Type I insulin-like growth factor receptor induces pulmonary tumorigenesis.

Despite the type I insulin-like growth factor receptor (IGF-IR) being highly expressed in more than 80% of human lung tumors, a transgenic model of IGF-IR overexpression in the lung has not been created. We produced two novel transgenic mouse models in which IGF-IR is overexpressed in either lung type II alveolar cells (surfactant protein C [SPC]-IGFIR) or Clara cells (CCSP-IGFIR) in a doxycycline-inducible manner. Overexpression of IGF-IR in either cell type caused multifocal adenomatous alveolar hyperplasia with papillary and solid adenomas. These tumors expressed thyroid transcription factor 1 and Kruppel-like factor 5 in most tumor cells. Similar to our previous work with lung tumors that developed in the mouse mammary tumor virus-IGF-II transgenic mice, the lung tumors that develop in the SPC-IGFIR and CCSP-IGFIR transgenic mice expressed high levels of the cyclic adenosine monophosphate response element binding protein that was localized primarily to the nucleus. Although elevated IGF-IR expression can initiate lung tumor development, tumors can become independent of IGF-IR signaling as IGF-IR down-regulation in established tumors produced tumor regression in some, but not all, of the tumors. These findings implicate IGF-IR as an important initiator of lung tumorigenesis and suggest that the SPC-IGFIR and CCSP-IGFIR transgenic mice can be used to further our understanding of human lung cancer and the role IGF-IR plays in this disease.

Circulating hormones and estrous stage predict cellular and stromal remodeling in murine uterus.

The understanding of how estrogen and progesterone (P(4)) drive uterine remodeling in rodents has largely been based on studies involving administration of exogenous hormones, using steroid receptor-deficient mice, or relying on vaginal smears. In all these cases, the actual serum levels of 17beta-estradiol (E(2)) and P(4) are not directly measured, and the relationship between physiological levels of female sex hormones and uterine remodeling in cycling mice has not been fully explored. Here, we measured the circulating levels of E(2) and P(4) in cycling mice and performed correlation analysis between hormone levels and epithelial and stromal uterine parameters, irrespective of the estrous stage. In parallel, these parameters were analyzed in relation to the more conventional method of vaginal smear classification of estrous stage. We found that circulating P(4) inversely correlated with uterine width, luminal epithelial proliferation, stromal apoptosis, and degradation of luminal epithelial basement membrane collagen type-IV. Circulating E(2) positively correlated with uterine width, stromal cell proliferation, and collagen type-I content, while it negatively correlated with glandular epithelial proliferation, loss of collagen type-IV surrounding glandular epithelium, and apoptosis in luminal, glandular, and stromal compartments. Our findings indicate that measuring P(4) or E(2) levels can predict many concurrent cellular and stromal events in the mouse uterus, suggesting that in naturally cycling mice cellular responses to hormone changes are not delayed, but occur very rapidly.

Insulin-like growth factor-II regulates PTEN expression in the mammary gland.

The tumor suppressor PTEN is altered in many cancers, including breast cancer, but only a handful of factors are known to control its expression. PTEN plays a vital role in cell survival and proliferation by regulating Akt phosphorylation, a key component of the phosphatidylinositol 3 kinase (PI3K) pathway. Here we show that insulin-like growth factor-II (IGF-II), which signals through PI3K, regulates PTEN expression in the mammary gland. IGF-II injection into mouse mammary gland significantly increased PTEN expression. Transgenic IGF-II expression also increased mammary PTEN protein, leading to reductions in Akt phosphorylation, epithelial proliferation, and mammary morphogenesis. IGF-II induced PTEN promoter activity and protein levels and this involved the immediate early gene egr-1. Thus, we have identified a novel negative feedback loop within the PI3K pathway where IGF-II induces PTEN expression to modulate its physiologic effects.

Increase in gelatinase-specificity of matrix metalloproteinase inhibitors correlates with antimetastatic efficacy in a T-cell lymphoma model.

The recognition that matrix metalloproteinases (MMPs) facilitate tumor cell invasion and metastasis has led to the development of synthetic MMP inhibitors (MMPIs) as cancer therapeutic agents. Because several Phase III trials failed recently to show efficacy of broad-spectrum MMPIs in advanced cancer, the feasibility of MMPs as therapeutic targets has been challenged. However, it has not yet been determined whether MMPIs that have increased specificity may have greater benefit. We show that MMP-9 expression closely correlates with the progression of liver metastasis in a T-cell lymphoma model. MMPIs with greater selectivity/specificity for MMP-9 in vitro showed greater efficacy against liver metastasis in vivo. These data demonstrate a link between increased specificity of MMPIs and enhanced anticancer activity.