Cancer chromosomal instability: therapeutic and diagnostic challenges

Chromosomal instability (CIN)-which is a high rate of loss or gain of whole or parts of chromosomes-is a characteristic of most human cancers and a cause of tumour aneuploidy and intra-tumour heterogeneity. CIN is associated with poor patient outcome and drug resistance, which could be mediated by evolutionary adaptation fostered by intra-tumour heterogeneity. In this review, we discuss the clinical consequences of CIN and the challenges inherent to its measurement in tumour specimens. The relationship between CIN and prognosis supports assessment of CIN status in the clinical setting and suggests that stratifying tumours according to levels of CIN could facilitate clinical risk assessment.     

Gene discovery in cervical cancer : towards diagnostic and therapeutic biomarkers

Cervical cancer is a potentially preventable disease; however, it remains the second most common malignancy in women worldwide. The human papillomavirus (HPV) is the single most important etiological agent in cervical cancer. HPV contributes to neoplastic progression through the action of two viral oncoproteins E6 and E7, which interfere with critical cell cycle pathways, tumor protein p53, and retinoblastoma protein. However, evidence suggests that HPV infection alone is insufficient to induce malignant changes, and other host genetic variations are important in the development of cervical cancer. Advances in molecular biology and high throughput technologies have heralded a new era in biomarker discovery and identification of molecular targets related to carcinogenesis. These advancements have improved our understanding of carcinogenesis and will facilitate screening, early detection, management, and personalized targeted therapy. A number of these developments and molecular targets associated with cervical cancer will be addressed in this review.     

Cancer therapy: reimbursement of new therapeutic technologies.

New drugs and technologies for cancer treatment are being developed at a rate that has created a reimbursement crisis. This article discusses third-party concerns about this problem and describes generic criteria that have proven to be useful in assessing any new technology. It is equally important to discontinue funding of ineffective and obsolete therapies as it is to devise a strategy for identifying and encouraging the development of new therapy that will be both clinically useful and cost-effective. Examples are provided to show that these are not necessarily mutually exclusive goals. Off-label application of standard therapy as well as the funding of new cancer therapy are considered. High-dose chemotherapy with autologous stem-cell support for treatment of a variety of neoplasms has become a major reimbursement challenge. Other technologies such as autolymphocyte therapy and use of colony-stimulating factors are considered in detail. Finally, a process for deciding how to fund new cancer therapy is described.     

癌胚抗原基因家族与肿瘤

癌胚抗原基因家族(carcinoembryonic antigen gene family)分两大类：癌胚抗原相关细胞黏附分子(CEA-related cell adhesion inolecule,CEACAM)与妊娠特异性糖蛋白(pregnanc Yspecific-glycoprotein,PSG),其中以CEACAM中的CEACAM1、CEACAM5、CEACAM6、CEACAM7等四种糖蛋白与肿瘤关系密切。     

NBN Gene Polymorphisms and Cancer Susceptibility: A Systemic Review

The relationship between DNA repair failure and cancer is well established as in the case of rare, high penetrant genes in high cancer risk families. Beside this, in the last two decades, several studies have investigated a possible association between low penetrant polymorphic variants in genes devoted to DNA repair pathways and risk for developing cancer. This relationship would be also supported by the observation that DNA repair processes may be modulated by sequence variants in DNA repair genes, leading to susceptibility to environmental carcinogens. In this framework, the aim of this review is to provide the reader with the state of the art on the association between common genetic variants and cancer risk, limiting the attention to single nucleotide polymorphisms (SNPs) of the NBN gene and providing the various odd ratios (ORs). In this respect, the NBN protein, together with MRE11 and RAD50, is part of the MRN complex which is a central player in the very early steps of sensing and processing of DNA double-strand breaks (DSBs), in telomere maintenance, in cell cycle control, and in genomic integrity in general. So far, many papers were devoted to ascertain possible association between common synonymous and non-synonymous NBN gene polymorphisms and increased cancer risk. However, the results still remain inconsistent and inconclusive also in meta-analysis studies for the most investigated E185Q NBN miscoding variant.     

