Metaplasia is the replacement of one differentiated somatic cell type with another differentiated somatic cell type in the same tissue. Typically, metaplasia is triggered by environmental stimuli, ...which may act in concert with the deleterious effects of microorganisms and inflammation. The cell of origin for intestinal metaplasia in the oesophagus and stomach and for pancreatic acinar-ductal metaplasia has been posited through genetic mouse models and lineage tracing but has not been identified in other types of metaplasia, such as squamous metaplasia. A hallmark of metaplasia is a change in cellular identity, and this process can be regulated by transcription factors that initiate and/or maintain cellular identity, perhaps in concert with epigenetic reprogramming. Universally, metaplasia is a precursor to low-grade dysplasia, which can culminate in high-grade dysplasia and carcinoma. Improved clinical screening for and surveillance of metaplasia might lead to better prevention or early detection of dysplasia and cancer.
Squamous cell carcinomas (SCCs) represent the most frequent human solid tumors and are a major cause of cancer mortality. These highly heterogeneous tumors arise from closely interconnected ...epithelial cell populations with intrinsic self-renewal potential inversely related to the stratified differentiation program. SCCs can also originate from simple or pseudo-stratified epithelia through activation of quiescent cells and/or a switch in cell-fate determination. Here, we focus on specific determinants implicated in the development of SCCs by recent large-scale genomic, genetic, and epigenetic studies, and complementary functional analysis. The evidence indicates that SCCs from various body sites, while clinically treated as separate entities, have common determinants, pointing to a unified perspective of the disease and potential new avenues for prevention and treatment.
Dotto and Rustgi focus on specific determinants implicated in the development of squamous cell carcinomas (SCCs) by recent large-scale genomic, genetic, and epigenetic studies, and complementary functional analysis. Their evidence indicates that SCCs from various body sites, while clinically treated as separate entities, have common determinants, pointing to a unified perspective of the disease and potential new avenues for prevention and treatment.
The genetic basis of sporadic colorectal cancer has illuminated our knowledge of human cancer genetics. This has been facilitated and catalyzed by an appreciation and deep understanding of the forms ...of colorectal cancer that harbor an inherited predisposition, including familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, the hamartomatous polyposis syndromes, and certain other rare syndromes. Identification of germline mutations in pivotal genes underlying the inherited forms of colorectal cancer has yielded many dividends, including functional dissection of critical molecular pathways that have been revealed to be important in development, cellular homeostasis, and cancer; new approaches in chemoprevention, molecular diagnostics and genetic testing, and therapy; and underscoring genotypic-phenotypic relationships.
Beset by poor prognosis, pancreatic ductal adenocarcinoma is classified as familial or sporadic. This review elaborates on the known genetic syndromes that underlie familial pancreatic cancer, where ...there are opportunities for genetic counseling and testing as well as clinical monitoring of at-risk patients. Such subsets of familial pancreatic cancer involve germline cationic trypsinogen or PRSS1 mutations (hereditary pancreatitis), BRCA2 mutations (usually in association with hereditary breast-ovarian cancer syndrome), CDKN2 mutations (familial atypical mole and multiple melanoma), or DNA repair gene mutations (e.g., ATM and PALB2, apart from those in BRCA2). However, the vast majority of familial pancreatic cancer cases have yet to have their genetic underpinnings elucidated, waiting in part for the results of deep sequencing efforts.
Metastasis is the leading cause of cancer-associated death but has been difficult to study because it involves a series of rare, stochastic events. To capture these events, we developed a sensitive ...method to tag and track pancreatic epithelial cells in a mouse model of pancreatic cancer. Tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis; this behavior was widely associated with epithelial-to-mesenchymal transition (EMT). Circulating pancreatic cells maintained a mesenchymal phenotype, exhibited stem cell properties, and seeded the liver. EMT and invasiveness were most abundant at inflammatory foci, and induction of pancreatitis increased the number of circulating pancreatic cells. Conversely, treatment with the immunosuppressive agent dexamethasone abolished dissemination. These results provide insight into the earliest events of cellular invasion in situ and suggest that inflammation enhances cancer progression in part by facilitating EMT and entry into the circulation.
Display omitted
► Invading cells exhibit EMT in an autochthonous model of pancreatic cancer ► Mutant cells enter the circulation before cancer is found on histology ► Circulating pancreatic cells (CPCs) express cancer stem cell-associated markers ► Inflammation is necessary and sufficient for EMT, invasion, and dissemination
Prior to detectable pancreatic tumor formation, pancreatic cells invade and enter the bloodstream, explaining why many cancer patients develop metastatic disease despite complete removal of small tumors.
CONTEXT Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently ...relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear. OBJECTIVE To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands. DESIGN, SETTING, AND PATIENTS Pooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10 206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data. MAIN OUTCOME MEASURES Performance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening). RESULTS Of 10 206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n = 3671 probands), the universal screening approach (sensitivity, 100%; 95% CI, 99.3%-100%; specificity, 93.0%; 95% CI, 92.0%-93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%-2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%-93.2%; specificity, 97.5%; 95% CI, 96.9%-98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%-2.4%; P < .001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%-93.6%; specificity, 96.7%; 95% CI, 96.0%-97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%-2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%-99.0%; specificity, 95.5%; 95% CI, 94.7%-96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%-2.6%; P < .001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach. CONCLUSION Universal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest.
