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This review gives an account of recent advances in our knowledge of the molecular mechanisms in colorectal cancer. Genetic changes in the germ line, combined with somatic mutations, occur in familial syndromes of colorectal cancer, whereas somatic mutations are the outstanding feature of sporadic colorectal cancer. Genetic changes drive the progression from adenoma to carcinoma and probably influence individual susceptibility and response to treatment. This review gives an account of recent advances in our knowledge of the molecular mechanisms of colorectal cancer. Genetic changes in the germ line, combined with somatic mutations, occur in familial syndromes of colorectal cancer, whereas somatic mutations are the outstanding feature of sporadic colorectal cancer. Every year in the United States, 160,000 cases of colorectal cancer are diagnosed, and 57,000 patients die of the disease, making it the second leading cause of death from cancer among adults. 1 The disease begins as a benign adenomatous polyp, which develops into an advanced adenoma with high-grade dysplasia and then progresses to an invasive cancer. 2 Invasive cancers that are confined within the wall of the colon (tumor–node–metastasis stages I and II) are curable, but if untreated, they spread to regional lymph nodes (stage III) and then metastasize to distant sites (stage IV). 3 – 5 Stage I and II tumors are . . .

Introduction Advances in our understanding of the molecular genetics and epigenetics of colorectal cancer have led to novel insights into the pathogenesis of this common cancer. These advances have revealed that there are molecular subtypes of colon polyps and colon cancer and that these molecular subclasses have unique and discrete clinical and pathological features. Although the molecular characterization of these subgroups of colorectal polyps and cancer is only partially understood at this time, it does appear likely that classifying colon polyps and cancers based on their genomic instability and/or epigenomic instability status will eventually be useful for informing approaches for the prevention and early detection of colon polyps and colorectal cancer. Conclusions In this review, we will discuss our current understanding of the molecular pathogenesis of the polyp to cancer sequence and the potential to use this information to direct screening and prevention programs.

Ablation of the kinases Mst1 and Mst2, orthologs of the Drosophila antiproliferative kinase Hippo, from mouse intestinal epithelium caused marked expansion of an undifferentiated stem cell compartment and loss of secretory cells throughout the small and large intestine. Although median survival of mice lacking intestinal Mst1/Mst2 is 13 wk, adenomas of the distal colon are common by this age. Diminished phosphorylation, enhanced abundance, and nuclear localization of the transcriptional coactivator Yes-associated protein 1 (Yap1) is evident in Mst1/Mst2-deficient intestinal epithelium, as is strong activation of β-catenin and Notch signaling. Although biallelic deletion of Yap1 from intestinal epithelium has little effect on intestinal development, inactivation of a single Yap1 allele reduces Yap1 polypeptide abundance to nearly wild-type levels and, despite the continued Yap hypophosphorylation and preferential nuclear localization, normalizes epithelial structure. Thus, supraphysiologic Yap polypeptide levels are necessary to drive intestinal stem cell proliferation. Yap is overexpressed in 68 of 71 human colon cancers and in at least 30 of 36 colon cancer-derived cell lines. In colon-derived cell lines where Yap is overabundant, its depletion strongly reduces β-catenin and Notch signaling and inhibits proliferation and survival. These findings demonstrate that Mst1 and Mst2 actively suppress Yap1 abundance and action in normal intestinal epithelium, an antiproliferative function that frequently is overcome in colon cancer through Yap1 polypeptide overabundance. The dispensability of Yap1 in normal intestinal homeostasis and its potent proliferative and prosurvival actions when overexpressed in colon cancer make it an attractive therapeutic target.

15-prostaglandin dehydrogenase (15-PGDH) is a negative regulator of tissue stem cells that acts via enzymatic activity of oxidizing and degrading PGE2, and related eicosanoids, that support stem cells during tissue repair. Indeed, inhibiting 15-PGDH markedly accelerates tissue repair in multiple organs. Here we have used cryo-electron microscopy to solve the solution structure of native 15-PGDH and of 15-PGDH individually complexed with two distinct chemical inhibitors. These structures identify key 15-PGDH residues that mediate binding to both classes of inhibitors. Moreover, we identify a dynamic 15-PGDH lid domain that closes around the inhibitors, and that is likely fundamental to the physiologic 15-PGDH enzymatic mechanism. We furthermore identify two key residues, F185 and Y217, that act as hinges to regulate lid closing, and which both inhibitors exploit to capture the lid in the closed conformation, thus explaining their sub-nanomolar binding affinities. These findings provide the basis for further development of 15-PGDH targeted drugs as therapeutics for regenerative medicine. Inhibition of 15-prostaglandin dehydrogenase (15-PGDH) is a promising therapeutic target for regenerative medicine. We report the structure of 15-PGDH in complex with two different inhibitors. Unexpectedly, access to the binding pocket is regulated by a dynamic “lid” of the enzyme.

