Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects.

Activating mutations in the ras oncogene are not considered sufficient to induce abnormal cellular proliferation in the absence of cooperating oncogenes. We demonstrate that the conditional expression of an endogenous K-ras(G12D) allele in murine embryonic fibroblasts causes enhanced proliferation and partial transformation in the absence of further genetic abnormalities. Interestingly, K-ras(G12D)-expressing fibroblasts demonstrate attenuation and altered regulation of canonical Ras effector signaling pathways. Widespread expression of endogenous K-ras(G12D) is not tolerated during embryonic development, and directed expression in the lung and GI tract induces preneoplastic epithelial hyperplasias. Our results suggest that endogenous oncogenic ras is sufficient to initiate transformation by stimulating proliferation, while further genetic lesions may be necessary for progression to frank malignancy.

Chronic traumatic pseudoaneurysm of polytetrafluoroethylene axillofemoral bypass graft in a quadriplegic patient.

A case of nonanastomotic pseudoaneurysm of a polytetrafluoroethylene (PTFE) axillofemoral bypass graft due to chronic abrasion and pressure of the graft by external sources is reported. A quadriplegic patient presented with a pulsatile mass beneath his seatbelt straps in the mid-left chest region, consistent by computed tomography angiography and duplex ultrasound with a pseudoaneurysm of the PTFE graft, which had been placed 9 years previously. The patient underwent a successful endovascular repair of the pseudoaneurysm, and at 6-month follow-up the mass had resolved. To our knowledge this represents the first case of a chronic nonanastomotic pseudoaneurysm of a PTFE axillofemoral bypass graft secondary to abrasion and pressure that was repaired via an endovascular approach.

Mist1-KrasG12D knock-in mice develop mixed differentiation metastatic exocrine pancreatic carcinoma and hepatocellular carcinoma.

Despite the prevalence of oncogenic Kras mutations in the earliest stages of pancreatic ductal adenocarcinoma, the cellular compartment in which oncogenic Kras initiates tumorigenesis remains unknown. To address this, we have gene targeted KrasG12D into the open reading frame of Mist1, a basic helix-loop-helix transcription factor that is expressed during pancreatic development and required for proper pancreatic acinar organization. Although the pancreata of Mist1(KrasG12D/+) mutant mice predictably exhibited acinar metaplasia and dysplasia, the frequent death of these mice from invasive and metastatic pancreatic cancer with mixed histologic characteristics, including acinar, cystic, and ductal features, was unexpected and in contrast to previously described mutant mice that ectopically expressed the Kras oncogene in either acinar or ductal compartments. Interestingly, many of the mutant mice developed hepatocellular carcinoma, implicating Mist1(KrasG12D/+) cells in both pancreatic and hepatic neoplasia. Concomitant Trp53+/- mutation cooperated with Mist1(KrasG12D/+) to accelerate lethality and was associated with advanced histopathologic findings, including parenchymal liver metastasis. These findings suggest that Mist1-expressing cells represent a permissive compartment for transformation by oncogenic Kras in pancreatic tumorigenesis.