Of birds and mice and men: comments on the use of animal models and molecular hybridization in the search for human tumor viruses.
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Animals↗
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The use of molecular genetic markers to demonstrate the effect of organ environment on clonal dominance in a human renal-cell carcinoma grown in nude mice.
Transduction of the SN12C human renal-cell carcinoma line with the neoR gene produces a genetically "tagged" cell population within which individual clones can be identified if they dominate the tumor during its growth in vivo. We used this technique to determine whether the clones that dominate the primary local tumor and its metastases are the same or different when the tumor is growing in different organ sites in nude mice. The results show that clonal dominance is influenced by the organ environment in which the primary tumor grows, i.e., distinct clones dominated in the kidney, colon and subcutaneous sites. In addition, tumors grown in the orthotopic site (kidney) were all populated by the same dominant clones, and each distant visceral metastasis retained the same clonality. SN12C neoR-cells grown in an epithelial, ectopic site (colon) produced tumors with uniquely different dominant clones, and their visceral metastases retained the dominant pattern expressed by the parent tumor from which they were derived. In contrast, SN12C tumors growing subcutaneously showed a random pattern of clonal dominance in both their primary and metastatic sites. Parallel cytogenetic analyses could not demonstrate these patterns. We conclude that the organ environment significantly influences clonal dominance of human renal carcinoma and that tumor injection into orthotopic sites may produce a more reproducible selection of dominant clones.
Animals↗
Activation and biological properties of endogenous retroviruses in radiation osteosarcomagenesis.
The activation of endogenous retroviruses (MuLV) by internal irradiation and the presence of activated retroviruses in radiation-induced murine osteosarcomas as well as their biological properties in vivo and in vitro were studied. Ecotropic and xenotropic MuLV were expressed dependent on the radiation dose in spleen, bone marrow and bone tissues of C57Bl/6 mice after 224Ra treatment. Radiation-induced osteosarcomas of BALB/c, C57Bl/6 and C3H X 101/F1 mice harboured infectious ecotropic and/or xenotropic viruses whereas in osteosarcomas of NMRI mice predominantly virus protein could be detected. In about 50% of the radiation-induced osteosarcomas of BALB/c mice an amplification of ecotropic proviruses could be detected. This was not found in clonally grown cells from non-tumorous tissues. MuLV from radiation-induced osteosarcomas induced osteopetrosis, osteomas and lymphomas after infection of newborn NMRI mice. In differentiating bone tissue the viruses were found to infect predominantly osteoblast precursor cells suggesting that virus infection results in increased growth and metabolic activity of these cells, which may be a possible mechanism for their pathogenic action in bone tissues.
Animals↗
Chromosome 5 allele loss in human colorectal carcinomas.
That the sporadic and inherited forms of a particular cancer could both result from mutations in the same gene was first proposed by Knudson. He further proposed that these mutations act recessively at the cellular level, and that both copies of the gene must be lost for the cancer to develop. In sporadic cases both events occur somatically whereas in dominant familial cases susceptibility is inherited through a germline mutation and the cancer develops after a somatic change in the homologous allele. This model has since been substantiated in the case of retinoblastoma, Wilms tumour, acoustic neuroma and several other tumours, in which loss of heterozygosity was shown in tumour material compared to normal tissue from the same patient. The dominantly inherited disorder, familial adenomatous polyposis (FAP, also called familial polyposis coli), which gives rise to multiple adenomatous polyps in the colon that have a relatively high probability of progressing to a malignant adenocarcinoma, provides a basis for studying recessive genes in the far more common colorectal carcinomas using this approach. Following a clue as to the location of the FAP gene given by a case report of an individual with an interstitial deletion of chromosome 5q, who had FAP and multiple developmental abnormalities, we have examined sporadic colorectal adenocarcinomas for loss of alleles on chromosome 5. Using a highly polymorphic 'minisatellite' probe which maps to chromosome 5q we have shown that at least 20% of this highly heterogeneous set of tumours lose one of the alleles present in matched normal tissue. This parallels the assignment of the FAP gene to chromosome 5 (see accompanying paper) and suggests that becoming recessive for this gene may be a critical step in the progression of a relatively high proportion of colorectal cancers.
Adenocarcinoma↗
The use of molecular hybridization to track the mode of transmission and distribution of murine mammary tumor viruses: a model for etiologic studies of human breast cancer.
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Animals↗
COMPARATIVE BIOCHEMISTRY OF THREE TRANSPLANTABLE MAMMARY TUMORS AS INFLUENCED BY STEROID THERAPY.