The esophagus and stomach, joined by a unique transitional zone, contain actively dividing epithelial stem cells required for organ homeostasis. Upon prolonged inflammation, epithelial cells in both ...organs can undergo a cell fate switch leading to intestinal metaplasia, predisposing to malignancy. Here we discuss the biology of gastroesophageal stem cells and their role as cells of origin in cancer. We summarize the interactions between the stromal niche and gastroesophageal stem cells in metaplasia and early expansion of mutated stem-cell-derived clones during carcinogenesis. Finally, we review new approaches under development to better study gastroesophageal stem cells and advance the field.
Rustgi, Que, and Wang discuss the biology of gastroesophageal stem cells and their role as the cell-of-origin in cancer. They summarize niche-stem cell interactions in metaplasia and early expansion of mutated stem-cell-derived clones during carcinogenesis. New approaches to study gastroesophageal stem cells and advance the field are also discussed.
Esophageal adenocarcinoma (EAC) arises from Barrett esophagus (BE), intestinal-like columnar metaplasia linked to reflux esophagitis. In a transgenic mouse model of BE, esophageal overexpression of ...interleukin-1β phenocopies human pathology with evolution of esophagitis, Barrett-like metaplasia and EAC. Histopathology and gene signatures closely resembled human BE, with upregulation of TFF2, Bmp4, Cdx2, Notch1, and IL-6. The development of BE and EAC was accelerated by exposure to bile acids and/or nitrosamines, and inhibited by IL-6 deficiency. Lgr5+ gastric cardia stem cells present in BE were able to lineage trace the early BE lesion. Our data suggest that BE and EAC arise from gastric progenitors due to a tumor-promoting IL-1β-IL-6 signaling cascade and Dll1-dependent Notch signaling.
► IL-1β overexpression in the mouse esophagus induces IL-6 dependent BE and EAC ► Bile acids accelerate intestinal metaplasia and dysplasia in this mouse model of BE ► Notch signaling in columnar cells, not goblet cells is associated with carcinogenesis ► BE and EAC likely arise from gastric cardia progenitor cells
MicroRNAs (miRNAs) are single-stranded, non-coding RNA molecules that regulate gene expression at the post-transcriptional level. Genes encoding miRNAs are located in regions of the genome that are ...commonly amplified, deleted, or rearranged. They are commonly dysregulated in human cancers and known to act as oncogenes or tumor suppressors. Members of the miR-200 miRNA family are downregulated in human cancer cells and tumors due to aberrant epigenetic gene silencing and play a critical role in the suppression of epithelial-to-mesenchymal transition (EMT), tumor cell adhesion, migration, invasion and metastasis, by targeting and repressing the expression of key mRNAs that are involved in EMT (ZEB1 and ZEB2), β-catenin/Wnt signaling (β-catenin), EGFR inhibitor resistance (ERRFI-1), and chemoresistance to therapeutic agents (TUBB3). Since the miR-200 family functions as putative tumor suppressors and represent biomarkers for poorly differentiated and aggressive cancers, restoration of miR-200 expression may have therapeutic implications for the treatment of metastatic and drug-resistant tumors.
Epithelium of the colon and intestine are renewed every 3 days. In the intestine there are at least two principal stem cell pools. The first contains rapid cycling crypt-based columnar (CBC) Lgr5+ ...cells, and the second is composed of slower cycling Bmi1-expressing cells at the +4 position above the crypt base. In the colon, however, the identification of Lgr5− stem cell pools has proven more challenging. Here, we demonstrate that the intermediate filament keratin-19 (Krt19) marks long-lived, radiation-resistant cells above the crypt base that generate Lgr5+ CBCs in the colon and intestine. In colorectal cancer models, Krt19+ cancer-initiating cells are also radioresistant, while Lgr5+ stem cells are radiosensitive. Moreover, Lgr5+ stem cells are dispensable in both the normal and neoplastic colonic epithelium, as ablation of Lgr5+ stem cells results in their regeneration from Krt19-expressing cells. Thus, Krt19+ stem cells are a discrete target relevant for cancer therapy.
Display omitted
•Krt19 marks long-lived colonic and intestinal stem cells above the crypt base•Krt19 stem cells render Lgr5+ CBCs dispensable in colon and intestine•Radioresistant Krt19+ cancer-initiating cells are distinct from Lgr5+ cells•Lgr5+ cancer stem cells are dispensable in Krt19+ cell-derived APC floxed tumors
Genetic-inducible fate-mapping studies suggest that intestinal epithelial cells are replaced from at least two principal stem cell pools. Asfaha et al. now identify Krt19+ cells in the colon that are long-lived, radioresistant cancer-initiating stem cells distinct from the previously described radiosensitive Lgr5+ stem cells.
PDF
