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PubMed2006

Meta-analysis and meta-review of thyroid cancer gene expression profiling studies identifies important diagnostic biomarkers.

PURPOSE: An estimated 4% to 7% of the population will develop a clinically significant thyroid nodule during their lifetime. In many cases, preoperative diagnoses by needle biopsy are inconclusive. Thus, there is a clear need for improved diagnostic tests to distinguish malignant from benign thyroid tumors. The recent development of high-throughput molecular analytic techniques should allow the rapid evaluation of new diagnostic markers. However, researchers are faced with an overwhelming number of potential markers from numerous thyroid cancer expression profiling studies. MATERIALS AND METHODS: To address this challenge, we have carried out a comprehensive meta-review of thyroid cancer biomarkers from 21 published studies. A gene ranking system that considers the number of comparisons in agreement, total number of samples, average fold-change and direction of change was devised. RESULTS: We have observed that genes are consistently reported by multiple studies at a highly significant rate (P < .05). Comparison with a meta-analysis of studies reprocessed from raw data showed strong concordance with our method. CONCLUSION: Our approach represents a useful method for identifying consistent gene expression markers when raw data are unavailable. A review of the top 12 candidates revealed well known thyroid cancer markers such as MET, TFF3, SERPINA1, TIMP1, FN1, and TPO as well as relatively novel or uncharacterized genes such as TGFA, QPCT, CRABP1, FCGBP, EPS8 and PROS1. These candidates should help to develop a panel of markers with sufficient sensitivity and specificity for the diagnosis of thyroid tumors in a clinical setting.

Biomarkers, Tumor↗
PubMed2002

Tracing transgene expression in cancer gene therapy: a requirement for rational progress in the field.

This review summarizes the status of gene therapy in medicine and the role of molecular imaging in its development. In gene therapy, genetic material is introduced into cells in order to generate a specific biological effect. Natural (viruses) or artificial molecular constructs, named gene therapy vectors, are used to achieve efficient cell transduction. This new form of therapy can be used for treating a broad variety of conditions including hereditary diseases, infections, degenerative disorders and cancer. Monitoring transgene expression using noninvasive imaging techniques is a necessary complement for the development of clinical gene therapy. Recent developments in magnetic resonance imaging afford the possibility of detecting gene transfer in vivo, but the most promising results have been obtained with positron emission tomography (PET). PET allows imaging gene therapy products by administration of a labeled substrate when the transgene codes for an enzyme or by administration of a labeled ligand when the transgene codes for a receptor. In the latter strategy, a membrane molecule (somatostatin or dopamine receptors) is used to detect the selective trapping of its radiolabeled ligand in the transduced cells. One of the approaches for the genetic treatment of cancer consists in transferring the "suicide genes" into tumor cells, the most common being the thymidine kinase (tk) of herpes viruses. Different nucleoside analogs can be labeled for its use as PET reporter probes in order to visualize tk expression. The results of pre-clinical studies are extremely encouraging. Reliable methods for the in vivo tracing of transgene expression in humans have to be developed in order for the field of gene therapy to mature. PET has emerged as a powerful tool to assist in achieving this goal.

Journal Article↗
PubMed2000

The dual impact of coxsackie and adenovirus receptor expression on human prostate cancer gene therapy.

In a recent paper, we reported a significant difference in coxsackie and adenovirus receptor (CAR) from several human bladder cancer cell lines that correlated with their sensitivities to adenoviral infection (Y. Li, R-C. Pong, J. M. Bergelson, M. C. Hall, A. I. Sagalowsky, C-P. Tseng, Z. Wang, and J. T. Hsieh, Cancer Res., 59: 325-330, 1999). In human prostate cancer, CAR protein is down-regulated in the highly tumorigenic PC3 cell line, which suggests that, in addition to its function as a viral receptor, CAR may have a pathophysiological role in prostate cancer progression. In this paper, we document that CAR does not merely enhance the viral sensitivity of prostate cancer cells but also acts as a tumor inhibitor for androgen-independent prostate cancer cells. Our data indicate that CAR is a potential therapeutic agent for increasing the efficacy of prostate cancer therapy.

Adenoviridae↗
PubMed1999

Aflatoxin, Tobacco, Ammonia and the p53 Tumor-Suppressor Gene: Cancer's Missing Link?

