Differentiation imbalance in single oesophageal progenitor cells causes clonal immortalization and field change

Multiple cancers may arise from within a clonal region of preneoplastic epithelium, a phenomenon termed ‘field change’. However, it is not known how field change develops. Here we investigate this question using lineage tracing to track the behaviour of scattered single oesophageal epithelial progenitor cells expressing a mutation that inhibits the Notch signalling pathway. Notch is frequently subject to inactivating mutation in squamous cancers. Quantitative analysis reveals that cell divisions that produce two differentiated daughters are absent from mutant progenitors. As a result, mutant clones are no longer lost by differentiation and become functionally immortal. Furthermore, mutant cells promote the differentiation of neighbouring wild-type cells, which are then lost from the tissue. These effects lead to clonal expansion, with mutant cells eventually replacing the entire epithelium. Notch inhibition in progenitors carrying p53 stabilizing mutations creates large confluent regions of doubly mutant epithelium. Field change is thus a consequence of imbalanced differentiation in individual progenitor cells.

[1]  Raphael Kopan,et al.  Bi-compartmental communication contributes to the opposite proliferative behavior of Notch1-deficient hair follicle and epidermal keratinocytes , 2007, Development.

[2]  A. Klein-Szanto,et al.  NOTCH1 and NOTCH3 coordinate esophageal squamous differentiation through a CSL-dependent transcriptional network. , 2010, Gastroenterology.

[3]  E. S. Pearson,et al.  On the Problem of the Most Efficient Tests of Statistical Hypotheses , 1933 .

[4]  Allon M. Klein,et al.  A Single Progenitor Population Switches Behavior to Maintain and Repair Esophageal Epithelium , 2012, Science.

[5]  Raphael Kopan,et al.  Elevated epidermal thymic stromal lymphopoietin levels establish an antitumor environment in the skin. , 2012, Cancer cell.

[6]  W. Pear,et al.  Impaired notch signaling promotes de novo squamous cell carcinoma formation. , 2006, Cancer research.

[7]  P. Gimotty,et al.  Notch receptor inhibition reveals the importance of cyclin D1 and Wnt signaling in invasive esophageal squamous cell carcinoma. , 2012, American journal of cancer research.

[8]  R. Metcalf,et al.  Archival analysis of p53 genetic and protein alterations in Chinese esophageal cancer. , 1991, Oncogene.

[9]  Yuchen Jiao,et al.  Comparative genomic analysis of esophageal adenocarcinoma and squamous cell carcinoma. , 2012, Cancer discovery.

[10]  F. Radtke,et al.  Loss of cutaneous TSLP-dependent immune responses skews the balance of inflammation from tumor protective to tumor promoting. , 2012, Cancer cell.

[11]  Allon M. Klein,et al.  Universal patterns of stem cell fate in cycling adult tissues , 2011, Development.

[12]  Raphael Kopan,et al.  Notch signaling in bulge stem cells is not required for selection of hair follicle fate , 2009, Development.

[13]  Y. Miki,et al.  Reduction of NOTCH1 expression pertains to maturation abnormalities of keratinocytes in squamous neoplasms , 2012, Laboratory Investigation.

[14]  D. Gillespie.  Exact Stochastic Simulation of Coupled Chemical Reactions , 1977 .

[15]  Benjamin D. Simons,et al.  A single type of progenitor cell maintains normal epidermis , 2007, Nature.

[16]  C. Lightdale,et al.  Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia. , 2012, Cancer cell.

[17]  Hans Clevers,et al.  Notch1 functions as a tumor suppressor in mouse skin , 2003, Nature Genetics.

[18]  Raphael Kopan,et al.  Skin-Derived TSLP Triggers Progression from Epidermal-Barrier Defects to Asthma , 2009, PLoS biology.

[19]  A. McKenna,et al.  The Mutational Landscape of Head and Neck Squamous Cell Carcinoma , 2011, Science.

[20]  F. Watt,et al.  Stimulation of human epidermal differentiation by Delta–Notch signalling at the boundaries of stem-cell clusters , 2000, Current Biology.

[21]  C. R. Leemans,et al.  A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. , 2003, Cancer research.

[22]  P. L. Krapivsky,et al.  Exact solution of a two-type branching process: clone size distribution in cell division kinetics , 2009, 0908.0484.

[23]  David Haussler,et al.  Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma , 2011, Proceedings of the National Academy of Sciences.

[24]  B. Powell,et al.  Expression of Notch Receptors and Ligands in the Adult Gut , 2004, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[25]  D. Slaughter,et al.  “Field cancerization” in oral stratified squamous epithelium. Clinical implications of multicentric origin , 1953, Cancer.

[26]  R. Gibbs,et al.  Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1 , 2011, Science.

[27]  C. Rubio,et al.  The induction of esophageal tumors in mice: dose and time dependency. , 1987, In vivo.

[28]  W. Pear,et al.  Notch signaling is an important regulator of type 2 immunity , 2005, The Journal of experimental medicine.

[29]  E. R. Burns,et al.  Circadian influence on the frequency of labeled mitoses method in the stratified squamous epithelium of the mouse esophagus and tongue , 1976, The Anatomical record.

[30]  Raphael Kopan,et al.  The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism , 2009, Cell.

[31]  Raphael Kopan,et al.  Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. , 2009, Cancer cell.

[32]  F. Watt,et al.  Cell shape controls terminal differentiation of human epidermal keratinocytes. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Hans Clevers,et al.  Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells , 2005, Nature.

[34]  D. Zelterman,et al.  Escaping the stem cell compartment: Sustained UVB exposure allows p53-mutant keratinocytes to colonize adjacent epidermal proliferating units without incurring additional mutations , 2001, Proceedings of the National Academy of Sciences of the United States of America.