Evolution and dynamics of pancreatic cancer progression

Yachida, Shinichi; Iacobuzio‐Donahue, Christine A.

doi:10.1038/onc.2013.29

Cited by 169 publications

(142 citation statements)

References 82 publications

(94 reference statements)

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“…There is growing evidence that individual tumors are composed of multiple clonal subsets with differing mutations resulting in various levels of intra-tumoral heterogeneity (ITH) (24)(25)(26)(27)(28)(29)(30)(31). Comparative sequencing of multiple PDAC lesions suggested that most somatic mutations occur in the primary tumor (founder mutations) prior to metastatic dissemination, and 'progressor' mutations occur during further clonal evolution(32).…”

Section: Intra-tumoral Heterogeneity In Pancreatic Cancermentioning

confidence: 99%

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

Dreyer

Chang

Bailey

et al. 2017

Clinical Cancer Research

141

114

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Pancreatic cancer has become the 3 rd leading cause of cancer death, with little improvement in outcomes despite decades of research. Surgery remains the only chance of cure, yet, only 20% will be alive at 5 years after pancreatic resection. Few chemotherapeutics provide any improvement in outcome, and even then, for approved therapies, the survival benefits are marginal. Genomic sequencing studies of pancreatic cancer have revealed a small set of consistent mutations found in most pancreatic cancers, and beyond that a low prevalence for targetable mutations. This may explain the failure of conventional clinical trial designs to show any meaningful survival benefit, except in small and undefined patient sub-groups. With the development of next generation sequencing technology, genomic sequencing and analysis can be performed in a clinically meaningful turnaround time. This can identify therapeutic targets in individual patients and personalize treatment selection.Incorporating pre-clinical discovery and molecularly guided therapy into clinical trial design has the potential to significantly improve outcomes in this lethal malignancy. In this review, we discuss the findings of recent large scale genomic sequencing projects in pancreatic cancer and the potential relevance of these data to therapeutic development.3

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Section: Intra-tumoral Heterogeneity In Pancreatic Cancermentioning

confidence: 99%

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

Dreyer

Chang

Bailey

et al. 2017

Clinical Cancer Research

141

114

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“…Most clinical cancer cells evolve and exist in a hostile microenvironment, characterized by acidosis, hypoxia, oxygen radicals (ROS) and nutrient deprivation. 2,3 It has been known that this environment induces genomic instability and selects for emergence of aggressive clones (clades) of cells, leading to genomic diversity, evident in intratumoral genetic heterogeneity, [4][5][6][7] which is a proximal cause of malignance and resistance. 8 Using dorsal window chambers, we have demonstrated that acidic environments promote tumor invasion and growth by degrading adjacent extracellular matrix].…”

Section: Introductionmentioning

confidence: 99%

Phenotypic changes of acid-adapted cancer cells push them toward aggressiveness in their evolution in the tumor microenvironment

Damaghi

Gillies

2017

Cell Cycle

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The inter-and intra-tumoral metabolic phenotypes of tumors are heterogeneous, and this is related to microenvironments that select for increased glycolysis. Increased glycolysis leads to decreased pH, and these local microenvironment effects lead to further selection. Hence, heterogeneity of phenotypes is an indirect consequence of altering microenvironments during carcinogenesis. In early stages of growth, tumors are stratified, with the most aggressive cells developing within the acidic interior of the tumor. However, these cells eventually find themselves at the tumor edge, where they invade into the normal tissue via acid-mediated invasion. We believe acid adaptation during the evolution of cancer cells in their niche is a Rubicon that, once crossed, allows cells to invade into and outcompete normal stromal tissue. In this study, we illustrate some acid-induced phenotypic changes due to acidosis resulting in more aggressiveness and invasiveness of cancer cells.

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“…A genetic progression model for pancreatic cancer was recently established [36]. In their model, metastatic PDAC arises from PanIN (pancreatic intraepithelial neoplasia) through multiple genetic and epigenetic events.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling of Pancreatic Cancer Reveals a Significant Deregulation of the TGF-β Pathway and the Discovery of Genes for Prognosis

Klein¹,

Pospisil²

2014

Global J. Hum. Genet. Gene Ther.

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Abstract:We have re-analyzed previously published gene expression data from ninety-four pancreatic ductal adenocarcinomas (PDAC) samples. We determined the gene expression profile of genes differentially expressed in PDAC compared to non-malignant pancreatic tissue. Using the 100 top-ranked genes, we were able to discriminate between PDAC and non-malignant pancreatic tissue. A hierarchical cluster analysis revealed only a 6 % false discovery rate. The prognostic strength of these discriminative genes was underscored by a SVM classification and 3-fold cross validation with an 89 % correct class assignment. The annotation of the 100 top-ranked genes revealed that most of the genes were involved in the processes of signal transduction, cell adhesion, extracellular matrix organization and cell migration. The most greatly affected signal cascade was the transforming growth factor receptor signaling pathway, which was significantly enriched in the top-ranked genes. Furthermore, we identified eleven genes that were associated with good prognosis.

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Evolution and dynamics of pancreatic cancer progression

Cited by 169 publications

References 82 publications

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

Phenotypic changes of acid-adapted cancer cells push them toward aggressiveness in their evolution in the tumor microenvironment

Gene Expression Profiling of Pancreatic Cancer Reveals a Significant Deregulation of the TGF-β Pathway and the Discovery of Genes for Prognosis

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