Stem cell dynamics and pretumor progression in the intestinal tract

Colorectal carcinogenesis is a process that follows a stepwise cascade that goes from the normal to an invisible pretumor stage ultimately leading to grossly visible tumor progression. During pretumor progression, an increasing accumulation of genetic alterations occurs, by definition without visible manifestations. It is generally thought that stem cells in the crypt base are responsible for this initiation of colorectal cancer progression because they are the origin of the differentiated epithelial cells that occupy the crypt. Furthermore, they are characterized by a long life span that enables them to acquire these cumulative mutations. Recent studies visualized the dynamics of stem cells both in vitro and in vivo. Translating this work into clinical applications will contribute to the evaluation of patients’ predisposition for colorectal carcinogenesis and may help in the design of preventive measures for high-risk groups. In this review, we outline the progress made in the research into tracing stem cell dynamics. Further, we highlight the importance and potential clinical value of tracing stem cell dynamics in pretumor progression

Stem cell dynamics and pretumor progression in the intestinal tract

Colorectal carcinogenesis is a process that follows a stepwise cascade that goes from the normal to an invisible pretumor stage ultimately leading to grossly visible tumor progression. During pretumor progression, an increasing accumulation of genetic alterations occurs, by definition without visible manifestations. It is generally thought that stem cells in the crypt base are responsible for this initiation of colorectal cancer progression because they are the origin of the differentiated epithelial cells that occupy the crypt. Furthermore, they are characterized by a long life span that enables them to acquire these cumulative mutations. Recent studies visualized the dynamics of stem cells both in vitro and in vivo. Translating this work into clinical applications will contribute to the evaluation of patients’ predisposition for colorectal carcinogenesis and may help in the design of preventive measures for high-risk groups. In this review, we outline the progress made in the research into tracing stem cell dynamics. Further, we highlight the importance and potential clinical value of tracing stem cell dynamics in pretumor progression

Multivariate analysis of immunohistochemical evaluation of protein expression in pancreatic ductal adenocarcinoma reveals prognostic significance for persistent Smad4 expression only

Background Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a 5-year survival rate of <5% and an average survival of only 6 months. Although advances have been made in understanding the pathogenesis of PDAC in the last decades, overall survival has not changed. Various clinicopathological and immunohistological variables have been associated with survival time but the exact role that these variables play in relation to survival is not clear. Methods and results To examine how the variables affected survival independently, multivariate analysis was conducted in a study group of 78 pancreatic ductal adenocarcinomas. The analysis included clinicopathological parameters and protein expression examined by immunohistochemistry of p53, Smad4, Axl, ALDH, MSH2, MSH6, MLH1 and PMS2. Lymph node ratio <0.2 (p=0.004), tumor free resection margins (p=0.044) and Smad4 expression (p=0.004) were the only independent prognostic variables in the multivariate analysis. Expression of the other proteins examined was not significantly related to survival. Conclusions Discrepancies with other studies in this regard are likely due to differences in quantification of immunohistochemical staining and the lack of multivariate analysis. It underscores the importance to standardize the methods used for the application of immunohistochemistry in prognostic studie

Undifferentiated carcinoma with osteoclastic giant cells (UCOCGC) of the pancreas associated with the familial atypical multiple mole melanoma syndrome (FAMMM)

The familial atypical multiple mole melanoma (FAMMM) syndrome is caused by a germline mutation of p16. More than 90% of the sporadic pancreatic carcinomas contain genetic alterations that inactivate p16. Patients with the FAMMM syndrome have an increased risk of developing pancreatic cancer. Ductal adenocarcinoma is the most common cancer of the pancreas and the one encountered in patients with FAMMM syndrome. Undifferentiated carcinoma with osteoclastic giant cells, also referred to as UCOCGC of the pancreas, is a rare variant of pancreatic cancer. An UCOCGC of the pancreas associated with FAMMM syndrome is described in this report. Molecular analysis confirmed a germline p16-Leiden deletion in the UCOCGC, accompanied by somatic loss of heterozygosity of the second p16 allele, and absence of p16 protein expression in the neoplastic cells. It is the first case reported and it provides additional evidence that UCOCGC can be considered as a variant of conventional ductal adenocarcinoma of the pancrea

Options, Futures, and Other Derivatives in Russia: An Overview

We report a case of pseudomyxoma peritonei (PMP) arising in a 62-year-old male patient with Lynch syndrome (LS). The patient's medical history included an adenocarcinoma of the colon for which a right hemicolectomy was performed and a pancreatectomy due to an intraductal papillary mucinous neoplasm (IPMN) with invasive colloid carcinoma. It was considered that the PMP could be a metastasis of the earlier colonic or pancreatic carcinoma. The pancreatic carcinoma, colon carcinoma, and PMP tissues were examined, and immunohistochemical and molecular analyses were performed to determine the PMP origin. Histopathologic examination revealed morphological similarities with the pancreatic colloid carcinoma, and further immunohistochemical and molecular analyses, including a shared GNAS mutation, confirmed the pancreatic origin of the PMP. In conclusion, this is a unique case of a patient with LS presenting with PMP originating from an IPMN with invasive colloid carcinoma, several years after pancreatectomy. The present case has important diagnostic implications. The IPMN should be considered as a rare extracolonic manifestation of LS, and pancreatic carcinoma origin should be considered in patients presenting with PMP. This case report highlights the added value of molecular diagnostics in daily pathology practice

