Princess Takamatsu symposia最新文献

{"title":"Cancer-stromal interaction through growth factor/cytokine networks implicated in growth of stomach cancer.","authors":"E Tahara","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Stomach cancer shows multiple gene changes, including both oncogenes and tumor suppressor genes. Among them, the one most frequently implicated in stomach cancer is the abnormal expression and amplification of the c-met gene. Moreover, stomach cancer cells express a broad spectrum of growth factors and cytokines that not only serve autocrine or paracrine growth of tumor cells, but also organize the complex networks between tumor cells and stromal cells. However, the scenario of cancer-stromal interaction differs depending on the two histological types-the well-differentiated or intestinal type and the poorly-differentiated or diffuse type-as the two types of stomach cancer may have different genetic pathways. The interaction between cell-adhesion molecules in the c-met overexpressed tumor cells and HGF from activated fibroblast may be involved in the progression and the morphogenesis of stomach cancer.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"24 ","pages":"187-94"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19945831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatocyte growth factor as mitogen, motogen and morphogen, and its roles in organ regeneration.","authors":"T Nakamura","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Hepatocyte growth factor (HGF) has been discovered, purified, and molecularly cloned as a potent mitogen for mature hepatocytes. HGF is a heterodimeric molecule composed of a 69 kDa alpha-subunit and a 34 kDa subunit. It contains four kringle domains in the alpha-subunit. It is produced by mesenchymal cells and predominantly acts on a wide variety of epithelial cells as a mitogen (stimulation of cell growth), a motogen (stimulation of cell motility), and a morphogen (induction of multicellular tissue-like structure). These pleiotropic functions of HGF are essential biological activities for the construction of normal tissue architecture. HGF may be one of the long-sought paracrine mediators of morphogenetic epithelial-mesenchymal interactions. On the other hand, HGF receptor was identified as the product of the c-met proto-oncogene, which encodes a 190-kDa transmembrane protein possessing tyrosine kinase domain. HGF mRNA and HGF protein are rapidly and markedly increased in the liver and plasma of rats with various types of liver injuries. HGF receptors on plasma membranes of the liver were almost completely down-regulated due to HGF binding and subsequent internalization. Therefore, HGF acts as a hepatotropic factor for liver regeneration. Recombinant HGF, intravenously injected into mice, remarkably enhances liver regeneration. After various renal and lung injuries, HGF mRNA, HGF protein, and HGF receptors in the kidney and lung are also rapidly altered prior to the onset of replication of renal tubular cells and lung alveolar epithelial cells Recombinant HGF intravenously injected into rats also remarkably enhances renal and lung regeneration. Thus, HGF acts as a renotropic factor in renal regeneration and as a plumotropic factor in lung regeneration. It is considered a key molecule for the construction of normal tissue structure during embryogenesis, organogenesis, and organ regeneration.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"24 ","pages":"195-213"},"PeriodicalIF":0.0,"publicationDate":"1994-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19945832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multistage prostate carcinogenesis: the role of hormones.","authors":"M C Bosland,&nbsp;H C Dreef-Van Der Meulen,&nbsp;S Sukumar,&nbsp;P Ofner,&nbsp;I Leav,&nbsp;X Han,&nbsp;J G Liehr","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Prostate cancer is the most frequently occurring non-skin cancer in men in the U.S.A. and other Western countries, but its etiology is poorly understood. Human prostate carcinogenesis has been viewed as a multi-step process involving progression from low histologic grade, small latent carcinoma, to large, higher grade, metastasizing carcinoma. However, recent data suggest that a variety of pathogenetic pathways exist. The precise role of hormones in the genesis of human prostate cancer remains largely undefined. It is difficult to investigate stages in the development of human prostate cancer, but some animal models provide opportunities in this regard. Short-term treatment of rats with chemical carcinogens will produce a low incidence (5-15%) of prostate cancer, provided that prostatic cell proliferation is enhanced during carcinogen exposure. A high carcinoma incidence can only be produced by chronic treatment with testosterone following administration of carcinogens such as N-methyl-N-nitrosourea (MNU). Testosterone markedly enhances prostate carcinogenesis even at doses that do not measurably increase circulating testosterone. Thus, testosterone is a strong tumor promoter for the rat prostate. All such MNU-initiated, testosterone-promoted