A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes

The known classes of genes that function as tumor suppressors and oncogenes have recently been expanded to include the microRNA (miRNA) family of regulatory molecules. miRNAs negatively regulate the stability and translation of target messenger RNAs (mRNA) and have been implicated in diverse processes such as cellular differentiation, cell-cycle control and apoptosis. Examination of tumor-specific miRNA expression profiles has revealed widespread dysregulation of these molecules in diverse cancers. Although studies addressing their role in cancer pathogenesis are at an early stage, it is apparent that loss- or gain-of-function of specific miRNAs contributes to cellular transformation and tumorigenesis. The available evidence clearly demonstrates that these molecules are intertwined with cellular pathways regulated by classical oncogenes and tumor suppressors such as MYC, RAS and p53. Incorporation of miRNA regulation into current models of molecular cancer pathogenesis will be essential to achieve a complete understanding of this group of diseases.     

Genetic alterations of tumor suppressor ING1 in human non-small cell lung cancer

The aim of this study was to investigate the function of the ING1 gene in lung carcinoma. To detect the inhibitory effect of ING1 in human lung cancer, recombinant ING1b plasmids were transfected into two lung cancer cell lines with different p53 status, A549 with wild-type p53 (wtp53) and SK-MES-1 with mutant p53. Apoptosis, cell cycle, growth rate and the expression of downstream gene p21waf1 were analyzed. In addition, the complex of p33ING1b and p53 was analyzed with coimmunoprecipitation. To detect the gene alteration and the expression of ING1, 70 cases of fresh-frozen lung carcinomas and 217 cases of formalin-fixed, paraffin-embedded specimens were examined for loss of heterozygosity (LOH) and p33ING1b protein expression by polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) and immunohistochemistry using tissue microarrays, respectively. Overexpression of ING1b inhibited the cell growth of A549 and SK-MES-1, induced cell cycle arrest and apoptosis. p21waf1 was up-regulated and a complex of p33ING1b and wtp53 was found after transfection of ING1b in the wtp53-positive lung cancer cell. High LOH frequency was found in lung carcinomas (55.7%) and p33ING1b expression was lost in 115 of 217 carcinomas (53.0%). Furthermore, there was a highly significant inverse correlation between expression and LOH frequency (P<0.05). ING1 can inhibit the growth of lung cancer cell lines through the induction of cell cycle arrest and apoptosis by forming a complex with wtp53 and up-regulating p21waf1. In human lung cancer, expression of the ING1 gene was reduced or lost and high LOH frequency of ING1 microsatellites was found. The LOH of microsatellites may down-regulate p33ING1b and/or affect its function, thereby, contributing to lung cell carcinogenesis.     

Dissecting the genetic alterations involved in lung carcinogenesis

During the past two decades, considerable efforts have been devoted to the identification of the genes that drive lung cancer development. In spite of such intense research, only a few genes harboring mutations have been found, thus hindering the improvement in lung cancer treatment. The present review describes the catalog of known genetic alterations and the recent advances in global expression profiles in lung tumors and briefly discusses their use in clinical management.     

Genetic alterations and DNA repair in human carcinogenesis

A causal association between genetic alterations and cancer is supported by extensive experimental and epidemiological data. Mutational inactivation of tumor suppressor genes and activation of oncogenes are associated with the development of a wide range of cancers. The link between mutagenesis and carcinogenesis is particularly evident for cancers induced by chemical exposures, which, in some cases, lead to characteristic patterns of mutations. These "genotoxic," direct-acting carcinogens form covalent adducts with DNA, which cause mutations during DNA replication. The link between mutagenesis and carcinogenesis is also supported by the observation that DNA repair defects are associated with an increased cancer risk. Normally, DNA repair mechanisms serve to suppress mutagenesis by correcting DNA damage before it can lead to heritable mutations. It has been postulated that mutagenesis plays a role in both the initiation phase and the progression phase of carcinogenesis, and that an essential step in the carcinogenic process is the development of a mutator state in which the normal cellular processes that suppress mutagenesis become compromised. Given the link between mutations and cancer, attempts have been made to use the mutational profile of cancer cells as an indicator of the causative agent. While this may be a valid approach in some cases, it is complicated by the role of endogenous processes in promoting mutagenesis. In addition, many important carcinogenic agents may enhance mutagenesis indirectly through suppression of DNA repair functions or stimulation of inappropriate cell proliferation. Epigenetic phenomena may also suppress gene expression without causing overt changes in DNA sequence.     

Role of oncogenes and tumour suppressor genes in human lung carcinogenesis.

