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Progress in biomedical imaging depends on the development of probes that combine low toxicity with high sensitivity, resolution, and stability. Toward that end, a new class of highly fluorescent core-shell silica nanoparticles with narrow size distributions and enhanced photostability, known as C dots, provide an appealing alternative to quantum dots. Here, C dots are evaluated with a particular emphasis on in-vivo applications in cancer biology. It is established that C dots are nontoxic at biologically relevant concentrations, and can be used in a broad range of imaging applications including intravital visualization of capillaries and macrophages, sentinel lymph node mapping, and peptide-mediated multicolor cell labeling for real-time imaging of tumor metastasis and tracking of injected bone marrow cells in mice. These results demonstrate that fluorescent core-shell silica nanoparticles represent a powerful novel imaging tool within the emerging field of nanomedicine.

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Ovarian cancer remains a major health concern worldwide, primarily in postmenopausal women. Among the most common genetic alterations in human sporadic epithelial ovarian cancer (EOC) are p53 mutations, defective retinoblastoma (RB) pathway (p16 INK4a /RB) and activation of oncogenes such as c-myc, K-ras and Akt. Although these alterations are frequently associated with poor clinical prognosis, their specific contributions to EOC formation remain unclear. In order to gain a better understanding of the roles of these proteins in vivo, a number of mouse models have been generated, largely based upon inducing specific genetic lesions in the ovarian surface epithelium from which the majority of carcinomas are thought to arise in humans. Here, we review the role of tumor suppressor p53 and the Rb pathway in EOC with particular attention to association of p53 to high grade serous carcinomas as opposed to low grade and benign tumors. We also provide an overview of the utility and application of genetically engineered mouse models, in particular towards rational drug design and development of improved imaging techniques in ovarian cancer.

The cell of origin and pathogenesis of the majority of adult soft tissue sarcomas (STS) remains poorly understood. Because mutations in both the P53 and RB tumor suppressor genes are frequent in STS in humans, we inactivated these genes by Cre-loxP-mediated recombination in mice with floxed p53 and Rb. Ninety-three percent of mice developed spindle cell/ pleomorphic sarcomas after a single subcutaneous injection of adenovirus carrying Cre-recombinase. Similar to human STS, these sarcomas overexpress Cxcr4, which contributes to their invasive properties. Using irradiation chimeras generated by transplanting bone marrow cells from mice carrying either the Rosa26Stop loxP LacZ or the Z/EG reporter , as well as the floxed p53 and Rb genes , into irradiated p53 loxP/loxP Rb loxP/loxP mice, it was determined that sarcomas do not originate from bone marrow-derived cells, such as macrophages, but arise from the local resident cells. At the same time , dermal mesenchymal stem cells isolated by strict plastic adherence and low levels of Sca-1 expression (Sca-1 low , CD31 neg CD45 neg ) have shown enhanced potential for malignant transformation according to soft agar, invasion, and tumorigenicity assays, after the conditional inactivation of both p53 and Rb. Sarcomas formed after transplantation of these cells have features typical for undifferentiated high-grade pleomorphic sarcomas. Taken together, our studies indicate that local Sca-1 low dermal mesenchymal stem/progenitor cells are preferential targets for malignant transformation associated with deficiencies in both p53 and Rb. (Am J

MET, a receptor protein tyrosine kinase activated by hepatocyte growth factor (HGF), is a crucial determinant of metastatic progression. Recently, we have identified p53 as an important regulator of MET-dependent cell motility and invasion. This regulation occurs via feedforward loop suppressing MET expression by miR-34-dependent and -independent mechanisms. Here, by using Dicer conditional knockout, we provide further evidence for microRNA-independent MET regulation by p53. Furthermore, we show that while MET levels increase immediately after p53 inactivation, mutant cells do not contain active phosphorylated MET and remain non-invasive for a long latency period at contrary to cell culture observations. Evaluation of mouse models of ovarian and prostate carcinogenesis indicates that formation of desmoplastic stroma, associated production of HGF by stromal cells and coinciding MET phosphorylation precede cancer invasion. Thus, initiation mutation of p53 is sufficient for preprogramming motile and invasive properties of epithelial cells, but the stromal reaction may represent a critical step for their manifestation during cancer progression.

The cancer stem cell concept assumes that cancers are mainly sustained by a small pool of neoplastic cells, known as cancer stem cells or tumor initiating cells, which are able to reproduce themselves and produce phenotypically heterogeneous cells with lesser tumorigenic potential. Cancer stem cells represent an appealing target for development of more selective and efficient therapies. However, direct testing of the cancer stem cell concept and assessment of its therapeutic implications in human cancers have been complicated by the use of immunocompromised mice. Genetically defined immunocompetent autochthonous mouse models of human cancer provide a valuable tool to address this problem. Furthermore, they allow for a better understanding of the relevance of mechanisms controlling normal stem cell compartment to carcinogenesis. Advantages and disadvantages of some of the existing mouse models are reviewed, and future challenges in cancer stem cell research are outlined.