tumors are adenocarcinomas mostly originating from the dorsolateral and anterior, but not ventral, prostate lobes. A high frequency (70%) of activation of the K-ras gene by a G35 to A mutation occurs in these carcinomas. A variable frequency of activation of H-ras and K-ras genes occurs in human prostate carcinomas. Another rat model, representing a different pathogenetic pathway, involves chronic administration of estradiol-17 beta in combination with low-dose testosterone. The resulting carcinomas are low-grade and originate exclusively from periurethral ducts of the dorsolateral and anterior prostate. We recently found a major adduct by 32P postlabeling analysis in the tissue region that includes these ducts, but not in, e.g., the ventral prostate, of rats treated for 16-24 weeks. While it is unknown whether testosterone is a tumor promoter in this system, the presence of a DNA adduct suggests that estradiol-17 beta acts as a tumor-initiating agent in this system.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"22 ","pages":"109-23"},"PeriodicalIF":0.0,"publicationDate":"1991-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13004848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"5-Methylcytosine as an endogenous mutagen in the p53 tumor suppressor gene.","authors":"W M Rideout,&nbsp;G A Coetzee,&nbsp;A F Olumi,&nbsp;C H Spruck,&nbsp;P A Jones","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Approximately 4% of cytosine residues in human DNA are modified post-synthetically into 5-methylcytosine (5mC) which is the only modified base present in vertebrate DNA. The function of 5mC is not fully understood, but methylation of promoter regions is often associated with transcriptional inactivity and may be part of a gene silencing mechanism. While undermethylation of promoter regions is correlated with expression, the same does not seem to be true for the remainder of genes since many genes are expressed while containing 5mC in their coding regions. This is significant because 5mC is known to be inherently mutagenic and it has been suggested that it is responsible for 30-40% of all human germline point mutations. We have used direct genomic sequencing to examine the methylation status of CpG sequences which serve as potential methylation sites in the human p53 gene. These sites, which are known to be hotspots for mutations in several human cancers, were found to be methylated in the target human tissues examined. The results suggest that 5mC may play a substantial role as an endogenous mutagen in the p53 gene and that the generation of these mutations does not require the direct interaction of a carcinogen with DNA. We have also compared the spectrum of p53 mutations reported in the literature for various human tumors. The patterns of mutations seen in different tumor types vary considerably and 5mC contributes to 63% of point mutations in colorectal cancer but only 13% in lung cancer. Mutations in lung cancer are therefore caused by a different mechanism than colorectal cancer and this presumably requires the direct interaction of carcinogens with DNA. Assessment of the proportion of 5mC induced mutations in the p53 gene therefore allows for an estimate of the relative importance of endogenous and exogenous mechanisms of carcinogenesis.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"22 ","pages":"207-19"},"PeriodicalIF":0.0,"publicationDate":"1991-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13006871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"myc, max, and a novel rlf-L-myc fusion protein in small-cell lung cancer.","authors":"I Västrik,&nbsp;T P Mäkelä,&nbsp;P J Koskinen,&nbsp;K Saksela,&nbsp;K Alitalo","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The functional properties of Myc proteins are likely to be modulated by interactions with other nuclear proteins. One such protein called Max has already been characterized (1). Through their homologous helix-loop-helix and leucine zipper structures, Myc and Max proteins form heterodimers that bind to specific DNA sequences more efficiently than Myc or Max alone. We have recently identified delta Max, a naturally occurring truncated version of Max, which is also able to dimerize with Myc in the nucleus, but is cytoplasmic in the absence of Myc. These two forms of Max can act either as enhancers or suppressors of cotransformation by c-myc and ras. Oncogenic activation of myc genes in human cancer involves deregulated myc expression. Oncogenes of the myc family are activated in several types of human tumors as a result of gene amplification or chromosomal translocation. We have recently characterized a gene fusion and a chimeric protein product formed by L-myc and part of a novel gene called rlf in small-cell lung cancer (SCLC) cell lines. Although the chimeric mRNAs were shown to be identical, they result from distinct DNA rearrangements. We have also established a physical linkage between normal rlf and L-myc using pulsed field gel electrophoresis. Thus, the rlf-L-myc gene fusions are due to similar but not identical intrachromosomal rearrangements at 1p32. Similar in vivo rearrangements involving rlf and L-myc have been found in at least one primary SCLC tumor. The presence of independent genetic lesions that cause the formation of identical chimeric rlf-L-myc proteins suggests a role for the fusion protein in the development of these SCLC tumors.