A genetically defined mouse ovarian carcinoma model for the molecular characterization of pathway-targeted therapy and tumor resistance

Abstract

Cell lines and tumors with defined genetic alterations provide ideal systems in which to test the molecular mechanisms of tumor sensitivity to pathway-targeted therapy. We have generated mouse ovarian epithelial tumor cell lines that contain various combinations of genetic alterations in the p53, c-myc, K-ras and Akt genes. Using both in vitro and in vivo approaches, we investigated the effect of rapamycin on cell proliferation, tumor growth, and the accumulation of peritoneal ascites. We demonstrated that rapamycin effectively inhibits the growth of tumors that rely on Akt signaling for proliferation, whereas tumors in which Akt signaling is not the driving force in proliferation are resistant to rapamycin. The introduction of activated Akt to the rapamycinresistant cells does not render the cells susceptible to rapamycin if they can use alternative pathways for survival and proliferation. Accordingly, the rapamycin-sensitive tumors develop resistance to rapamycin when presented with alternative survival pathways, such as the mitogen-activated extracellular kinase signaling pathway. The combination of rapamycin and the mitogen-activated extracellular kinase inhibitor PD98059 is required to diminish proliferation in these cell lines. Our results indicate that mammalian target of rapamycin inhibitors may be effective in a subset of tumors that depend on Akt activity for survival but not effective in all tumors that exhibit Akt activation. Tumors with alternative survival pathways may require the inactivation of multiple individual pathways for successful treatment.mouse model ͉ ovarian cancer ͉ rapamycin

HOXB13 promotes ovarian cancer progression

“…The observation that HOXB13 is expressed in a high percentage of human ovarian cancer cell lines and tumors, and that the expression of HOXB13 in human breast cancer is associated with a more aggressive clinical course compared with breast tumors that do not express HOXB13, raises the possibility that HOXB13 may play an important role in tumor progression. The possibility that HOXB13 promotes ovarian tumor growth was tested by ectopic expression of this gene by replication-competent avian leukosis virus long terminal repeat with splice acceptor (RCAS) retroviral delivery in T1 ovarian cancer cells, a cell line generated from mouse ovarian surface epithelial cells that contains genetic alterations in p53, c-myc, and K-ras (15)(16)(17) and has undetectable expression of endogenous HOXB13 by RT-PCR analysis ( Fig. 2A) and Western blotting (Fig.…”

Stimulated PI3K-AKT Signaling Mediated through Ligand or Radiation-Induced EGFR Depends Indirectly, but not Directly, on Constitutive K-Ras Activity

“…It seems to be clear that activation of AKT via PI3K occurs through phosphorylation by phosphoinositide-dependent kinase-1 and/or phosphoinositide-dependent kinase-2 at serine and threonine residues (Ser 472/473 , Thr 308 ). Several authors reported that especially phosphorylation of AKT at Ser 473 is associated with resistance to chemotherapy/ radiotherapy (36)(37)(38)(39)(40), and it has been proposed that activated AKT promotes survival of cells exposed to ionizing radiation through inhibition of apoptosis (41,42) or enhancement of DNA double-strand break repair (31).…”

Models of ovarian cancer metastasis: Murine models

“…All of the genetically engineered mouse models described above have the potential for being valuable models of metastatic ovarian cancer. The avian retroviral gene delivery technique described by Orsulic et al is particularly useful for the analysis of different combinations of multiple genetic alterations and their collaboration in tumor initiation and progression [2] aswell asfor testing pathway-targeting therapies [19]. An important advantage of the MISIIR-TAg model is the short latency of metastatic disease because of germline expression of the transgene.…”