adenocarcinoma include regular surveillance and/or ablation of the Barrett's epithelia. An observational study recently published in this journal of Veterans Administration patients supported an effect by nonsteroidal anti-inflammatory drugs (NSAIDs) and statins in reducing the development of adenocarcinoma in patients with Barrett's esophagus (Gastroenterology 2010;138:2260–2266). In this issue of Gastroenterology, Kastelein et al report on an observational study in The Netherlands that followed 570 patients with Barrett's esophagus for the development of either high-grade dysplasia or adenocarcinoma. Over a median follow-up of 4.5 years, 38 cases of high-grade dysplasia or adenocarcinoma developed among the Barrett's esophagus patients. The authors then evaluated the entire cohort for the use of NSAIDs and statins, either alone or in combination. Using a multivariate model that adjusted for age, gender, Barrett's esophagus length, baseline histology, and other medications, the authors found that the development of high-grade dysplasia or adenocarcinoma is significantly reduced in patients who used NSAIDs (hazard ratio [HR], 0.47; 95% confidence interval, 0.24–0.93) or statins (HR, 0.46) alone. Only the use of nonselective, and not cyclo-oxygenase-2 selective, NSAIDs demonstrated a significant lower risk. For the statins, lower risk was observed only for men older than 60 years of age. When a multivariate model was applied to patients who used both NSAIDs and statins, an additive effect in reducing the risk of progression of Barrett's esophagus to high-grade dysplasia or adenocarcinoma was observed (Figure 1). This study adds to the growing evidence that the progression of Barrett's esophagus may be pharmacologically influenced. See page 2000. Screening for Esophageal Varices in ChildrenUpper gastrointestinal endoscopy is the gold standard for screening for esophageal varices and is a key component of guidelines used in the care and management of adults with cirrhosis. However, this screening method is invasive, can be associated with adverse events, and is expensive, particularly if it needs to be repeated every two to three years. This has led to a search for noninvasive alternatives to the screening of high risk varices. The need for such noninvasive screening methods is all the more urgent in the pediatric patient population. In this issue of Gastroenterology, Gana et al report the findings of a prospective study involving 8 centers throughout the world of noninvasive tests in >100 children with portal hypertension. The 4 noninvasive tests studied were a clinical prediction rule (CPR), previously validated in a retrospective study, that is calculated from the platelet count, a spleen length (measured by ultrasonography) standard deviation (z)-score (SSAZ) and the albumin concentration, the ratio of platelet count and spleen length z-score (P/SSAZ), platelet count alone, and spleen length alone (SSAZ). In multivariate analysis, the CPR was an independent predictor of varices. In receiver operator characteristic curve analysis, the best predictors of esophageal varices of any size, in decreasing order, were the P/SSAZ, the CPR, the platelet count alone, the SSAZ, and the albumin concentration (Figure 2). The best predictors of large esophageal varices, in decreasing order, were platelet count, P/SSAZ, and the CPR. In the 16 children who underwent repeat endoscopy during the study period, the change in the CPR correlated with the observed changes in varices. These results demonstrate that noninvasive tests, in particular the CPR and the platelet count, may be able to predict the presence of esophageal varices in children with portal hypertension and obviate the need for endoscopic screening in many.See page 2009. Upper gastrointestinal endoscopy is the gold standard for screening for esophageal varices and is a key component of guidelines used in the care and management of adults with cirrhosis. However, this screening method is invasive, can be associated with adverse events, and is expensive, particularly if it needs to be repeated every two to three years. This has led to a search for noninvasive alternatives to the screening of high risk varices. The need for such noninvasive screening methods is all the more urgent in the pediatric patient population. In this issue of Gastroenterology, Gana et al report the findings of a prospective study involving 8 centers throughout the world of noninvasive tests in >100 children with portal hypertension. The 4 noninvasive tests studied were a clinical prediction rule (CPR), previously validated in a retrospective study, that is calculated from the platelet count, a spleen length (measured by ultrasonography) standard deviation (z)-score (SSAZ) and the albumin concentration, the ratio of platelet count and spleen length z-score (P/SSAZ), platelet count alone, and spleen length alone (SSAZ). In multivariate analysis, the CPR was an independent predictor of varices. In receiver operator characteristic curve analysis, the best predictors of esophageal varices of any size, in decreasing order, were the P/SSAZ, the CPR, the platelet count alone, the SSAZ, and the albumin concentration (Figure 2). The best predictors of large esophageal varices, in decreasing order, were platelet count, P/SSAZ, and the CPR. In the 16 children who underwent repeat endoscopy during the study period, the change in the CPR correlated with the observed changes in varices. These results demonstrate that noninvasive tests, in particular the CPR and the platelet count, may be able to predict the presence of esophageal varices in children with portal hypertension and obviate the need for endoscopic screening in many. See page 2009. Dependence Receptors and Colorectal CancerDependence receptors exhibit