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"22 ","pages":"307-18"},"PeriodicalIF":0.0,"publicationDate":"1991-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12834417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multistep hepatocarcinogenesis in transgenic mice harboring SV40 T-antigen gene.","authors":"T Kitagawa,&nbsp;O Hino,&nbsp;G H Lee,&nbsp;H Li,&nbsp;J Liu,&nbsp;K Nomura,&nbsp;K Ohtake,&nbsp;Y Furuta,&nbsp;S Aizawa","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>We have developed transgenic mice that inherit albumin promoter-regulated simian virus 40 (SV40) large T-antigen gene, expressed specifically in hepatocytes. These mice all develop multifocal hepatocellular carcinomas (HCCs) at around 5 months and die of liver insufficiency by 7 months in remarkable synchrony. The liver tissue appears normal in the initial 3 weeks, and thereafter rapid cytomegalic degeneration of original hepatocytes, proliferation of quasi-regenerative hepatocytes, neoplastic cell foci, nodules and finally HCCs develop in sequence. Considerable variation existed both in morphological and enzymatic features and in T-antigen expression among neoplastic lesions, including carcinomas. Oligonucleotide hybridization studies revealed activating point mutations of the c-H-ras oncogene in 40% (10/25) of tumors obtained at around 6 months. The positive signals were, however, considerably weaker in half of them suggesting that such tumors comprised cells both with and without ras mutation. Sequential observation of culture cell lines established from tumors also revealed the appearance of activated c-H-ras with time, which was associated with biological progression. Thus, in this model system, ras activation may be an event occurring in a relatively late phase of carcinogenesis associated with progression of tumors. Karyotype analysis of cell lines revealed remarkable chromosomal instability. In studies of sister chromatid exchange in hepatocytes, twice as frequent occurrence was demonstrated in transgenic mice as in their counterpart hepatocytes. Thus T-antigen may be contributing as a mutagen to the hepatocarcinogenesis, in addition to its cytotoxic and growth modifying activities.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"22 ","pages":"349-60"},"PeriodicalIF":0.0,"publicationDate":"1991-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12834418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transforming and c-fos promoter/enhancer-stimulating activities of a GDP/GTP exchange protein for small GTP-binding proteins.","authors":"Y Takai,&nbsp;K Kaibuchi,&nbsp;A Kikuchi,&nbsp;M Kawata,&nbsp;T Sasaki,&nbsp;T Yamamoto","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>There is a superfamily of ras p21/ras p21-like small GTP-binding proteins (G proteins). Small G proteins have GDP-bound inactive and GTP-bound active forms which are interconvertible by GDP/GTP exchange and GTPase reactions. The former and latter reactions are regulated by GDP/GTP exchange proteins (GEPs) and GTPase activating proteins (GAPs), respectively. We have isolated two types of GEP: one is a stimulatory type called GDP dissociation stimulator (GDS) and the other is an inhibitory type called GDP dissociation inhibitor (GDI). Among the GEPs thus far isolated, only smg GDS is active on Ki-ras p21. This GEP is also active on smg p21 and rho p21, but is inactive on Ha-ras p21. For the action of smg GDS, the post-translational processing of the C-terminal region of its substrate small G proteins is essential. Point-mutated Ki-ras p21 strongly transforms NIH/3T3 cells and markedly stimulates the c-fos promoter/enhancer in this cell line, whereas normal Ki-ras p21 is almost inactive in these activities. smg GDS induces the Ki-ras p21 activation which eventually leads to the transformation of NIH/3T3 cells and to the stimulation of the c-fos promoter/enhancer in this cell line. Thus, smg GDS plays an important role in regulating the activity of Ki-ras p21 as well as of other small G proteins.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"22 ","pages":"197-204"},"PeriodicalIF":0.0,"publicationDate":"1991-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13006870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor suppressor genes involved in metastasis of lung and colorectal carcinomas.","authors":"J Yokota,&nbsp;K Ookawa,&nbsp;R Nishikawa,&nbsp;Y Sameshima","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Inactivation of tumor suppressor genes is now believed to play an important role in various progression stages of human cancers. To clarify the possible involvement of tumor suppressor gene inactivation in the acquisition of metastatic potential in lung and colorectal carcinoma cells, we examined various genetic alterations in both primary tumors and metastases obtained from patients with lung and colorectal carcinomas. In lung carcinoma, loss of heterozygosity on chromosomes 3p, 13q, and 17p is a common genetic alteration, and both RB and p53 genes are inactivated as a result of chromosome 13q and 17p losses. In some cases, allelic loss on chromosome 11p and amplification of myc family oncogenes occur during tumor progression. In colorectal carcinoma, p53 and DCC alterations were detected in 100% of metastases, and sequential accumulation of allelic losses on chromosomes 13q, 14q, and 18q in the process of metastasis was observed. These results indicate that a subset of tumor suppressor genes is involved in metastasis of lung and colorectal carcinomas.