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Acid Phosphatase↗
Immunologic study of antigens and molecular hybridization of nucleic acids from milk of breast cancer patients.
Comparative study has shown that by the gel diffusion assay both anti-HEp-2 virus serum and anti-breast cancer milk ultrasediment serum precipitated an identical antigen in human milk specimens, which was not identical with the group specific antigen of the HEp-2 virus. At the same time tha anti-breast cancer milk serum did not precipitate the HEp-2 virus. However, molecular hybridization experiments revealed nucleotide sequences homologous to nucleic acids of oncornavirus of D-type in milk obtained from breast carcinoma patients as well as in milk of healthy donors.
Antigens, Neoplasm↗
Significance of CD44 gene products for cancer diagnosis and disease evaluation.
With increasing emphasis on the early detection of cancer, the search is on for reliable markers that will be clinically helpful in the diagnosis of small tumours and in the assessment of their metastatic potential. This report presents evidence that an abnormal pattern of activity of the CD44 gene is a promising candidate for both of these purposes in various types of malignancy. By a mechanism known as alternative splicing this gene can produce different messenger RNA molecules (transcripts) which are detectable, after amplification, as separate bands in electrophoretic gels. In neoplasia many abnormal variant transcripts are produced. A previous finding in animal experiments, that one such variant might be important in metastasis, prompted our study of human tumour tissue, benign and malignant, and of corresponding normal tissues. We studied tumour tissue from 34 patients with neoplastic disease (mostly breast or colon cancer) and normal or non-malignant diseased breast or colonic tissue from 11 patients and peripheral blood leucocytes from 4 healthy volunteers. CD44 gene activity was studied by amplifying messenger RNA with the polymerase chain reaction (PCR) followed by electrophoresis and blot hybridisation. In malignant tissues there was gross overproduction of each of 9 or more alternatively-spliced large molecular variants in all samples, whereas in the control samples only the standard product was routinely detected with occasional minimal quantities of one or two small variants. Furthermore, the band pattern permitted differentiation between the 23 cases with metastatic tumours of the breast or colon and the 8 with no detectable metastases. Calibration studies seeding blood with tumour cells showed that the technique can detect as few as 10 tumour cells among 10(7) leucocytes (1 ml of blood). Analysis of CD44 splice variants may prove to have applications not just to the early detection of metastatic potential in surgical biopsy specimens but also, if our findings are confirmed, in readily available bodily fluids, to the early diagnosis of cancer in screening programmes, to the assessment of remaining disease in the body and to the early detection of recurrences.
Adult↗
Allele loss occurs frequently at hMLH1, but rarely at hMSH2, in sporadic colorectal cancers with microsatellite instability.
Mutations at the hMSH2 and hMLH1 mismatch repair loci have been implicated in the pathogenesis of colorectal cancer. Tumours with two allelic mutations at a mismatch repair locus develop replication errors (RERs). In the hereditary non-polyposis colorectal cancer (HNPCC) syndrome, one mutation is inherited and the other acquired somatically: in RER+ sporadic colorectal cancers, both mutations are somatic. RER+ tumours tend to have a low frequency of allele loss, presumably because they acquire most mutations through RERs. However, before a second mismatch repair mutation has occurred somatically, there is no reason to suppose that allele loss occurs less frequently in tumours that are to become RER+. Indeed, this second mutation might itself occur by allele loss. We have searched for allele loss at the hMSH2 and hMLH1 loci in RER+ and RER- sporadic colorectal cancers. Loss occurred at the hMLH1 locus in 7/17 (41%) RER+ tumours, compared with 6/40 (15%) RER- cancers (chi2=3.82, P approximately 0.05). At hMSH2, 2/22 RER+ sporadic cancers (9%) had lost an allele, compared with 2/40 (5%) RER- cancers (chi2=0.03, P>0.5). Taken together with previous studies which focused on colorectal cancers from HNPCC families, the data suggest that allele loss at hMLH1, but not at hMSH2, contributes to defective mismatch repair in inherited and sporadic colorectal cancer.
Adaptor Proteins, Signal Transducing↗
Mutational profile of the PTEN gene in primary human astrocytic tumors and cultivated xenografts.
