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.
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.
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► 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.
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.
The intestinal epithelium is highly proliferative and consists of crypt invaginations that house stem cells and villus projections with differentiated cells. There exists a dynamic equilibrium ...between proliferation, migration, differentiation, and senescence that is regulated by several factors. Among these are RNA binding proteins (RBPs) that bind their targets in a both context dependent and independent manner. RBP–RNA complexes act as rheostats by regulating expression of RNAs both co- and post-transcriptionally. This is important, especially in response to intestinal injury, to fuel regeneration. The manner in which these RBPs function in the intestine and their interactions with other pivotal pathways in colorectal cancer may provide a framework for new insights and potential therapeutic applications.
Intestinal epithelial cells harbor proliferation–differentiation gradient spanning crypts to villi. This is regulated by two stem cell populations.
RNA binding proteins (RBPs) provide a nexus of regulation of intestinal epithelial homeostasis, adaptation to injury, and contribution to malignant transformation.
These specific RBPs that have been reported in the published literature in the context of intestinal epithelial biology and colorectal cancer include: LIN28, Musashi (MSI), insulin-like growth factor 2 mRNA binding proteins (IGF2BP/IMP), MEX3A, CUGBP Elav-Like Family Member 1 (CELF1), RNA binding protein 3 (RBM3), and Hu-Antigen R (HUR).
These specific RBPs play important roles in intestinal regeneration following injury.
These specific RBPs are overexpressed in human colorectal cancer and overexpression of some of them has been shown to be sufficient to transform the intestinal epithelium in mouse models.
EMT, MET, Plasticity, and Tumor Metastasis Bakir, Basil; Chiarella, Anna M.; Pitarresi, Jason R. ...
Trends in cell biology,
10/2020, Letnik:
30, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Cancer cell identity and plasticity are required in transition states, such as epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET), in primary tumor initiation, ...progression, and metastasis. The functional roles of EMT, MET, and the partial state (referred to as pEMT) may vary based on the type of tumor, the state of dissemination, and the degree of metastatic colonization. Herein, we review EMT, MET, pEMT, and plasticity in the context of tumor metastasis.
Cellular plasticity plays an important role in tumor progression, metastasis, and chemoresistance.Cells may shift along the EMT–MET spectrum, such that EMT and MET may not be dichotomous fates, as evidenced by partial EMT.The requirements of EMT and MET in primary tumorigenesis and metastasis are context dependent and require rigorous evaluation of the model systems employed.
Esophageal Carcinoma Rustgi, Anil K; El-Serag, Hashem B
The New England journal of medicine,
12/2014, Letnik:
371, Številka:
26
Journal Article
Recenzirano
The 5-year survival rate in esophageal cancer, although poor, has improved over the past decade. This review discusses the epidemiologic aspects, pathogenesis, prevention, and therapy of esophageal ...adenocarcinoma and squamous-cell carcinoma, focusing on recent advances.
Esophageal adenocarcinoma has become the predominant type of esophageal cancer in North America and Europe, and gastroesophageal reflux disease (GERD) and obesity are the main risk factors. Barrett’s esophagus, the recognized precursor lesion, can be detected by means of endoscopic screening, which is followed by treatment of precancerous lesions and monitoring for the development of neoplastic progression. Esophageal squamous-cell carcinoma remains the predominant esophageal cancer in Asia, Africa, and South America and among African Americans in North America. Alcohol and tobacco use are the main risk factors, and esophageal squamous dysplasia is the precursor lesion. The 5-year survival rate for . . .
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.
Colorectal metastasis is a predominant basis for mortality and poses challenges with current therapies.Colorectal metastasis relies on genetic factors, interactions with the tumor microenvironment, ...and other external factors.Therapeutic interventions targeting metastatic colorectal cancer (mCRC) can be classified into three categories: systemic chemotherapy, targeted therapy, and immunotherapy.Emerging technologies and innovations to treat mCRC, such as adoptive cell transfer, fecal microbiota transplantation, and nanoparticles, are underway.
Metastatic colorectal cancer (mCRC) remains a lethal disease with an approximately 14% 5-year survival rate. While early-stage colorectal cancer (CRC) can be cured by surgery with or without adjuvant chemotherapy, mCRC cannot be eradicated due to a large burden of disseminated cancer cells comprising therapy-resistant metastasis-competent cells. To address this gap, recent studies have focused on further elucidating the molecular mechanisms underlying colorectal metastasis and recognizing the limitations of available therapeutic interventions. In this review, we discuss newfound factors that regulate CRC cell dissemination and colonization of distant organs, such as genetic mutations, identification of metastasis-initiating cells (MICs), epithelial–mesenchymal transition (EMT), and the tumor microenvironment (TME). We also review current treatments for mCRC, therapeutic regimens undergoing clinical trials, and trending preclinical studies being investigated to target treatment-resistant mCRC.
The pancreas is a complex organ comprised of three critical cell lineages: islet (endocrine), acinar, and ductal. This review will focus upon recent insights and advances in the biology of pancreatic ...ductal cells. In particular, emphasis will be placed upon the regulation of ductal cells by specific transcriptional factors during development as well as the underpinnings of acinar-ductal metaplasia as an important adaptive response during injury and regeneration. We also address the potential contributions of ductal cells to neoplastic transformation, specifically in pancreatic ductal adenocarcinoma.
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