Gene Mutations and Aneuploidy: The Instability That Causes Cancer

Cancer cells have been characterized with activated mutant oncogenes and inactivated or deleted tumor suppressor genes. Cancer cells are also aneuploid, displaying a jumble of chromosomal anomalies including gain or loss of whole chromosomes or transposed chromosomal fragments. Whether mutation of specific genes or aneuploidy is more critical for tumorigenesis is very much a contentious issue. We recently showed that activated oncogenes induce oxidative damage that is exacerbated by conventional cell culture conditions. This “culture shock” or a loss of p53 function creates a precarious environment that permits oncogenes to induce rapid chromosomal instability and transformation. We found that mutant genes and aneuploidy were prerequisites and collaborators for neoplastic transformation.     

Gene Signatures in Breast Cancer: Current and Future Uses

Gene signatures have been developed for estrogen receptor-positive breast cancer to complement pathological factors in providing prognostic information. The 70-gene and the 21-gene signatures identify patients who may not require adjuvant chemotherapy. Gene signatures in triple-negative disease and HER2-positive disease have not been fully developed yet, although studies demonstrate heterogeneity within these subgroups. Further research is needed before genotyping will help in making clinical decisions in triple-negative and HER2-positive disease. Molecular subtyping of breast cancer led to define luminal, basal, and HER2-enriched subtypes, which have specific clinical behavior. This approach may lead to identify new subgroups requiring specific therapies. Standardization of techniques will be required to translate investigations to the clinic.     

Cancer Stem Cell-Related Gene Periostin: A Novel Prognostic Marker for Breast Cancer

We investigated the expression status of periostin in breast cancer stem cells and its clinical implications in order to lay a foundation for managing breast cancer. CD44+/CD24−/line- tumor cells (CSC) from clinical specimens were sorted using flow cytometry. Periostin expression status was detected in CSC cells and 1,086 breast cancer specimens by Western blot and immunohistochemistry staining, with the CSC ratio determined by immunofluorescence double staining. The relationship between the periostin protein and clinico-pathological parameters and prognosis was subsequently determined. As a result, CSC cells are more likely to generate new tumors in mice and cell microspheres that are deficient in NOD/SCID compared to the control group. Periostin protein was expressed higher in CSC cells compared to the control cells and was found to be related to CSC chemotherapy resistance. Moreover, periostin expression was found to be related to the CSC ratio in 1,086 breast cancer specimens (P = 0.001). In total, 334 (30.76%) of the 1,086 breast cases showed high periostin expression. After universal and Spearman regression correlation analysis, periostin was observed to be related to histological grade, CSC ratio, lymph node metastasis, tumor size, and triple-negative breast cancer (all P<0.05). Furthermore, periostin was shown to attain a significantly more distant bone metastasis and worse disease-specific survival than those with none or low-expressed periostin protein (P = 0.001). In the Cox regression test, periostin protein was detected as an independent prognostic factor (P = 0.001). In conclusion, periostin was found to be related to the CSC and an independent prognostic factor for breast cancer. It is also perhaps a potential target to breast cancer.     

Cancer vaccines as a therapeutic modality: the long trek

The development of cancer vaccines has been one of the several false dawns in which initial promising Phase I and Phase II clinical data have not been followed up with conclusive Phase III trials. In this review, we describe some of the successes and failures, and review the most likely reasons for Phase III failure, such as protocol changes, which are common between Phase II and III, and poorly defined patient groups. Nevertheless, significant survival results have been reported with autologous vaccines for colorectal, renal and, more recently, prostate cancer. In addition, it is becoming evident that immunotherapy is potentially synergistic with other treatment modalities, such as chemotherapy, which can reduce T-regulatory activity that inhibits the immune response to cancer vaccines. This potential for synergy should allow cancer vaccines to become part of the standard treatment regimen for many common tumours.This article is a symposium paper from the “Robert Baldwin Symposium: 50 years of Cancer Immunotherapy”, held in Nottingham, Great Britain, on 30 June 2005.     