Six families of activated protooncogenes, ras, raf, fur, neu, jun and myc have so far been associated with human lung cancer. Human bronchial epithelial cells in vitro are being used to investigate the functional role of these specific oncogenes and growth regulatory genes in carcinogenesis and tumour progression. When transferred into normal human bronchial epithelial cells by the highly efficient protoplast fusion method, the v-Ha-ras oncogene initiates a cascade of events leading to decreased responsiveness of these cells to inducers of squamous differentiation, aneuploidy and, less frequently, 'immortality' and tumorigenicity with metastasis in athymic nude mice. Transfection of the SV40 T antigen gene results in nontumorigenic cell lines that have a nearly normal pathway of terminal squamous differentiation and can be transformed into malignant cells by transfected Ha-ras, N-ras or Ki-ras. The combination of transfected c-myc and c-raf-1 also transforms human bronchial epithelial cells into neoplastic cells that exhibit some phenotypic traits found in small-cell carcinomas. These and other results indicate that proto-oncogenes dysregulate the pathways of growth and differentiation of human bronchial epithelial cells and play an important role in human carcinogenesis. Analyses of allelic deletion and somatic cell hybrids are being used to identify the chromosomal localization of tumour suppressor genes. We have examined 54 non-small-cell bronchogenic carcinomas with 13 polymorphic markers. Loss of heterozygosity was more frequent than among 23 squamous-cell carcinomas than among 23 adenocarcinomas or eight large-cell carcinomas. Loss of heterozygosity for chromosome 17p was found in 89% of cases of squamous-cell carcinoma and 18% of adenocarcinomas. Analysis of chromosome 11 for allelic deletions revealed two commonly deleted regions (11p13 and 11p15.5). Somatic cell hybrids between normal human bronchial epithelial cells and Hut292DM, a lung carcinoma cell line, had a finite lifespan in vitro and were nontumorigenic in athymic nude mice. Tumour suppressive effects of individual or combinations of specific human chromosomes on Hut292DM are being examined by formation of microcell-cell hybrids. Chromosome 11 has tumour suppressor activity in these hybrids. Both of these studies suggest that tumour suppressor genes play a dominant role in lung carcinogenesis and provide in-vitro model systems for isolating these genes by subtraction library and insertional mutagenesis techniques.     

多肿瘤标志物蛋白芯片监测肺癌复发进展及转移的临床意义

背景与目的 据第十一届世界肺癌大会报告,肺癌已成为癌症死亡的主要原因,因此通过多种途径对肺癌患者进行监测具有重要的临床意义.本研究的目的是探讨多肿瘤标志物蛋白芯片监测肺癌复发进展及转移的临床价值.方法 对近年来检测了4次以上肿瘤标志物的44例肺癌患者根据临床疗效与病情分为六个等级,分析各肿瘤标志物表达水平与临床疗效病情分级的相关性,并建立疾病复发进展及转移的判别方程.结果 腺癌的临床疗效病情分级与CA199、CEA、CA242、AFP以及CA125有相关性;鳞癌只与CA125具有相关性;小细胞肺癌与CA199、CA125有相关性.根据判别方程,腺癌女性患者的判断准确率最高(89.4%),其次是腺癌男性(80.4%)、鳞癌(78.3%)和小细胞肺癌(66.7%).结论 多肿瘤标志物蛋白芯片的检测对于肺癌尤其是腺癌的复发进展及转移的监测具有重要临床价值.     

多种癌基因联合表达判断非小细胞肺癌预后的研究

目的　探讨多种癌基因蛋白表达与非小细胞肺癌 (NSCLC)预后的关系。方法　 1981～ 1994年 ,15 8例符合条件患者进入本研究。免疫组化方法检测Pan -ras,cmyc ,c -erbB2 ,EGFR和p 5 3等基因蛋白表达。Kaplan -Meier法计算生存率、局控率及远处转移率 ,Log-Rank法检验差异性 ,多因素分析为Cox模型。用记分方法探讨多种癌基因表达与预后关系。结果　全组 5年生存率、局控和远处转移率分别为 4 4 %、6 3%和 4 0 %。单个癌基因单因素分析 :Pan -ras、p 5 3与NSCLC远处转移有关 (P=0 .0 39,0 .0 6 )。多因素分析 :5个癌基因与NSCLC三项观察指标均无关。采用记分方法综合多种癌基因蛋白表达分析可提高其对NSCLC预后预测意义。结论　 1.多种癌基因综合分析较单一癌基因对NSCLC预后判断更具价值。 2 .癌基因对预后判断主要是对远处转移预测     

Rho蛋白在肿瘤发生发展中的作用

Rho蛋白是参与细胞内信号转导的重要蛋白,Rho家族成员及其各自的已知下游效应分子参与调节细胞的增殖、基因表达,同时是改变细胞骨架组装、调控细胞迁移进而参与肿瘤发生发展的关键因子,具有潜在而罩要的临床应用价值。     

Rho蛋白在肿瘤发生发展中的作用

Rho蛋白是参与细胞内信号转导的重要蛋白,Rho家族成员及其各自的已知下游效应分子参与调节细胞的增殖、基因表达,同时是改变细胞骨架组装、调控细胞迁移进而参与肿瘤发生发展的关键因子,具有潜在而重要的临床应用价值。     

Transitions between lung cancer phenotypes--implications for tumor progression.