Aflatoxin, the fungal carcinogen first identified in 1960, is now recognized as the prototypical laboratory carcinogen. It causes mutations in the p53 tumor-suppressor gene as well as ras mutations, which are involved in the majority of human cancers. Aflatoxin has been shown to contaminate tobacco products. Tobacco-related cancers, including those associated with ETS, often show the same p53 mutations associated with aflatoxin exposure. The role of ammonia in neutralizing aflatoxin contamination is examined, as well as the potential role of the FDA in regulating aflatoxin contamination of tobacco products.

Journal Article↗
PubMed2002

The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway.

VHL is part of an SCF related E3-ubiquitin ligase complex with 'gatekeeper' function in renal carcinoma. However, no mutations have been identified in VHL interacting proteins in wild type VHL tumors. We previously reported that the TRC8 gene was interrupted by a t(3;8) translocation in a family with hereditary renal and non-medullary thyroid cancer. TRC8 encodes a multi-membrane spanning protein containing a RING-H2 finger with in vitro ubiquitin ligase activity. We isolated the Drosophila homologue, DTrc8, and studied its function by genetic manipulations and a yeast 2-hybrid screen. Human and Drosophila TRC8 proteins localize to the endoplasmic reticulum. Loss of either DTrc8 or DVhl resulted in an identical ventral midline defect. Direct interaction between DTrc8 and DVhl was confirmed by GST-pulldown and co-immunoprecipitation experiments. CSN-5/JAB1 is a component of the COP9 signalosome, recently shown to regulate SCF function. We found that DTrc8 physically interacts with CSN-5 and that human JAB1 localization is dependent on VHL mutant status. Lastly, overexpression of DTrc8 inhibited growth consistent with its presumed role as a tumor suppressor gene. Thus, VHL, TRC8, and JAB1 appear to be linked both physically and functionally and all three may participate in the development of kidney cancer.

3T3 Cells↗
PubMed1995

Cancer gene therapy: principles, problems, and perspectives.

Despite enormous efforts focused on the development of new drugs and the use of novel drug combinations, including high-dose regimens supported by bone marrow and blood stem cell transplantation procedures, progress in the treatment of disseminated human cancer has been marginal. Remarkable advances in our understanding of the molecular biology of cancer has provided the possibility to employ new, selective tools of genetic intervention for more successful tumor treatment. We are now witnessing the inception of gene therapy. However, gene therapists face many drawbacks, including selectivity, specificity, sensitivity, and safety of gene transfer. Despite this there are already over 70 clinical protocols accepted for genetic approaches to cancer worldwide. Strategies currently under clinical investigation and discussed here include: (a) the enhancement of tumor immunogenicity by insertion of cytokine genes, genes coding for products of the major histocompatibility complex, and those for lymphocyte costimulatory ligands, (b) the vectoring of tumoricidal cytokines into cells that can potentially home on tumors to release their toxic products locally, (c) the use of tumor-specific pro-drug activators, i.e., the insertion of enzymatically pro-drug-activating genes fused to promoter systems which rely on differential (ideally tumorspecific) transcription control, (d) gene-marking strategies which may provide new indicators for minimal, residual, and relapsed tumor disease, (e) artificial repression of gene functions by insertion of genes encoding for complementary (antisense) mRNA to the gene of interest (e.g., oncogenes, drug resistance genes).

Forecasting↗
PubMed1998

Analysis of cyclin E and CDK2 in ovarian cancer: gene amplification and RNA overexpression.

Cyclins and their associated kinases (cdks) play a key role in controlling the cell cycle, a process whose disregulation can potentially lead to uncontrolled cell growth and hence to cancer. We have studied the role of both cyclin E and its associated kinase cdk2 in ovarian cancer. Primary, metastatic, recurrent and benign ovarian tumors were screened for cyclin E and cdk2 gene amplification. Cyclin E was shown to be amplified in 21% and cdk2 in 6.4% of the cases analyzed. Cyclin E and cdk2 RNA expression levels were determined by semi-quantitative RT-PCR analysis in a partially overlapping series of samples and compared to the expression levels of normal ovarian surface epithelial cells. Cyclin E RNA was overexpressed in 29.5% and cdk2 in 6.5% of ovarian tumors tested. We determined that in most cases gene amplification leads to higher RNA levels for cyclin E and that the overall levels of cyclin E and cdk2 RNA were correlated. We hypothesize that cyclin E and cdk2 are, in part co-regulated and that they may concur to ovarian tumor development.