The genetic abnormality most frequently identified in glioblastomas is loss of alleles on chromosome 10. We have performed a comprehensive study of the PTEN tumor suppressor gene on 10q23, including loss of heterozygosity (LOH) analysis, multiplex PCR, mutation analysis, and reverse transcription PCR (RT-PCR). In total, 151 glioblastomas, 41 anaplastic astrocytomas, 15 astrocytomas, and 13 glioma cell lines were analyzed as well as 23 xenografts derived from primary glioblastomas, which allows a comparison of the PTEN gene status in primary tumors versus xenografts. Homozygous deletions were found in 7% of the glioblastomas and 40% showed mutation of a single retained allele. This mutation frequency is higher than reported previously. The large number of mutations identified allows the presentation of a mutational profile along the coding sequence. The majority of mutations appear to affect conserved residues or structurally conserved regions. PTEN alterations were selected for in xenografts, and there is evidence that they may even facilitate establishment of xenografts. No alterations were found in astrocytomas and only 5% of anaplastic astrocytomas had mutations. Thus, loss of wild type PTEN represents one of the major abnormalities associated with astrocytic tumor progression to glioblastoma and provides a strong selective growth advantage when cultivating glioblastoma tissue in xenografts. No correlation with EGFR amplification was evident.
Alleles↗
Primary lymphoma of the central nervous system: a clinicopathologic study.
We performed clinicopathologic examinations of 27 cases of primary lymphoma of the central nervous system not related to acquired immune deficiency syndrome. We considered age and change of performance status (PS) to be especially important in clinical examination. We also conducted pathological studies of these tumors and the characteristics of their cells, in order to characterize pathological subtypes, cell kinetics, and involvement of viruses. PS of patients more than 70 years old decreased markedly before treatment and did not show the improvement after treatment that was exhibited by those under 70 years of age. Low PS (60% or less) after initial treatment, high MIB-1 positivity (over 44.0%), and high counts of AgNOR (over 4.56/cell) were significantly associated with lower survival rates. Patients with immunoblastic lymphoma and high MIB-1 positivity are likely to die from general debilitation, without evidence of recurrence from imaging. Preoperative steroid therapy was significantly associated with higher apoptotic positivity.
Adult↗
T-cell lymphoma of the vulva in a renal allograft recipient with associated hemophagocytosis.
The risk of B-cell lymphoma is greatly increased in transplant patients, whereas T-cell lymphomas have only rarely been reported in these patients. Although T-cell lymphomas in nonimmunosuppressed patients may be associated with either human T-cell lymphotropic virus type I (HTLV-I) or Epstein-Barr virus (EBV), these viruses have not been reported in association with post-transplant T-cell lymphoma. We report a case of T-cell lymphoma of the vulva arising in a renal allograft recipient receiving azathioprine and prednisone. The unusual clinical presentation led to difficulty in diagnosis because of a resemblance to either an infectious process or squamous cell carcinoma. The large cell lymphoma involved the dermis and subcutaneous fat of the vulva and was associated with hemophagocytosis in lymph nodes and bone marrow. The tumor had a mature, aberrant T-cell immunophenotype (CD3+ CD4+ CD7+ CD2- CD5- CD30+). Rearrangement of the T-cell receptor beta and gamma chain genes was found, but there was no evidence of either EBV or HTLV-I genomes. This case adds to the clinical and morphologic spectrum of T-cell lymphomas reported in allograft recipients and suggests that known lymphotropic viruses do not commonly have a role in post-transplant T-cell lymphoma.
Antigens, CD↗
Flat adenoma as a precursor of colorectal carcinoma in hereditary nonpolyposis colorectal carcinoma.
BACKGROUND: Because flat adenoma shows a higher malignancy rate compared with other types of polyps, it is considered to play an important role in the carcinogenesis of colorectal carcinoma. In the present study, we examined flat adenomas in hereditary nonpolyposis colorectal carcinoma (HNPCC) patients. METHODS: Nine HNPCC patients who presented with flat adenomas were examined. All patients underwent either surgery or endoscopic polypectomy for colorectal carcinoma and/or adenoma. In all patients, annual colonoscopy had been performed once a year throughout the follow-up period after the initial treatment. When colorectal polyps were detected during follow-up colonoscopy, all lesions were endoscopically excised. Clinicopathologic features and microsatellite instability of both malignant lesions and adenomas were examined. RESULTS: Thirteen malignant lesions were detected: seven advanced carcinomas and six early carcinomas. Among 4 early carcinomas with submucosal invasion, 3 lesions (75%) were categorized as superficial type, with a configuration similar to flat adenoma. The frequency of flat adenoma was strikingly high in HNPCC patients in the present study. Among 73 polyps detected, 37 (50.7%) were flat adenomas. Both malignant lesions and flat adenomas had proximal predominance, 61.5% and 59.5%, respectively. Eleven of 15 lesions (73.3%) showed replication error. CONCLUSIONS: These results suggest the importance of flat adenoma as a precursor of colorectal carcinoma in some groups of HNPCC patients. Further study is essential to elucidate the natural history of flat adenomas in HNPCC patients.
