Mechanisms of tumor metastasis: cell biological aspects and clinical implications

The clinical course – and hence the prognosis – of patients suffering from malignant tumors are essentially determined by the capability of tumor cells to metastasize. During the past decade knowledge about genetic aberrations, as well as molecular and cell biological mechanisms which are involved in the regulation of tumor metastasis, has dramatically increased and consequently led to the development of new theoretical and experimental strategies in cancer treatment. The objective of this review is not only to give an overview about the principal cell biological and molecular mechanisms of tumor metastasis, but also to discuss potential therapeutical options resulting from this knowledge. Received: 9 March 2000 / Accepted: 6 April 2000     

Liver tumor promotion by the cyanobacterial cyclic peptide toxin microcystin-LR

Summary Certain waterblooms of toxic cyanobacteria (blue-green algae) are a health threat because of their production of toxic peptides, termed microcystins, which cause liver damage in wild and domesticated animals. The most widely studied microcystin is microcystin-LR, a heptapeptide containing the twol-amino acids, leucine and arginine. The inhibition of protein phosphatase type 1 and type 2A activities by microcystin-LR is similar to that of the known protein phosphatase inhibitor and tumor promoter okadaic acid. We show in this report that microcystin-LR, applied below the acute toxicity level, dose-dependently increases the number and percentage area of positive foci for the placental form of glutathioneS-transferase in rat liver, which was initiated with diethylnitrosamine. The result was obtained independently through two animal experiments. This observation indicates that microcystin-LR is a new liver tumor promoter mediated through inhibition of protein phosphatase type 1 and type 2A activities. This provides further evidence that the okadaic acid pathway is a general mechanism of tumor promotion in various organs, such as mouse skin, rat glandular stomach and rat liver.Abbreviations DEN diethylnitrosamine - DMBA 7,12-dimethylbenz[a]anthracene - GST-P glutathioneS-transferase placental form     

Serum KL-6 as a novel tumor marker for hepatocellular carcinoma in hepatitis C virus infected patients.

The up-regulation of MUC1 protein is associated with malignant phenotype of cancer. We investigated the significance of KL-6, one of the MUC1 antigens, as a tumor marker in hepatitis C virus positive hepatocellular carcinoma (HCC). Serum KL-6 was determined in 203 patients with chronic hepatitis (CH), 47 patients with liver cirrhosis (LC) and 78 patients with HCC. KL-6 was higher in HCC compared to non-HCC (p=0.0005) and was higher in patients with multiple HCC nodules compared to a single nodule (p=0.02). There was no correlation between KL-6 and existent tumor markers for HCC such as alpha-fetoprotein, lens culinaris agglutinin-reactive alpha-fetoprotein or des-gamma-carboxyprothrombin. In the prospective analysis, the cumulative incidence of HCC was significantly greater in CH and LC patients with high initial KL-6 (above 400U/ml) compared to the others (p=0.02). Moreover, in the prospective observation of 25 patients whose HCC was completely cured by radiofrequency ablation therapy, the cumulative incidence of distant recurrences was significantly greater in patients with high initial KL-6 compared to the others (p=0.005). These results suggest that serum KL-6 could be a novel tumor marker in the diagnosis and the prediction of prognosis of HCC that may have additive value to the existent markers.     

Use of cultured human tissues and cells in carcinogenesis research

Summary A variety of approaches are used to study carcinogenesis. Recent advances in techniques for culture of human tissues and cells have provided additional experimental systems of study the process of carcinogenesis and the genetics of cancer.The Journal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest Editorials on current and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the author.     

Synergistic effect of Epstein-Barr virus and tumor promoters on induction of lymphoma and carcinoma in nude mice