Adult↗
PubMed1999

Cancer gene therapy--fantasy or foresight?

Gene therapy is an exciting new method of treatment that may have far-reaching implications on the way we manage diseases in the future. Cancer has become the principal focus of this futuristic research. The breathtaking pace of gene discovery in the last two decades, coupled with the birth of recombinant DNA technology, gave rise to the concept that genes may be manipulated and used as drugs. Genetic modification of cells can be carried out in petri dishes (ex vivo) or within the living system (in vivo). In order for the therapeutic genes to exert their effect, they have to be transported into the cell nucleus where transcription takes place. Liposomes and genetically modified viruses have been extensively used as gene vectors. The ideal vector remains elusive. It would be one that can achieve tumour-specific, sustained, and regulatable gene expression without host toxicity. As a result of the past decade of intense gene therapy research, we have learned that it is a rational scientific concept that works remarkably well in petri dishes and in laboratory animals. However, early clinical gene therapy experimentations paled in comparison. This apparent disparity between dramatic preclinical successes and the very modest clinical results of gene therapy does not in anyway nullify the concept of gene therapy. Instead, it exposes the folly of underestimating the technical complexity of gene manipulation in human diseases. Fortunately, technical hurdles such as those confronting gene therapy today are not insurmountable; they need, however, much ingenuity, resolution and time to be overcome. It is reassuring that recent advances in gene therapy provide abundant evidence that the premature infant, born of unrealistic pressure, is indeed healthy and thriving. With proper nurturing and patience, there is no doubt that, in time, it will bear fruit.

Animals↗
PubMed2002

RUNX: a trilogy of cancer genes.

The RUNX family of transcription factors plays pivotal roles during normal development and in neoplasias. Recent data involve RUNX3 as an important tumor suppressor in gastric cancers and pose interesting questions about how perturbed levels and interspecific competition among RUNX family members may contribute to tumorigenesis.

Animals↗
PubMed1999

Implication of N-acetylglucosaminyltransferases III and V in cancer: gene regulation and signaling mechanism.

N-acetylglucosaminyltransferases III (GnT-III) and V (GnT-V) play a pivotal role in the processing of N-linked glycoproteins, and are highly involved in cancer progression and metastasis. Expression of GnT-III and GnT-V in the liver is enhanced during hepatocarcinogenesis, although they are not expressed in the normal liver. Gene expression of GnT-V is regulated by a transcriptional factor, ets-1, which is involved in angiogenesis and invasion of tumor cells. When the formation of the product of GnT-V, GlcNAc-beta1-6 branches, is inhibited by overexpression of GnT-III, lung metastasis of melanoma cells is suppressed. Modification of glycoprotein receptors such as the receptors for epidermal growth factor and nerve growth factor by GnT-III sense transfection changes an intracellular signaling pathway, which may lead to a variety of biological alterations in tumor cells. In this review, we focus on cancer progression and metastasis in relation to GnT-III and GnT-V.

Animals↗
PubMed1999

Correlates of intentions to obtain genetic counseling and colorectal cancer gene testing among at-risk relatives from three ethnic groups.

OBJECTIVES: An understanding of factors associated with interest in genetic counseling and intentions to obtain colorectal cancer susceptibility testing is an important foundation for developing education, counseling, and genetic services and policies. MATERIALS AND METHODS: A survey was mailed to first-degree relatives of patients diagnosed with colorectal cancer. The respondents (n = 426, 77% response rate) are siblings and adult children of Caucasian, Japanese, and Hawaiian ethnicity. Data collection was guided by a conceptual framework and included questions on demographics, family cancer history, predisposing factors (cancer worry, perceived risk, well-being), and enabling factors (decision preferences, social support, and health care factors). Logistic regression analysis on two binary dependent variables (interest in counseling and intentions to get genetic testing) was performed using Generalized Estimating Equations to account for family clusters. RESULTS: Forty-five % of respondents were interested in genetic counseling, and 26% "definitely" intended to get genetic testing for colon cancer when available. For counseling interest, the most important predictors were education, Hawaiian ethnicity, cancer worry, and family support. Cancer worry, perceived risk, and age (older) were directly, and Japanese ethnicity was inversely, associated with testing intentions. CONCLUSIONS: High rates of interest in cancer genetic testing are similar to those found in other studies. Ethnic differences reveal a paradox between objective population risk (higher for Japanese) and greater concerns (among Hawaiians). The substantial lack of awareness of family history warrants further research. Culturally sensitive education and counseling are needed for managing the likely high demand for personalized information about hereditary cancer risk.

