Somatic activation of the K-ras oncogene causes early onset lung cancer in mice

Abstract

About 30% of human tumours carry ras gene mutations. Of the three genes in this family (composed of K-ras, N-ras and H-ras), K-ras is the most frequently mutated member in human tumours, including adenocarcinomas of the pancreas ( approximately 70-90% incidence), colon ( approximately 50%) and lung ( approximately 25-50%). To construct mouse tumour models involving K-ras, we used a new gene targeting procedure to create mouse strains carrying oncogenic alleles of K-ras that can be activated only on a spontaneous recombination event in the whole animal. Here we show that mice carrying these mutations were highly predisposed to a range of tumour types, predominantly early onset lung cancer. This model was further characterized by examining the effects of germline mutations in the tumour suppressor gene p53, which is known to be mutated along with K-ras in human tumours. This approach has several advantages over traditional transgenic strategies, including that it more closely recapitulates spontaneous oncogene activation as seen in human cancers.

K-ras activation generates an inflammatory response in lung tumors

“…using either adenoviral Cre or transgenic systems to induce the expression of mutant K-ras within the lung (Fisher et al, 2001;Jackson et al, 2001;Johnson et al, 2001;Meuwissen et al, 2001). However, the robust nature of inflammation in the CC10-Cre/LSL-K-ras G12D model and the high concentrations of chemotactic substances elaborated by these tumor cells have not been previously reported and therefore provide a unique opportunity to dissect the means by which inflammatory cells are recruited to sites of tumorigenesis, and the roles that these cells play in tumor progression vs suppression.…”

Identification of RASSF8 as a candidate lung tumor suppressor gene

“…KRAS2 mutations play a causative role in lung cancer development, since transgenic mice carrying an activated KRAS2 gene develop lung cancer early in life and at high frequency (Johnson et al, 2001). In human lung cancer, the presence of KRAS2 mutations is associated with poor prognosis (De Gregorio et al, 1998;Huncharek et al, 1999).…”

Paired-like homeoprotein ESXR1 acts as a sequence-specific transcriptional repressor of the human K-ras gene

“…K-ras mutation has been detected in 70-90% of pancreatic carcinomas, 50% of colorectal carcinomas, and 20-50% of lung carcinomas (Forrester et al, 1987;Rodenhuis et al, 1987;Bos, 1989;Hruban et al, 1993). In tumor cells carrying K-ras mutation, the presence of oncogenic K-Ras is necessary for maintenance of the transformed phenotype (Fisher et al, 2001;Johnson et al, 2001;Meuwissen et al, 2001). Given this, several techniques, such as techniques using farnesyl-transferase inhibitors, antisense oligonucleotides, ribozymes or siRNAs, have been developed to inhibit the activity of Ras (Adjei, 2001;Andreyev et al, 2001;Brummelkamp et al, 2002).…”

“…In addition to activation by point mutations, K-ras has been found to be amplified or overexpressed in some cancers (Galiana et al, 1995). Studies using genetically engineered mice have shown that the presence of oncogenic K-ras is not only essential for the initiation of tumorigenesis but also necessary for maintenance of the transformed state (Fisher et al, 2001;Johnson et al, 2001;Meuwissen et al, 2001). Thus, K-Ras is a crucial molecular target in therapeutic strategies to inhibit tumor cell growth.…”