Balb/c nude mice were subcutaneously transplanted with fetal nasopharyngeal mucosa infected with B95-8 Epstein-Barr virus (EBV). n-Butyrate and/or 12-O-tetradecanoylphorbol 13-acetate (TPA) were injected subcutaneously on the third day and once a week thereafter. About 10 days later, tumor masses gradually grew in these mice. Histopathological examination was carried out 15 weeks later. Three cases of lymphomas (two T cell lymphomas and one B cell lymphoma) were observed in the group receiving EBV and TPA, and one T cell lymphoma and three cases of undifferentiated carcinoma were found in the group receiving EBV, TPA and n-butyrate, but no case was found in the control groups that were transplanted with fetal nasopharyngeal tissue infected with EBV, or TPA and n-butyrate alone. Polymerase chain reaction amplification and in situ hybridization revealed that lymphoma and carcinoma cells contained the EBV LMP1 and EBERs genes. LMP1 protein was also found in the carcinoma. The T and B cell lymphomas and the nasopharyngeal carcinoma in nude mice were derived from human nasopharyngeal mucosa; this was proved by using human specific monoclonal antibodies to CD3 for T cells, to CD20 for B cells, and to epithelial membrane antigen for epithelial cells. Nucleotide sequence analysis indicated that the homologies of EBV LMP1 genes in the induced malignant lymphomas and undifferentiated carcinomas to the B95-8 cell gene were around 96% and 99% respectively. The results showed that EB virus can infect nasopharyngeal mucosa of the human fetus and consequently induce malignant transformation by the synergistic effect of the tumor promoters, and that EBV DNA can persist in the lymphomas and carcinomas. Received: 6 April 1998 / Accepted: 25 June 1998     

Butylated hydroxytoluene (BHT) induction of pulmonary inflammation: a role in tumor promotion

Chronic pulmonary inflammatory diseases predispose towards lung cancer by unknown mechanisms. Butylated hydroxytoluene (BHT) administration to mice causes lung injury and a subsequent inflammatory response, and when administered chronically to certain inbred strains following carcinogen treatment, increases lung tumor multiplicity. We hypothesize that inflammation promotes lung tumor growth in this model system and have begun to examine this hypothesis by assessing inflammatory parameters in inbred strains that vary in their susceptibility to promotion. Positive correlations were found between susceptibilities to tumor promotion and BHT induction of alveolar macrophage and lymphocyte infiltration into alveolar airspaces, and increased vascular permeability (P < .03, P < .04, and P < .005, respectively). The amounts of pulmonary cyclooxygenase (COX)-1 and COX-2 did not strongly correlate with promotion. Because persistent elevation of macrophage content is the hallmark of a chronic inflammatory response, the alveolar macrophage population was depleted by adding chlorine to the drinking water prior to carcinogenesis. This treatment reduced lung tumor multiplicity following 2-stage carcinogenesis (P < .05). These correlations between inflammatory and tumorigenic responses to BHT, along with decreased tumorigenesis after macrophage depletion, are consistent with a role of inflammation in promotion. Inflammatory mediators may provide targets for early diagnosis and chemoprevention.     

Tumor suppressor and hepatocellular carcinoma

A few signaling pathways are driving the growth of hepatocellular carcinoma. Each of these pathways possesses negative regulators. These enzymes, which normally suppress unchecked cell proliferation, are circumvented in the oncogenic process, either the over- activity of oncogenes is sufficient to annihilate the activity of tumor suppressors or tumor suppressors have been rendered ineffective. The loss of several key tumor suppressors has been described in hepatocellular carcinoma. Here, we systematically review the evidence implicating tumor suppressors in the development of hepatocellular carcinoma.     

Hyperthermia and hyperglycemia for manipulated inhibition of tumor microcirculation

Summary There are no differences in principle between our results and those obtained by other authors with respect to tumor microcirculation inhibition by hyperthermia alone. To attain therapeutically relevant selective inhibition of microcirculation in tumor tissue, however, a combination of hyperthermia with hyperglycemia is the method of choice.     

Methylation in esophageal carcinogenesis

INTRODUCTION Esophageal cancer is one of the least studied and deadliest cancers, with a remarkable geographical distribution and a low likelihood of cure[1]. Therefore, the current challenges in the management of esophageal cancer are to obtain a better understanding of the underlying molecular biological alterations to provide new treatment options. Cancer of the esophagus exists in two main forms with different etiological and pathological characteristics-esophagealsquamous cell carcino…     