Adult↗
PubMed2001

Knowledge, attitudes, and interest in breast-ovarian cancer gene testing: a survey of a large African-American kindred with a BRCA1 mutation.

BACKGROUND: This study assessed counseling and testing needs from the perspective of adult members of a large African-American kindred with a BRCA1 mutation. METHODS: Interviews were conducted with 95 male and female kindred members to elicit information on sociodemographics, attitudes toward health care providers, breast cancer screening behaviors, and religious/spiritual beliefs, as well as to evaluate psychological distress, beliefs, knowledge, and attitudes related to genetic testing. RESULTS: Knowledge about breast and ovarian cancer genetics was limited. Adherence to screening recommendations was low among females with no personal breast or ovarian cancer history. The majority (67%) wished to discuss risk factors with a health care provider. Most participants (82%) indicated that they would have a genetic test if it were available. Significant predictors of intent to undergo testing were having at least one first-degree relative with breast and/or ovarian cancer (OR = 5.1; 95% CI = 1.2-20.9) and perceived risk of being a gene carrier > or =50% (OR = 64.3; 95% CI = 5.1-803.9) or reporting that they did not know their risk of being a gene carrier (OR = 10.9; 95% CI = 2.1-57.7). Cited barriers to testing included cost and availability. CONCLUSION: There is a high interest level in genetic testing despite limited knowledge about cancer genetics among these high-risk African Americans. Our study provides information for designing a genetic education and counseling intervention for this and similar families.

Adult↗
PubMed2004

Growth hormone (GH) receptors in prostate cancer: gene expression in human tissues and cell lines and characterization, GH signaling and androgen receptor regulation in LNCaP cells.

Various hormones and growth factors have been implicated in progression of prostate cancer, but their role and the underlying molecular mechanism(s) involved remain poorly understood. In this study, we investigated the role of human growth hormone (GH) and its receptor (GHR) in human prostate cancer. We first demonstrated mRNA expression of GHR and of its exon 9-truncated isoform (GHR(tr)) in benign prostate hyperplasia (BPH) and prostate adenocarcinoma patient tissues, as well as in LNCaP, PC3 and DU145 human prostate cancer cell lines. GHR mRNA levels were 80% higher and GHR(tr) only 25% higher, in the carcinoma tissues than in BPH. Both isoforms were also expressed in LNCaP and PC3 cell lines and somewhat less so in DU145 cells. The LNCaP cell GHR protein was further characterized, on the basis of its M(r) of 120kDa, its binding to two different GHR monoclonal antibodies, its high affinity and purely somatogenic binding to (125)I-hGH and its ability to secrete GH binding protein, all characteristic of a functional GHR. Furthermore, GH induced rapid, time- and dose-dependent signaling events in LNCaP cells, including phosphorylation of JAK2 tyrosine kinase, of GHR itself and of STAT5A (JAK2-STAT5A pathway), of p42/p44 MAPK and of Akt/PKB. No effect of GH (72h) could be shown on basal or androgen-induced LNCaP cell proliferation nor on PSA secretion. Interestingly, however, GH caused a rapid (2-12h) though transient striking increase in immunoreactive androgen receptor (AR) levels (< or =5-fold), followed by a slower (24-48h) reduction (< or = 80%), with only modest parallel changes in serine-phosphorylated AR. In conclusion, the GH-induced activation of signaling pathways, its effects on AR protein in LNCaP cells and the isoform-specific regulation of GHR in prostate cancer patient tissues, suggest that GH, most likely in concert with other hormones and growth factors, may play an important role in progression of human prostate cancer.

Animals↗
PubMed2000

A cancer gene therapy approach utilizing an anti-erbB-2 single-chain antibody-encoding adenovirus (AD21): a phase I trial.