proapoptotic activity in the absence of their respective ligand. Receptors for netrin-1, a laminin-related protein, are prototypical of this recently described family of receptors. Binding of netrin-1 to its 2 major receptors, UNC5H and DCC (Deleted in Colorectal Cancer), by inhibiting apoptosis, has been shown to regulate endothelial and epithelial cell survival and promote tumor development. Up-regulation of netrin-1 inhibits tumor cell death in vitro and is associated, as is the inactivation of UNC5C, with the development and progression of intestinal tumors in animal models, consistent with a role for UNC5C as a tumor suppressor. In this issue of Gastroenterology, Coissieux et al investigate the role of germline mutations in the human UNC5C gene in colorectal carcinogenesis in 3 independent cohorts from France, Finland, and the United States. Four distinct and previously unreported missense mutations in UNC5C were identified. In the French cohort, the single missense mutation, A628K, located in exon 11 that codes for an intracellular domain involved in the proapoptotic activity of UNC5C, significantly predisposed patients to colorectal cancer. A similar trend was observed in the US cohort, although the difference between probands and controls did not reach significance. In addition, the A628K mutation co-segregated with colorectal cancer in 3 French families. Loss of proapoptotic activity of the UNC5C A628K variant was confirmed in transfected human embryonic kidney (HEK293T) cells by assays of apoptosis, including caspase-3 activity assay (Figure 3) and TUNEL staining. These findings suggest that the germline A682K mutation in UNC5C, a gene in the netrin-1–dependence receptor family, by preventing apoptosis, has a role in the development of colorectal cancer in certain populations. Further study for mutations in other genes implicated in this receptor family may provide additional insight into colorectal carcinogenesis.See page 2039. Dependence receptors exhibit proapoptotic activity in the absence of their respective ligand. Receptors for netrin-1, a laminin-related protein, are prototypical of this recently described family of receptors. Binding of netrin-1 to its 2 major receptors, UNC5H and DCC (Deleted in Colorectal Cancer), by inhibiting apoptosis, has been shown to regulate endothelial and epithelial cell survival and promote tumor development. Up-regulation of netrin-1 inhibits tumor cell death in vitro and is associated, as is the inactivation of UNC5C, with the development and progression of intestinal tumors in animal models, consistent with a role for UNC5C as a tumor suppressor. In this issue of Gastroenterology, Coissieux et al investigate the role of germline mutations in the human UNC5C gene in colorectal carcinogenesis in 3 independent cohorts from France, Finland, and the United States. Four distinct and previously unreported missense mutations in UNC5C were identified. In the French cohort, the single missense mutation, A628K, located in exon 11 that codes for an intracellular domain involved in the proapoptotic activity of UNC5C, significantly predisposed patients to colorectal cancer. A similar trend was observed in the US cohort, although the difference between probands and controls did not reach significance. In addition, the A628K mutation co-segregated with colorectal cancer in 3 French families. Loss of proapoptotic activity of the UNC5C A628K variant was confirmed in transfected human embryonic kidney (HEK293T) cells by assays of apoptosis, including caspase-3 activity assay (Figure 3) and TUNEL staining. These findings suggest that the germline A682K mutation in UNC5C, a gene in the netrin-1–dependence receptor family, by preventing apoptosis, has a role in the development of colorectal cancer in certain populations. Further study for mutations in other genes implicated in this receptor family may provide additional insight into colorectal carcinogenesis. See page 2039. c-Met+ Cancer Stem CellsPancreatic adenocarcinoma remains among the most lethal human cancers. Similar to other tumors, pancreatic cancer has been hypothesized to harbor a small population of cancer stem cells from which the bulk of tumors cells derive. The resistance of cancer stem cells to radiation and the targeting of conventional chemotherapies at the bulk of non–stem cell tumor cells represent potential reasons for the poor outcome of current therapies.Prior studies utilized fluorescence-activated cell sorting to isolate a population of pancreatic cancer cells that expressed the cell surface marker profile CD44+CD24+ESA+. When as few as 100 such cells were injected into an immunodeficient mouse, tumors resulted that closely resembled their human counterpart, and suggested that this enriched cell population harbored cancer stem cells (Cancer Res 2007;67:1030–1037).In this issue of Gastroenterology, Li et al extend their previous studies by characterizing cells isolated using c-Met as a marker. c-Met is a tyrosine kinase receptor expressed by normal stem and progenitor cells. Its only known ligand is hepatocyte growth factor. c-Met is also expressed by cancer cells and promotes cell invasion and metastasis. In the present study, Li et al isolated putative cancer stem cells using only c-Met as a marker for fluorescence-activated cell sorting-mediated isolation. When isolated cells with high c-Met levels were implanted in immunodeficient mice, they produced tumors that grew at a rate similar to cancer cells isolated with the previously used cancer markers CD44 or CD133. In addition, using c-METhigh and CD44 together in tandem to isolate cells significantly increased the rate of tumor formation. The c-METhigh cells could also be grown in vitro as spheroid colonies in nonadherent cultures, a characteristic