Why are lymph nodes a strong predictor of metastases? “What did the lymph nodes show?” is the question whose answer is apprehensively awaited by every colon cancer patient. Even in the age of molecular medicine, the absence or presence of colon cancer spread to regional lymph nodes remains the strongest predictor of whether surgery has cured the cancer, or whether an individual may harbor occult metastatic disease and thus require adjuvant chemotherapy to reduce the risk of lethal cancer metastases recurring in distant organs ( 1 – 3 ). But is colon cancer spread to lymph nodes a precursor of spread to another organ (e.g., the liver) or rather an indicator of colon cancer cells' metastatic competence? On page 55 of this issue, Naxerova et al. ( 4 ) provide molecular evidence that, in many instances, colon cancer metastases in the liver (and possibly other distant organs), originate from distinct clone(s) that differ from the founder(s) of cancer deposits in the lymph nodes.

Tissue damage can be caused by injury, disease, and even certain medical treatments. There is great interest in identifying drugs that accelerate tissue regeneration and recovery, especially drugs that might benefit multiple organ systems. Zhang et al. describe a compound with this desired activity, at least in mice (see the Perspective by FitzGerald). SW033291 promotes recovery of the hematopoietic system after bone marrow transplantation, prevents the development of ulcerative colitis in the intestine, and accelerates liver regeneration after hepatic surgery. It acts by inhibiting an enzyme that degrades prostaglandins, lipid signaling molecules that have been implicated in tissue stem cell maintenance. Science , this issue 10.1126/science.aaa2340 ; see also p. 1208 A compound that inhibits prostaglandin degradation enhances tissue regeneration in multiple organs in mice. [Also see Perspective by FitzGerald ] Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here, we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. The same compound also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. Thus, 15-PGDH inhibition may be a valuable therapeutic strategy for tissue regeneration in diverse clinical contexts.

Tumor epithelial cells develop within a microenvironment consisting of extracellular matrix, growth factors, and cytokines produced by nonepithelial stromal cells. In response to paracrine signals from tumor epithelia, stromal cells modify the microenvironment to promote tumor growth and metastasis. Here, we identify interleukin 33 (IL-33) as a regulator of tumor stromal cell activation and mediator of intestinal polyposis. In human colorectal cancer, IL-33 expression was induced in the tumor epithelium of adenomas and carcinomas, and expression of the IL-33 receptor, IL1RL1 (also referred to as IL1-R4 or ST2), localized predominantly to the stroma of adenoma and both the stroma and epithelium of carcinoma. Genetic and antibody abrogation of responsiveness to IL-33 in theApcMin/ ⁺ mouse model of intestinal tumorigenesis inhibited proliferation, induced apoptosis, and suppressed angiogenesis in adenomatous polyps, which reduced both tumor number and size. Similar to human adenomas, IL-33 expression localized to tumor epithelial cells and expression of IL1RL1 associated with two stromal cell types, subepithelial myofibroblasts and mast cells, inApcMin/ ⁺ polyps. In vitro, IL-33 stimulation of human subepithelial myofibroblasts induced the expression of extracellular matrix components and growth factors associated with intestinal tumor progression. IL-33 deficiency reduced mast cell accumulation inApcMin/ ⁺ polyps and suppressed the expression of mast cell-derived proteases and cytokines known to promote polyposis. Based on these findings, we propose that IL-33 derived from the tumor epithelium promotes polyposis through the coordinated activation of stromal cells and the formation of a protumorigenic microenvironment.

INTRODUCTION:Preliminary data suggest that an encapsulated balloon (EsoCheck), coupled with a 2 methylated DNA biomarker panel (EsoGuard), detects Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) with high accuracy. The initial assay requires sample freezing upon collection. The purpose of this study was to assess a next-generation EsoCheck sampling device and EsoGuard assay in a much-enlarged multicenter study clinically enhanced by using a Clinical Laboratory Improvement Amendments of 1988-compliant assay and samples maintained at room temperature.METHODS:Cases with nondysplastic BE (NDBE), dysplastic BE (indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia), EAC, junctional adenocarcinoma, plus endoscopy controls without esophageal intestinal metaplasia, were prospectively enrolled. Medical assistants at 6 institutions delivered the encapsulated balloon per orally with inflation in the stomach. The inflated balloon sampled the distal 5 cm of the esophagus and then was deflated and retracted into the capsule, preventing sample contamination. EsoGuard bisulfite sequencing assayed levels of methylated vimentin and methylated cyclin A1.RESULTS:A total of 243 evaluable patients-88 cases (median age 68 years, 78% men, 92% White) and 155 controls (median age 57 years, 41% men, 88% White)-underwent adequate EsoCheck sampling. The mean procedural time was approximately 3 minutes. Cases included 31 with NDBE, 16 with indefinite for dysplasia/low-grade dysplasia, 23 with high-grade dysplasia, and 18 with EAC/junctional adenocarcinoma. Thirty-seven NDBE and dysplastic BE cases (53%) were short-segment BE (<3 cm). Overall sensitivity was 85% (95% confidence interval 0.78-0.93) and specificity was 85% (95% confidence interval 0.79-0.90). Sensitivity for NDBE was 84%. EsoCheck/EsoGuard detected 100% of cancers (n = 18).DISCUSSION:EsoCheck/EsoGuard demonstrated high sensitivity and specificity in detecting BE and BE-related neoplasia.

Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. To catalog the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene \"mountains\" and a much larger number of gene \"hills\" that are mutated at low frequency. We describe statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications for understanding the nature and heterogeneity of human cancers and for using personal genomics for tumor diagnosis and therapy.