@article{CeteciCeteciZanuccoetal.2012,
  author    = {Ceteci, Fatih and Ceteci, Semra and Zanucco, Emanuele and Thakur, Chitra and Becker, Matthias and El-Nikhely, Nefertiti and Fink, Ludger and Seeger, Werner and Savai, Rajkumar and Rapp, Ulf R.},
  title     = {E-Cadherin Controls Bronchiolar Progenitor Cells and Onset of Preneoplastic Lesions in Mice},
  series = {Neoplasia},
  volume    = {14},
  journal   = {Neoplasia},
  number    = {12},
  doi       = {10.1593/neo.121088},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135407},
  pages     = {1164-1177},
  year      = {2012},
  abstract  = {Although progenitor cells of the conducting airway have been spatially localized and some insights have been gained regarding their molecular phenotype, relatively little is known about the mechanisms regulating their maintenance, activation, and differentiation. This study investigates the potential roles of E-cadherin in mouse Clara cells, as these cells were shown to represent the progenitor/stem cells of the conducting airways and have been implicated as the cell of origin of human non-small cell lung cancer. Postnatal inactivation of E-cadherin affected Clara cell differentiation and compromised airway regeneration under injury conditions. In steady-state adult lung, overexpression of the dominant negative E-cadherin led to an expansion of the bronchiolar stem cells and decreased differentiation concomitant with canonical Wnt signaling activation. Expansion of the bronchiolar stem cell pool was associated with an incessant proliferation of neuroepithelial body-associated Clara cells that ultimately gave rise to bronchiolar hyperplasia. Despite progressive hyperplasia, only a minority of the mice developed pulmonary solid tumors, suggesting that the loss of E-cadherin function leads to tumor formation when additional mutations are sustained. The present study reveals that E-cadherin plays a critical role in the regulation of proliferation and homeostasis of the epithelial cells lining the conducting airways.},
  language  = {en}
}
@phdthesis{Thakur2012,
  author    = {Thakur, Chitra},
  title     = {Lineage tracing of metastasis in a mouse model for Non-small cell lung cancer (NSCLC)},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85420},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2012},
  abstract  = {Non-small cell lung cancer (NSCLC) is the deadliest form of lung cancer and has a poor prognosis due to its high rate of metastasis. Notably, metastasis is one of the leading causes of death among cancer patients. Despite the clinical importance, the cellular and molecular mechanisms that govern the initiation, establishment and progression of metastasis remain unclear. Moreover, knowledge gained on metastatic process was largely based on cultured or in vitro manipulated cells that were reintroduced into immune-compromised recipient mice. In the present study, a spontaneous metastasis mouse model for NSCLC was generated with a heritable fluorescent tag (DsRed) driven by CAG (combination of cytomegalovirus early enhancing element and chicken beta actin) promoter in alveolar type II cells (SpC-rtTA/TetO-Cre/LSL-DsRed). This approach is essential, keeping in mind the reprogramming nature of Myc oncogene (Rapp et al, 2009). Such genetic lineage tracing approach not only allowed us to monitor molecular and cellular changes during development of primary tumor but also led us to identify the different stages of secondary tumor development in distant organs. Upon combined expression of oncogenic C Raf-BXB and c-Myc (MYC-BXB-DsRed) in lung alveolar type II epithelial cells, macroscopic lung tumors arose comprising of both cuboidal and columnal cellular features. C Raf-BXB induced tumors (CRAF-DsRed) exhibit cuboidal morphology and is non-metastatic whereas Myc-BXB induced lung tumors (Myc-BXB-DsRed) present cuboidal-columnar cellular features and is able to undergo metastasis mainly in liver. Surprisingly, cystic lesions which were negative for SpC (Surfactant protein C) and CCSP (Clara cell secretory protein), strongly expressed DsRed proteins indicating its origin from lung alveolar type II cells. Moreover, early lung progenitor markers such as GATA4 (GATA-binding protein 4) and TTF1 (Thyroid Transcription Factor 1) were still expressed in these early cystic lesions suggesting metastasis as a faulty recapitulation of ontogeny (Rapp et al, 2008). Interestingly, mixed cystic lesions and metastatic tumors contained DsRed and SpC positive cells. These results demonstrate secondary tumor progression from cystic, mixed cystic to malignant transformation. Our results shed tremendous light on reprogramming of metastasizing cells during secondary tumor development. Moreover, such fluorescent tagged metastatic mice model can also be used to track the migration ability of metastatic cancer cell to different organs and its potential to differentiate into other cell types such as blood vessel or stromal cell within the primary tumor.},
  subject      = {Lungenkrebs},
  language  = {en}
}