| dc.description.abstract |
<p>Studying the early stages of cancer can provide important insight into the molecular
basis of the disease. In many human cancers, such as prostate, pancreatic, and colon
cancer, a pre-neoplastic, or intermediate, stage of the disease has been identified.
The pre-neoplastic stage is presumed to be a transition during which normal cells
undergo malignant transformation. However, the link between the pre-neoplastic cells
and end-stage disease has never been formally established. To investigate the fate
of such cells, the patched (ptc) mutant mouse, a model for the brain tumor medulloblastoma
was used. Pre-neoplastic cells (PNCs) are found in most ptc mutants during early adulthood,
but only 15% of these animals develop tumors. Although PNCs are found in mice that
develop tumors, the ability of PNCs to give rise to tumors has never been demonstrated
directly, and the fate of cells that do not form tumors remains unknown. Genetic fate
mapping and orthotopic transplantation provided definitive evidence that PNCs give
rise to tumors and showed that the predominant fate of PNCs that do not form tumors
is differentiation. Moreover, N-myc, a gene commonly amplified in medulloblastoma,
can dramatically alter the fate of PNCs, preventing differentiation and driving progression
to tumors. Importantly, N-myc allows PNCs to grow independently of hedgehog signaling,
making the resulting tumors resistant to hedgehog antagonists. These studies provide
the first direct evidence that PNCs can give rise to tumors, and demonstrate that
identification of genetic changes that promote tumor progression is critical for designing
effective therapies for cancer.</p>
|
|