Adenoma↗
Allelic loss of chromosome 17p, mutation of the p53 gene, and microsatellite instability in right- and left-sided colorectal cancer.
BACKGROUND: Epidemiologic and genetic studies suggest that cancer of the right and left sides of the bowel arise through different mechanisms. To investigate the molecular mechanisms, allelic loss of chromosome 17p, p53 mutations, and microsatellite instability were analyzed in colorectal cancer according to tumor site. METHODS: Using the polymerase chain reaction and single strand conformation polymorphism (PCR-SSCP) method, mutations within exons 5-8 of the p53 gene were examined in 108 colorectal cancers including 30 right-sided and 78 left-sided colorectal cancers. Allelic loss of chromosome 17p was studied by restriction fragment length polymorphism analysis, and genetic instability was examined for replication error (RER) at three microsatellite loci on chromosomes 2p, 17p, and 17q. RESULTS: Allelic loss was observed in 61% (14 of 23 informative cases) of right-sided tumors and in 60% (26 of 43 informative cases) of left-sided tumors. PCR-SSCP analysis demonstrated that 63 of 108 tumors had a mutated p53 gene in exons 5, 6, 7, or 8. When comparing the frequency of mutation in each exon based on tumor site, the frequency of mutation in exon 8 in right-sided (2 of 18 informative cases) tumors was significantly lower than that observed in left-sided (17 of 45 informative cases) tumors. RER(+) was observed in 43% of right-sided tumors, whereas 24% of left-sided tumors were RER(+). Although the difference was not statistically significant, a trend was observed between RER(+) phenotype and tumor site. CONCLUSIONS: Our results suggest that the molecular mechanisms of colorectal carcinogens may differ between right- and left-sided tumors.
Alleles↗
Genomic instability in colorectal cancers in Turkey.
Microsatellite instability in a subset of colorectal cancers from North America, Europe and Japan has been reported. We examined 88 colorectal cancers from Turkish patients. Five different microsatellite loci (1 mono- and 4 dinucleotide repeat regions) were tested. Eight tumors displayed replication errors (RERs) with at least 2 different markers. Right-sided tumors showed significantly higher frequency of microsatellite instability compared with left-sided tumors. The frequency of RER phenotype was slightly higher in tumors occurring in younger (<50 years old) than in older patients (13% vs. 8%), and there was no association between sex and genomic instability. The frequency of genomic instability in our study group was 9%, whereas the reported frequencies in tumors from other countries varied between 12% and 16%.
Colorectal Neoplasms↗
NUCLEAR SIZE IN CARCINOMA OF THE CERVIX: ITS RELATION TO DNA CONTENT AND TO PROGNOSIS.
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Carcinoma↗
Analysis of p53 gene mutations in low- and high-grade astrocytomas by polymerase chain reaction-assisted single-strand conformation polymorphism and immunohistochemistry.
Using polymerase chain reaction-assisted single-strand conformation polymorphism (PCR-SSCP) and immunohistochemical analyses, mutations in the p53 tumor suppressor gene were examined in 19 low- and high-grade gliomas. By PCR-SSCP and nucleotide analyses, p53 gene mutation was seen in 7 gliomas. Out of the 7 mutations, 3 were located at the CpG site of the previously proposed hot-spot codons 248 and 273, 2 were at codons 171 and 214 and the other 2 were in intron 5, 1 at the splice acceptor site and the other in the vicinity of the splice donor site. The latter 4 mutations have not, or only rarely, been observed in gliomas or in other tumors. However, their effect on the structural and functional alteration of the p53 protein was suggested by positive intranuclear p53 immunostaining in neoplastic cells in 3 mutations including the 1 at the splice acceptor site. In connection with glioma grading, the p53 gene mutation was shown to have occurred in both low- and high-grade gliomas, often in most of the neoplastic cells, as suggested by lack of distinct normal bands and ladders in SSCP and direct sequencing, respectively. The absence of recurrence and malignant transformation over a considerably long postoperative time in our low-grade glioma cases suggested that the p53 gene mutation might not be sufficient for the progression from low- to high-grade gliomas. The frequency of detection of mutation was 7/19(37%) by PCR-SSCP, 8/19(42%) by immunohistochemistry and 10/19(53%) by both methods. The results of PCR-SSCP and immunohistochemistry were consistent in 14 cases (73.7%), but not in 5 cases(26.3%).(ABSTRACT TRUNCATED AT 250 WORDS)
Astrocytoma↗