A recombinant reporter system for monitoring reactivation of an endogenously DNA hypermethylated gene.

Reversing abnormal gene silencing in cancer cells due to DNA hypermethylation of promoter CpG islands may offer new cancer prevention or therapeutic approaches. Moreover, such approaches may be broadly applicable to enhance the efficacy of radiotherapy, chemotherapy, or immunotherapy. Here, we demonstrate the powerful utility of a novel gene reporter system to permit studies of the dynamics, mechanisms, and translational relevance of candidate therapies of this type in human colon cancer cells.

Cigarette smoke induces epithelial to mesenchymal transition and increases the metastatic ability of breast cancer cells.

Background: Recent epidemiological studies demonstrate that both active and involuntary exposure to tobacco smoke increase the risk of breast cancer. Little is known, however, about the molecular mechanisms by which continuous, long term exposure to tobacco smoke contributes to breast carcinogenesis because most previous studies have focused on short term treatment models. In this work we have set out to investigate the progressive transforming effects of tobacco smoke on non-tumorigenic mammary epithelial cells and breast cancer cells using in vitro and in vivo models of chronic cigarette smoke exposure.

Personalized chemotherapy profiling using cancer cell lines from selectable mice.

Purpose: High-throughput chemosensitivity testing of low-passage cancer cell lines can be used to prioritize agents for personalized chemotherapy. However, generating cell lines from primary cancers is difficult because contaminating stromal cells overgrow the malignant cells.

Experimental Design: We produced a series of hypoxanthine phosphoribosyl transferase (hprt)-null immunodeficient mice.

Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells.

Reversal of promoter DNA hypermethylation and associated gene silencing is an attractive cancer therapy approach. The DNA methylation inhibitors decitabine and azacitidine are efficacious for hematological neoplasms at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not explain the prolonged time to response observed in patients.

Serial analysis of gene expression identifies connective tissue growth factor expression as a prognostic biomarker in gallbladder cancer.

Background: Gallbladder cancer (GBC) is an uncommon neoplasm in the United States, but one with high mortality rates. This malignancy remains largely understudied at the molecular level such that few targeted therapies or predictive biomarkers exist.

Experimental Design: We built the first series of serial analysis of gene expression (SAGE) libraries from GBC and nonneoplastic gallbladder mucosa, composed of 21-bp long-SAGE tags.

Molecular profiling of matched samples identifies biomarkers of papillary thyroid carcinoma lymph node metastasis.

Biomarkers of papillary thyroid carcinoma (PTC) metastasis can accurately identify metastatic cells and aggressive tumor behavior. To find new markers, serial analysis of gene expression (SAGE) was done on three samples from the same patient: normal thyroid tissue, primary PTC, and a PTC lymph node metastasis. This genomewide expression analysis identified 31 genes expressed in lymph node metastasis, but not in the primary tumor.

Molecular genetics of pancreatic intraepithelial neoplasia.

Background: Recent evidence suggests that noninvasive precursor lesions, classified as pancreatic intraepithelial neoplasia (PanIN), can progress to invasive pancreatic cancer. This review will discuss the major genetic alterations in PanIN lesions.

Methods: A comprehensive review of the literature was performed in order to find studies on the molecular profile of human PanIN lesions.

Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers.

In the context of pancreatic cancer, metastasis remains the most critical determinant of resectability, and hence survival. The objective of this study was to determine whether Hedgehog (Hh) signaling plays a role in pancreatic cancer invasion and metastasis because this is likely to have profound clinical implications. In pancreatic cancer cell lines, Hh inhibition with cyclopamine resulted in down-regulation of snail and up-regulation of E-cadherin, consistent with inhibition of epithelial-to-mesenchymal transition, and was mirrored by a striking reduction of in vitro invasive capacity (P < 0.

Target discovery and validation in pancreatic cancer.

Pancreatic cancer is a lethal disease and rational strategies for early detection and targeted therapies are urgently required to alleviate the dismal prognosis of this neoplasm. The use of global RNA and protein expression-profiling technologies, such as DNA microarrays, serial analysis of gene expression, and mass spectrometric analysis of proteins, have led to identification of cellular targets with considerable potential for clinical application and patient care. These studies underscore the importance of pursuing large-scale profiling of human cancers not only for furthering our understanding of the pathogenesis of these malignancies but also for developing strategies to improve patient outcomes.

PLXDC1 (TEM7) is identified in a genome-wide expression screen of glioblastoma endothelium.

Glioblastomas are a highly aggressive brain tumor, with one of the highest rates of new blood vessel formation. In this study we used a combined experimental and bioinformatics strategy to determine which genes were highly expressed and specific for glioblastoma endothelial cells (GBM-ECs), compared to gene expression in normal tissue and endothelium. Starting from fresh glioblastomas, several rounds of negative and positive selection were used to isolate GBM-ECs and extract total RNA.