The purpose of this Phase I study was to determine the feasibility of using an anti-erbB-2-encoding adenovirus (Ad21) to treat erbB-2-overexpressing ovarian cancer. Recurrent ovarian cancer patients were treated i.p. with Ad21 in dosages ranging from 1 x 10(9) to 1 x 10(11) pfu. Patients were monitored after treatment for evidence of clinical toxicity and efficacy. Peritoneal aspirates and serum samples were obtained to assess for evidence of gene transfer/expression, for generation of wild-type vector, and antiadenoviral humoral response. Fifteen patients were treated per study specifications. Treatment-specific grade 1/2 fever was experienced by 9 of 15 (60%) patients. Other transient grade 1/2 constitutional, pain, and gastrointestinal symptoms were also experienced. No dose-limiting vector-related toxicity was experienced. Of 13 patients evaluable for response, 5 (38%) had stable disease and 8 (61%) had evidence of progressive disease. One patient with nonmeasurable disease normalized her CA125 at the 8-week evaluation, and one patient with nonmeasurable disease remained without clinical evidence of disease for 6 months after treatment. PCR analysis of peritoneal aspirates demonstrated the presence of Ad21 in 84.6%, 84.6%, and 61.6% of evaluable specimens at days 2, 14, and 56 after treatment, respectively. No wild-type virus was detected. Reverse transcription-PCR analysis demonstrated expression of the anti-erbB-2 sFv-encoding gene in 10 of 14 evaluable patients at day 2. Five of six evaluable patients had an increase in antiadenovirus antibody titer. This study suggests that adenoviral-mediated gene therapy using an anti-erbB-2-directed intrabody is feasible in the context of human ovarian cancer.

Adenoviruses, Human↗
PubMed1998

Status of deleted in colorectal cancer gene expression correlates with neuroblastoma metastasis.

Neuroblastoma is an embryonal tumor of neural crest origin noted for its heterogeneity at the clinical, histologic, and molecular levels. The deleted in colorectal cancer (DCC) protein is an adhesion family molecule of unequivocal importance in neural development that has also been implicated in several malignancies, including neuroblastoma, through its apparent loss of function. Immunohistochemical assessment of the DCC protein was performed on a group of 49 neuroblastoma specimens and examined in relation to important clinical, histologic, and molecular parameters. DCC expression was significantly associated with neuroblastoma dissemination as primary tumors from Stage 1 to 3 patients (15/20, 75%) more frequently exhibited the DCC protein than those from Stage 4 patients (5/13, 38%; p = 0.0415). Primary tumors were more frequently DCC-positive (20/33, 61%) as compared with metastatic deposits (3/16, 19%; p = 0.0063), and a single case of a paired primary and metastatic deposit demonstrated the apparent loss of DCC gene expression with tumor progression. The remaining five paired specimens were DCC-negative in both the primary tumor and metastatic deposit. No significant association was appreciated between DCC expression and patient age, the Shimada histologic classification, or N-Myc amplification. These results provide evidence that DCC expression may be lost in the course of metastatic spread in a subset of neuroblastomas. Moreover, DCC function is implicated in neuroblastoma dissemination in a manner independent of N-Myc.

Cell Adhesion Molecules↗
PubMed2005

Breast cancer gene expression profiling: clinical trial and practice implications.

The advent of high-throughput array-based technology and the sequencing of the human genome has provided the opportunity to begin comprehensive molecular and genetic profiling of cancers. Such efforts have, in a limited time, given us new insights into breast cancer biology and confirmed that the disease is considerably more heterogeneous than can be predicted by traditional histopathological methods. The estrogen receptor has been found to be the most dominant factor influencing the molecular composition of breast cancer and, in addition, novel subgroups of breast cancer with differing clinical outcomes have been observed. These may have substantial management implications for breast cancer patients and facilitate individualized rather than empirical oncological prescription. Furthermore, new methods of prognostic classification have been developed using array technology. The challenges ahead lie in refining the use of the technology, proper validation of discoveries, and the large-scale collaborative efforts necessary for the incorporation of genomic knowledge into the design and conduct of clinical trials. This will lead, ultimately, to the application of user-friendly tools derived from this technology to everyday patient care.

Biomarkers, Tumor↗