sirolimus and Carcinoma--Acinar-Cell

The role of tuberous sclerosis complex (TSC) in the pathogenesis of pancreatic cancers remains largely unknown. The present study shows that neurogenin 3 directed Cre deletion of Tsc1 gene induces the development of pancreatic acinar carcinoma. By cross-breeding the Neurog3-cre mice with Tsc1 (loxp/loxp) mice, we generated the Neurog3-Tsc1-/- transgenic mice in which Tsc1 gene is deleted and mTOR signaling activated in the pancreatic progenitor cells. All Neurog3-Tsc1-/- mice developed notable adenocarcinoma-like lesions in pancreas starting from the age of 100 days old. The tumor lesions are composed of cells with morphological and molecular resemblance to acinar cells. Metastasis of neoplasm to liver and lung was detected in 5% of animals. Inhibition of mTOR signaling by rapamycin significantly attenuated the growth of the neoplasm. Relapse of the neoplasm occurred within 14 days upon cessation of rapamycin treatment. Our studies indicate that activation of mTOR signaling in the pancreatic progenitor cells may trigger the development of acinar carcinoma. Thus, mTOR may serve as a potential target for treatment of pancreatic acinar carcinoma.

Topics: Animals; Antibiotics, Antineoplastic; Basic Helix-Loop-Helix Transcription Factors; Blotting, Western; Carcinoma, Acinar Cell; Female; Humans; Immunohistochemistry; Liver Neoplasms; Lung Neoplasms; Male; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nerve Tissue Proteins; Pancreas; Pancreatic Neoplasms; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins; Ultrasonography

Cross-talk between the canonical Wnt and mammalian target of rapamycin (mTOR) signaling pathways occurs at multiple levels in the cell and likely contributes to the oncogenic effects of these pathways in human cancer. To gain more insight into the interplay between Wnt and mTOR signaling in salivary gland tumorigenesis, we developed a mouse model in which both pathways are constitutively activated by the conditional inactivation of the Apc and Pten tumor suppressor genes. Loss of either Apc or Pten alone did not cause tumor development. However, deletion of both genes resulted in the formation of salivary gland tumors with 100% penetrance and short latency that showed a remarkable morphologic similarity to human acinic cell carcinoma. Treatment of tumor-bearing mice using the mTOR inhibitor rapamycin led to complete regression of tumors, indicating that tumor growth was dependent on continued mTOR signaling. Importantly, we found that human salivary gland acinic cell carcinomas also express markers of activated mTOR signaling. Together, these results suggest that aberrant activation of mTOR signaling plays a pivotal role in acinar cell neoplasia of the salivary gland. Because rapamycin analogues are approved for treating other types of human malignancies, our findings suggest that rapamycin therapy should be evaluated for treating patients with salivary gland acinic cell carcinoma.

Topics: Adenomatous Polyposis Coli Protein; Animals; Antibiotics, Antineoplastic; Apoptosis; Carcinoma, Acinar Cell; Female; Flow Cytometry; Humans; Immunohistochemistry; Male; Mice; Mice, 129 Strain; Mice, Knockout; PTEN Phosphohydrolase; Salivary Gland Neoplasms; Salivary Glands; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Burden

We have generated an EL1-luc/TAg transgenic mouse model that develops spontaneous and bioluminescent acinar cell carcinomas. We applied this model to noninvasively monitor tumor development and drug response.. EL1-luc/TAg transgenic mice of 11 weeks of age were treated with rapamycin (5 mg/kg, i.p.) or vehicle for 6 to 12 weeks. Tumor development was monitored through bioluminescence imaging and necropsy at the study end point.. EL1-luc/TAg transgenic mice showed pancreas-specific bioluminescence signal before tumor progression and produced increasing light emission from the onset of the pancreatic acinar cell carcinomas. The latency of tumor development ranged from 10 to >20 weeks of age in these mice. Progression of the primary acinar cell carcinoma was accompanied by emergence of metastatic lesions in the abdominal organs, including liver and gastrointestinal fat tissues. Rapamycin treatment suppressed tumor development.. The EL1-luc/TAg mouse provides a noninvasive approach for monitoring spontaneous acinar cell carcinoma development and comprises a convenient tool for the evaluation of novel therapeutics against pancreatic cancers. Tumor growth suppression through inhibition of the mammalian target of rapamycin pathway further validates this model as clinically relevant.

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma, Acinar Cell; Disease Models, Animal; Drug Monitoring; Longitudinal Studies; Luminescent Measurements; Mice; Mice, Transgenic; Pancreas; Pancreatic Neoplasms; Sirolimus