The Leptin Gene Family and Colorectal Cancer: Interaction with Smoking Behavior and Family History of Cancer

Background

Pathologic condition associated with metabolic syndrome traits seems to increase the risk of colorectal cancer. One mechanism underlying this relationship may involve the growth-promoting effects of the circulation hormones associated with obesity and insulin resistance, such as leptin.

Methodology/Principal Findings

A two-stage case-control study was used to explore the role of polymorphisms of Leptin (LEP) and Leptin receptor (LEPR), either alone or in combination with environmental factors in colorectal carcinogenesis. In stage 1, 20 single nucleotide polymorphisms (SNPs) that tag common SNPs in these two genes were genotyped among 470 cases and 458 controls. In stage 2, another population with 314 cases and 355 controls were genotyped for the two most promising SNPs from stage 1. LEPR rs12037879 only presented modestly increased colorectal cancer risk, with odds ratios of 1.41 (95% confidence interval [CI] 1.13–1.76) and 1.74 (95%CI 1.08–2.81) for GA and AA genotype when compared with GG genotype in combined population. Smokers carrying LEPR rs12037879 A allele presented 1.67-fold (95%CI 1.39-fold to 2.01-fold) increased colorectal cancer risk when compared with non-smokers carrying GG genotype in combined analysis. Individuals with family history of cancer harboring LEPR rs12037879 A allele showed 1.52-fold (95%CI: 1.24-fold to 1.86-fold) increased colorectal cancer risk, compared with individuals without family history of cancer harboring GG genotype. Multifactor gene-environment interaction analysis revealed significant interactions among LEPR rs12037879, LEPR rs6690625, smoking status and family history of cancer, exhibiting a gradient of increased colorectal cancer risk along with the increasing number of risk factors (P = 9.82×10⁻¹⁰).

Conclusions/Significance

Our research supports that polymorphisms in LEPR may be associated with marginal increase in the risk for colorectal cancer. Moreover, this association could be strengthened by cigarette smoking and family history of cancer.     

癌症的miRNA基因治疗

MiRNAs是一种内源非编码小RNA,具有进化上的保守性,在各物种中广泛分布.MiRNAs的作用是反向调节其靶基因的mRNA,研究发现在所有的人类癌症细胞中,miRNA的表达都有异常,即miRNA在肿瘤的形成、生长和扩散过程中发挥重要的作用.本文重点介绍了几种癌症的miRNA治疗方法,为将来的miRNA基因治疗奠定了基础.此外,还简要介绍了相关的基因传递系统及目前面临的挑战.     

Cancer imaging with CEA antibodies: historical and current perspectives.

This article reviews the history and status of cancer imaging with radiolabeled antibodies against carcinoembryonic antigen (CEA). Although CEA and many other cancer-associated antigens are not distinct for neoplasia, the quantitative increase of these markers in malignant tissues provides a sufficient differential for selective antibody targeting. Animal studies with xenografted human tumors provided the first evidence of the prospects of this technology, followed by initial clinical success with purified goat whole IgG antibodies to CEA, labeled with 131I and with the use of dual-isotope subtraction methods. Subsequently, improved and earlier imaging could be accomplished with monoclonal antibody fragments, which then would permit the use of shorter-lived radionuclides, such as 111In, 123I, and 99mTc. The preferred use of a monoclonal anti-CEA IgG Fab' fragment, labeled with 99mTc by a recently developed, simple and rapid kit, has enabled the detection of small lesions, including those in the liver, within 4 h of injection. By means of SPECT imaging, a high sensitivity and specificity for RAID could be achieved.     

The Neural/Immune Gene Ontology: clipping the Gene Ontology for neurological and immunological systems

Background  

The Gene Ontology (GO) is used to describe genes and gene products from many organisms. When used for functional annotation of microarray data, GO is often slimmed by editing so that only higher level terms remain. This practice is designed to improve the summarizing of experimental results by grouping high level terms and the statistical power of GO term enrichment analysis.