displayed by cancer stem cells.In addition to c-Met's role as a biomarker for cancer stem cells, the authors also evaluated whether c-Met itself served a functional role (Figure 4). c-Met function was reduced using 2 different approaches, the use of the c-Met specific tyrosine kinase inhibitor, XL184, or shRNA to reduce c-Met expression. Using either approach compromised the formation of spheroid colonies in vitro.c-Met's role in tumor growth was also tested in vivo using human pancreatic adenocarcinomas established in immunodeficient mice. The XL184 c-Met inhibitor reduced tumor growth rate and the development of metastasis. The reduction of tumor growth was reduced even further when XL184 was combined with the commonly used chemotherapeutic agent for pancreatic cancer, gemcitabine.In summary, Li et al have identified c-Met as a marker for pancreatic cancer stem cells. In addition, they have demonstrated that c-Met serves a significant role in tumor growth and metastasis and thus serves as a promising candidate for the development of therapeutic strategies.See page 2218. Pancreatic adenocarcinoma remains among the most lethal human cancers. Similar to other tumors, pancreatic cancer has been hypothesized to harbor a small population of cancer stem cells from which the bulk of tumors cells derive. The resistance of cancer stem cells to radiation and the targeting of conventional chemotherapies at the bulk of non–stem cell tumor cells represent potential reasons for the poor outcome of current therapies. Prior studies utilized fluorescence-activated cell sorting to isolate a population of pancreatic cancer cells that expressed the cell surface marker profile CD44+CD24+ESA+. When as few as 100 such cells were injected into an immunodeficient mouse, tumors resulted that closely resembled their human counterpart, and suggested that this enriched cell population harbored cancer stem cells (Cancer Res 2007;67:1030–1037). In this issue of Gastroenterology, Li et al extend their previous studies by characterizing cells isolated using c-Met as a marker. c-Met is a tyrosine kinase receptor expressed by normal stem and progenitor cells. Its only known ligand is hepatocyte growth factor. c-Met is also expressed by cancer cells and promotes cell invasion and metastasis. In the present study, Li et al isolated putative cancer stem cells using only c-Met as a marker for fluorescence-activated cell sorting-mediated isolation. When isolated cells with high c-Met levels were implanted in immunodeficient mice, they produced tumors that grew at a rate similar to cancer cells isolated with the previously used cancer markers CD44 or CD133. In addition, using c-METhigh and CD44 together in tandem to isolate cells significantly increased the rate of tumor formation. The c-METhigh cells could also be grown in vitro as spheroid colonies in nonadherent cultures, a characteristic displayed by cancer stem cells. In addition to c-Met's role as a biomarker for cancer stem cells, the authors also evaluated whether c-Met itself served a functional role (Figure 4). c-Met function was reduced using 2 different approaches, the use of the c-Met specific tyrosine kinase inhibitor, XL184, or shRNA to reduce c-Met expression. Using either approach compromised the formation of spheroid colonies in vitro. c-Met's role in tumor growth was also tested in vivo using human pancreatic adenocarcinomas established in immunodeficient mice. The XL184 c-Met inhibitor reduced tumor growth rate and the development of metastasis. The reduction of tumor growth was reduced even further when XL184 was combined with the commonly used chemotherapeutic agent for pancreatic cancer, gemcitabine. In summary, Li et al have identified c-Met as a marker for pancreatic cancer stem cells. In addition, they have demonstrated that c-Met serves a significant role in tumor growth and metastasis and thus serves as a promising candidate for the development of therapeutic strategies. See page 2218. Nonsteroidal Anti-Inflammatory Drugs and Statins Have Chemopreventative Effects in Patients With Barrett's EsophagusGastroenterologyVol. 141Issue 6PreviewThe incidence of Barrett's esophagus and esophageal adenocarcinoma has increased despite surveillance of patients with Barrett's esophagus. Limited data indicate that nonsteroidal anti-inflammatory drug (NSAID) and statin use reduce the risk for esophageal adenocarcinoma. We investigated whether NSAID or statin use reduces the risk of neoplastic progression from Barrett's esophagus. Full-Text PDF c-Met Is a Marker of Pancreatic Cancer Stem Cells and Therapeutic TargetGastroenterologyVol. 141Issue 6PreviewGrowth of many different tumor types requires a population of self-renewing cancer stem cells (CSCs). c-Met is a marker of normal mouse pancreatic stem and progenitor cells; we investigated whether it is also a marker of human pancreatic CSCs that might be developed as a therapeutic target. Full-Text PDF A Clinical Prediction Rule and Platelet Count Predict Esophageal Varices in ChildrenGastroenterologyVol. 141Issue 6PreviewThe validation of noninvasive tests to diagnose esophageal varices is a priority in children because repeated endoscopic evaluations are too invasive. We measured the ability of a previously developed noninvasive clinical prediction rule (CPR) to predict the presence of esophageal varices in children. Full-Text PDF Variants in the Netrin-1 Receptor UNC5C Prevent Apoptosis and Increase Risk of Familial Colorectal CancerGastroenterologyVol. 141Issue 6PreviewExpression of the netrin-1 dependence receptor UNC5C is reduced in many colorectal tumors; mice with the UNC5C mutations have increased progression of intestinal tumors. We investigated whether specific variants in UNC5C increase risk of colorectal cancer (CRC). Full-Text PDF