Pyogenic granuloma: an unrecognized cause of gastrointestinal bleeding

Pyogenic granuloma is a lobular capillary hemangioma that mostly occurs on the skin, but it is also encountered on the mucosal surface of the oral cavity. Only a few cases in other parts of the digestive tract have been reported in Japanese patients. In this report, two Caucasian patients are described, who presented with gastrointestinal bleeding due to the presence of a pyogenic granuloma. One was located in the distal esophagus and could be treated with local excision and laser-photocoagulation therapy. The other one was located in the small intestine and was removed by surgical resection. Although extremely rare, pyogenic granuloma as a cause of gastrointestinal bleeding needs consideration. The lesion is benign, presumably reactive and can be adequately treated by excision or laser photocoagulation. Immunohistochemistry and/or polymerase chain reaction for herpesvirus 8 can reliably distinguish pyogenic granuloma from Kaposi's sarcoma, an important differential diagnosi

Pancreatic intraepithelial neoplasia and pancreatic tumorigenesis: of mice and men

Context.-Pancreatic cancer has a poor prognosis with a 5-year survival of less than 5%. Early detection is at present the only way to improve this outlook. This review focuses on the recent advances in our understanding of pancreatic carcinogenesis, the scientific evidence for a multistaged tumor progression, and the role genetically engineered mouse models can play in recapitulating the natural course and biology of human disease. Objectives.-To illustrate the stepwise tumor progression of pancreatic cancer and genetic alterations within the different stages of progression and to review the findings made with genetically engineered mouse models concerning pancreatic carcinogenesis. Data Sources.-A review of recent literature on pancreatic tumorigenesis and genetically engineered mouse models. Conclusions.-Pancreatic cancer develops through stepwise tumor progression in which preinvasive stages, called pancreatic intraepithelial neoplasia, precede invasive pancreatic cancer. Genetic alterations in oncogenes and tumor suppressor genes underlying pancreatic cancer are also found in pancreatic intraepithelial neoplasia. These mutations accumulate during progression through the consecutive stages of pancreatic intraepithelial neoplasia lesions. Also in genetically engineered mouse models of pancreatic ductal adenocarcinoma, tumorigenesis occurs through stepwise progression via consecutive mouse pancreatic intraepithelial neoplasia, and these models provide important tools for clinical applications. Nevertheless differences between mice and men still remai

Mice lacking functional CD95-ligand display reduced proliferation of the intestinal epithelium without gross homeostatic alterations

Homeostasis of the continuously self-renewing intestinal tract involves cell proliferation, migration, differentiation along the crypt-villus-axis and shedding of cells into the gut lumen. CD95-ligand (FAS-ligand, CD95L) is a cytokine that is known for its capacity to induce apoptosis by binding its cognate receptor, CD95 (Fas). More recently, it was discovered that CD95L can also induce other cellular responses, such as proliferation, differentiation and cell migration. CD95L is highly expressed in Paneth cells of the small intestine which are in close contact with intestinal stem cells. This suggests a potential role for CD95L in controlling stem cell function and, possibly, intestinal homeostasis. We analyzed the intestines of mice deficient for functional CD95L (gld) for potential alterations in the diversity of stem-cell-lineages and parameters of intestinal homeostasis. Stem cell diversity was assessed by analyzing methylation patterns of the non-transcribed mMYOD gene. Proliferation was analyzed by BrdU labeling and differentiation was assessed by immunohistochemistry. Of all parameters analyzed, only epithelial cell proliferation was significantly reduced in the small intestines of gld-mice, but not in their colons which lack CD95L expression. We conclude that CD95L has a proliferation-stimulating role during normal turnover of the small intestine, but has a marginal effect on overall intestinal homeostasis

Analysis of LKB1 mutations and other molecular alterations in pancreatic acinar cell carcinoma

Acinar cell carcinoma is a rare non-ductal neoplasm of the pancreas with poorly defined molecular genetic features. Recently, biallelic inactivation of LKB1 was described in an acinar cell carcinoma of a Peutz-Jeghers patient carrying a heterozygous germline LKB1 mutation, and inhibition of mTOR signaling resulted in partial remission of the tumor. To explore the potential of mTOR inhibitors in sporadic acinar cell carcinoma, the LKB1 gene was investigated in five sporadic acinar cell carcinomas by sequence analysis, methylation analysis and mRNA expression. In addition, microsatellite instability and methylation of a number of tumor suppressor genes were investigated and KRAS, TP53, CDKN1A, SMAD4 and CTNNB1 were studied by mutation analysis and immunohistochemistry. No mutations, deletions or promoter hypermethylation of LKB1 were found in any of the sporadic acinar cell carcinomas, and mRNA expression of LKB1 was not altered. Amplifications at chromosome 20q and 19p were found in 100 and 80% of the cases, respectively. In addition, hypermethylation of one or more tumor suppressor genes was found in 80% of cases. One case harbored a TP53 mutation, and expression of SMAD4 and CTNNB1 was altered in one case each. No KRAS mutations or microsatellite instability were found. To conclude, no evidence for a role for LKB1 in tumorigenesis of sporadic pancreatic acinar cell carcinoma was found. However, copy number variations and hypermethylation were found in a majority of cases. Molecular pathways involved in acinar cell carcinoma-tumorigenesis differ from those involved in ductal pancreatic neoplasms. Further studies are needed to increase our understanding of molecular pathogenesis of acinar cell carcinoma, which may eventually result in development of new therapeutic target