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"22 ","pages":"71-6"},"PeriodicalIF":0.0,"publicationDate":"1991-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13005407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A population perspective on multistage carcinogenesis.","authors":"S H Moolgavkar","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The concept of multistage carcinogenesis is one of the central dogmas of cancer research today. Recent laboratory work suggests that many specific genetic changes are associated with carcinogenesis. At the same time, there is increasing evidence that cell proliferation kinetics are important in carcinogenesis. In 1971, Knudson proposed his now celebrated two-mutation model for embryonal tumors. In fact, a two-mutation model that explicitly considers cell kinetics is the most parsimonious model consistent with the incidence of both childhood and adult cancer in human populations. This model has been known to be consistent, as well, with other epidemiologic and experimental data. But can such a model be reconciled with the laboratory evidence suggesting that many genetic alterations are required for malignant transformation? In this paper, I examine multistage carcinogenesis from the population perspective. Can cancer incidence data in populations provide some insight into the number and nature of stages involved in malignant transformation? I focus attention on carcinoma of the colon because of the considerable amount of information that is now available on the genetics of these tumors. Also, as is the case with retinoblastoma, colon cancer occurs in sporadic and dominantly inherited forms. A comparison of the incidence of these two forms of colon cancer suggests that mutation at the familial adenomatous polyposis (FAP) locus is not necessary for colon cancer, and that inheritance of the gene for FAP is not equivalent to inheriting one of the essential steps on the pathway to colon cancer. Thus, colon cancer does not follow the retinoblastoma paradigm. The incidence of colon cancer in the general population and among polyposis subjects is consistent with two or three mutations on the pathway to malignancy. A three-mutation model is more consistent with the genetic alterations observed in colon carcinogenesis. I present and discuss a working model for colon cancer.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"22 ","pages":"381-91"},"PeriodicalIF":0.0,"publicationDate":"1991-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12834279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional loss of tumour suppressor genes in multistage chemical carcinogenesis.","authors":"A Balmain,&nbsp;C J Kemp,&nbsp;P A Burns,&nbsp;A B Stoler,&nbsp;D J Fowlis,&nbsp;R J Akhurst","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Studies of multistage carcinogenesis in mouse skin have provided many of the early concepts of tumour initiation, promotion and progression. Genetic approaches have led to the identification of a number of mutational alterations in proto-oncogenes and tumour suppressor genes which take place at specific stages of carcinogenesis in this particular system. Initiation involves, at least in a proportion of tumours, mutational activation of the cellular H-ras proto-oncogene. Trisomy of chromosome 7, which develops during the premalignant clonal expansion phase, possibly as a consequence of tumour promoter treatment, is followed by further alterations on chromosome 7 which lead to a relative increase in the expression of mutant ras alleles. The p53 tumour suppressor gene undergoes mutational alteration and loss of heterozygosity in a proportion of squamous carcinomas but this particular gene does not appear to be involved in the further transition of squamous carcinomas to highly undifferentiated spindle cell tumours. The latter transition appears to be a recessive event which can be complemented by fusion with cells at earlier stages of malignancy. Mouse skin carcinogenesis therefore continues to provide invaluable information on the nature of the genetic and biological transitions which occur during the step-wise progression of normal cells to malignancy.</p>","PeriodicalId":77594,"journal":{"name":"Princess Takamatsu symposia","volume":"22 ","pages":"97-108"},"PeriodicalIF":0.0,"publicationDate":"1991-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13005408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}