Abstract B22: Oncogene activation of K‐ras in resident myofibroblasts leads to development of spontaneous bronchioalveolar carcinoma in mice

Stromal myofibroblasts, also known as carcinoma‐associated fibroblasts, are recruited to neoplastic lesions and act as accomplices in promoting tumor progression. By secreting various growth factors, cytokines, extracellular matrix molecules, and matrix remodeling proteins, stromal myofibroblasts enhance tumor cell proliferation, angiogenesis, and tumor cell invasion. In contrast, the role of resident myofibroblasts in tumorigenesis is largely unknown. Our preliminary results strongly suggest that resident myofibroblasts may act as contributors to tumorigenesis. Selective expression of the oncogenic mutant of K‐ras (K‐rasG12D) in alpha smooth muscle actin‐positive (αSMA+) stromal myofibroblasts is achieved by crossing αSMA‐Cre+ transgenic mice to the LSL‐KrasG12D f/+ mouse model (hereafter αSMA^KrasG12D). While αSMA^KrasG12D mice were phenotypically normal at birth, these mice developed spontaneous bronchioalveolar carcinoma by 5 weeks of age at 100% tumor penetrance. We speculate that genetic mutations in stromal myofibroblasts can disrupt stromal‐epithelial homeostasis, driving hyperproliferation of epithelial cells. This fosters further accumulation of genetic mutations in the epithelial compartment, and thus, result in carcinogenesis.

Citation Information: Cancer Res 2009;69(23 Suppl):B22.