Progression from a treatment-sensitive to a treatment-resistant tumor state is a virtually universal phenomenon in patients with small-cell lung carcinoma (SCLC). In such individuals, this tumor progression may involve transitions from a SCLC to a non-SCLC lung cancer phenotype. We are investigating the cell and molecular biology aspects of these transitions and have derived a cell culture model of one such change, oncogene-induced transition of SCLC to the large-cell undifferentiated lung cancer phenotype. Here we discuss the potential implication of this model for understanding the cell lineage and molecular events regulating normal bronchial epithelial cell differentiation and their relationships to the histogenesis and behavior of lung cancers.     

Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression

Carcinogenesis is a complex, multistep, multipath process often described as "somatic evolution". Conventional models of cancer progression are typically based on the genetic and epigenetic changes observed in malignant and premalignant tumors. We have explored an alternative approach that emphasizes the selection forces within adaptive landscapes governing growth and evolution in in situ, microinvasive, and metastatic cancers. In each environment, specific barriers to proliferation act as strong selection forces that determine the optimal phenotypic properties that permit tumor growth and invasion. Thus, the phenotypic properties or "hallmarks" of cancer can be viewed as successful adaptations to these microenvironmental selection forces. In turn, these selection pressures are not static but will dynamically change as a result of tumor population growth and evolution. Here, we emphasize the role of hypoxia and acidosis in the progression of tumor from in situ to invasive cancer. This is a consequence of early tumor cell proliferation on epithelial surfaces, which are separated from the underlying blood supply by the intact basement membrane. As tumor cells proliferate further away from the basement membrane, the diffusion-reaction kinetics of substrate and metabolite flow to and from the blood vessels result in regional hypoxia and acidosis. Cellular adaptation to the former include upregulation of glycolysis and to the latter include upregulation of Na+/H+ exchangers (NHE1) and other acid-regulating proteins such as carbonic anhydrase. We propose this phenotype is critical for subsequent malignant growth of primary and metastatic cancers.     

Metabolic tumor burden predicts for disease progression and death in lung cancer

PURPOSE: In lung cancer, stage is an important prognostic factor for disease progression and survival. However, stage may be simply a surrogate for underlying tumor burden. Our purpose was to assess the prognostic value of tumor burden measured by 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging. PATIENTS AND METHODS: We identified 19 patients with lung cancer who had staging PET-CT scans before any therapy, and adequate follow-up (complete to time of progression for 18, and death for 15 of 19). Metabolically active tumor regions were segmented on pretreatment PET scans semi-automatically using custom software. We determined the relationship between times to progression (TTP) and death (OS) and two PET parameters: total metabolic tumor volume (MTV), and standardized uptake value (SUV). RESULTS: The estimated median TTP and OS for the cohort were 9.3 months and 14.8 months. On multivariate Cox proportional hazards regression analysis, an increase in MTV of 25 ml (difference between the 75th and 25th percentiles) was associated with increased hazard of progression and of death (5.4-fold and 7.6-fold), statistically significant (p = 0.0014 and p = 0.001) after controlling for stage, treatment intent (definitive or palliative), age, Karnofsky performance status, and weight loss. We did not find a significant relationship between SUV and TTP or OS. CONCLUSIONS: In this study, high tumor burden assessed by PET MTV is an independent poor prognostic feature in lung cancer, promising for stratifying patients in randomized trials and ultimately for selecting risk-adapted therapies. These results will need to be validated in larger cohorts with longer follow-up, and evaluated prospectively.     

Genetic alterations in prostate cancer

Prostate cancer is the most common nondermatologic malignancy in men. Prostate cancer is characterized by clinical and biologic heterogeneity that has complicated molecular and epidemiologic studies. Like other epithelial malignancies, prostate tumors exhibit complex karyotypic abnormalities and harbor many specific genetic alterations. Although recent work has begun to elucidate many of the specific mutations associated with prostate cancer, we still lack a clear understanding of the complement of genetic changes that suffice to program the malignant state. Here, we review our current understanding of the genetic changes found in prostate cancer and explore the connections between specific genetic alterations and malignant phenotypes including cell growth, survival, invasion, and metastasis.     

癌基因与抑癌基因的表达研究进展

肿瘤的发生发展本质上是细胞原癌基因的激活和抑癌基因的失活造成的.癌基因和抑癌基因的研究对探索肿瘤发病机制,寻找预防和治疗肿瘤的新措施具有重要意义.本文较全面地介绍了癌基因和抑癌基因的种类以及它们对细胞的调控作用和致癌、抑癌的分子机制,特别是总结了近年来癌基因及抑癌基因的研究进展.