肺癌患者异常糖链糖蛋白与传统肿瘤标志物的相关性分析

目的通过回顾性分析肺癌患者异常糖链糖蛋白(TAP)水平以及传统肿瘤标志物癌胚抗原(CEA)、鳞状细胞癌抗原(SCC)、糖类抗原125(CA125)、神经元特异性烯醇化酶(NSE)和细胞角蛋白19片段(CYFRA21-1)水平,探讨肺癌患者TAP与传统肿瘤标志物之间的相互关系。 方法分别采用凝聚素亲和法及电化学发光免疫分析法检测我院呼吸内科经治的181例肺癌患者TAP和5种血清学肿瘤标志物的水平,对所得TAP与5种血清学肿瘤标志物的数据进行spearman相关性检验分析。 结果肺癌患者TAP与CEA呈正相关(P＝0.016),而与SCC、CA125、NSE及CYFRA21-1之间没有相关性(P值均>0.05);亚组分析,腺癌、鳞癌患者的TAP与CEA均呈正相关(P值分别为0.021,0.044),腺癌、鳞癌、小细胞癌及未分类癌患者的TAP与CA125均呈正相关(P值分别0.046,0.007,0.001,0.006),而这四类癌的TAP与SCC、NSE和CYFRA21-1之间没有明显相关性(P值均>0.05)。 结论肺癌患者TAP值是CEA、CA125等多种肿瘤异常蛋白水平的综合体现,尤其在肺腺癌患者中与传统肿瘤标志物具有较好的正相关性。     

Further identification of protein kinase C isozymes in mouse epidermis

In the current study, the protein kinase C (PKC) isozymes present in mouse epidermis have been identified using immunological and chromatographic methods. Six PKC isozymes, PKC, PKC, PKC, PKC, PKC, and PKC, were identified in unfractionated epidermal preparations by protein immunoblotting. The subcellular distribution and presence of these isozymes was further verified by hydroxyapatite (HA) chromatography with the exception of PKE, which could not be detected following HA chromatography. The five PKC isozymes recovered following HA chromatography were detected in both epidermal cytosol and particulate fractions, although PKC was found in a much higher proportion relative to the other PKC isozymes in the particulate fraction using histone H1 as the substrate. The biochemical properties of the epidermal PKC isozymes partially purified by HA chromatography agreed with those reported for other tissues and further supported their immunological identification in epidermal preparations. The activities of HA chromatography peaks corresponding to PKC, PKC, and PKC were found to be dependent on both Ca²⁺ and phosphatidylserine (PtdSer), whereas, the activities of HA peaks corresponding to PKC and PKC were Ca²⁺-independent but PtdSer-dependent. The HA peak corresponding to PKC also displayed a characteristic biphasic modulation by arachidonic acid (activation at low, inactivation at high concentrations) and inactivation by preincubation with PtdSer. PKC activity was also characteristic, in that it was dependent on PtdSer and was not increased by the phorbol ester, 12-O-tetradecanoylphorbol 13-acetate. Some differences in substrate specificity were also observed between the epidermal PKC isozymes. The presence of multiple isozymes of PKC in mouse epidermis suggests that the different isozymes may play distinct roles in signal transduction and tumor promotion in this tissue.Abbreviations PKC protein kinase C - HA hydroxyapatite - PtdSer phosphatidylserine - TPA 12-O-tetradecanoylphorbol 13-acetate This work was supported by USPHS grants CA 38871 (J.D.), CA 57596 (J.D.) and core grant CA 16672     

Aryl hydrocarbon hydroxylase induction levels in patients with malignant tumors associated with smoking

Summary The levels of aryl hydrocarbon hydroxylase (AHH) inducibility were assessed in 173 patients with cancers statistically associated with smoking, i.e., squamous cell and transitional cell carcinomas, at various sites. In 34 patients with carcinomas of the oral cavity, 41 patients with laryngeal carcinomas, and 22 patients with pulmonary carcinomas there was a highly significant overrepresentation of high inducers, whereas 30 patients with carcinomas of the renal pelvis and ureter and 46 patients with urinary bladder carcinomas did not differ significantly in this respect from a control population comprising 92 subject with no history of neoplastic disease.The results add further support to the concept of AHH as a major activator of carcinogens belonging to the group of polycyclic aromatic hydrocarbons (PAH) when these affect·the oral cavity and/or the respiratory tract.The role of AHH in urothelial carcinogenesis seems to be less explicit.     

肿瘤蛋白质组学与消化系肿瘤生物标记

肿瘤蛋白质组学是通过蛋白质组技术研究肿瘤细胞中蛋白质及其相互作用的新的学科。将蛋白质组学技术用于研究肿瘤的发病机制、寻找新的肿瘤诊断生物标记以及采用组织蛋白质组图谱进行早期诊断等早已引起了人们的广泛关注。肿瘤蛋白质组学可能会引起肿瘤临床实践的重大革命。本文对近年发现的肿瘤生物标记进行了回顾,分析了肿瘤蛋白质组学在肿瘤生物标记发展中的前景。