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PubMed1994

Primary care approach to lymphadenopathy.

Lymphadenopathy is a common presenting symptom. It is a manifestation of many disease processes ranging from self-limiting ones to those that are incurable and fatal. The diagnostic factors used to evaluate the etiology of one or more enlarged lymph nodes include: the age of the patient, the clinical history, the physical examination, and the anatomic location/nodal history and characteristics. With the selection of the proper tests, unnecessary or invasive treatments can be avoided. Ultimately, when a neoplastic process is suspected, a lymph node biopsy is the definitive test.

Biopsy↗
PubMed1984

Clinical and pathologic description of 17 cases of corneal intraepithelial neoplasia.

In 17 patients with corneal intraepithelial neoplasia (dysplasia), the epithelium formed a gray plaque at the corneal limbus adjacent to a conjunctival papilloma in seven cases, leukoplakia in six cases, a pterygium in one case, and a pinguecula in one case. The lesion was an extension of a similar neoplastic process of the conjunctiva in 15 cases, was associated with chronic conjunctivitis in one case, and was isolated to the cornea in one case. Fine white dots mottled the opalescent, ground-glass sheet, whose fimbriated leading edge consisted of sharply demarcated gray fingers that extended to the visual axis in some cases. The disorder can wax and wane spontaneously, shown in one case observed for 16 years. Histopathologically, the thick, hypercellular corneal epithelium abutted sharply against adjacent normal epithelium and demonstrated both cellular pleomorphism and poor intercellular adhesion in the deeper layers. The adjacent conjunctival neoplastic lesions ranged from mild dysplasia to invasive squamous cell carcinoma. Ultrastructurally, the corneal epithelium showed a marked decrease in desmosomal attachments, an abundance of intracytoplasmic filaments characteristic of keratin, and a loss of epithelial basement membrane and hemidesmosomes. The lesion did not extend into Bowman's zone. We classify this dysplastic process as a mild form of corneal intraepithelial dysplasia, a term used to designate the spectrum of epithelial changes ranging from dysplasia to carcinoma in situ. The virulence of the corneal lesion itself is low.

Adult↗
PubMed2006

Exploitation of the Toll-like receptor system in cancer: a doubled-edged sword?

The toll-like receptor (TLR) system constitutes a pylogenetically ancient, evolutionary conserved, archetypal pattern recognition system, which underpins pathogen recognition by and activation of the immune system. Toll-like receptor agonists have long been used as immunoadjuvants in anti cancer immunotherapy. However, TLRs are increasingly implicated in human disease pathogenesis and an expanding body of both clinical and experimental evidence suggests that the neoplastic process may subvert TLR signalling pathways to advance cancer progression. Recent discoveries in the TLR system open a multitude of potential therapeutic avenues. Extrapolation of such TLR system manipulations to a clinical oncological setting demands care to prevent potentially deleterious activation of TLR-mediated survival pathways. Thus, the TLR system is a double-edge sword, which needs to be carefully wielded in the setting of neoplastic disease.

Disease Progression↗
PubMed1992

Genetic alterations underlying colorectal tumorigenesis.

Colorectal tumours have proven to be an excellent system in which to identify and study the genetic alterations involved in the development of a common human neoplasm. A prevalent view is that colorectal tumours appear to arise as the result of multiple genetic alterations in the alleles of both oncogenes and tumour suppressor genes. The accumulation of genetic alterations appears to accompany the clinical and biological progression of the tumours and may determine the phenotype of the tumour cells. In addition to the many somatic alterations identified at various stages of colorectal tumour development, recent studies have led to the identification of the adenomatous polyposis coli (APC) gene, which, when mutated in the germline, predisposes to the development of colorectal tumours. On the basis of studies of inherited and somatic mutations in colorectal tumours, a genetic model for colorectal cancer development has been proposed. Although the model is undoubtedly incomplete, it nevertheless provides a useful framework for further studies of the multiple events that underlie human tumour initiation and progression. Numerous questions remain to be answered, including identification of the normal function of the genes implicated in tumorigenesis, how mutations in these genes arise and are selected for and what the relative contribution of the altered genes is to various stages of the neoplastic process. Nevertheless, an optimistic outlook is that fundamental insights into the pathogenesis of human cancer are within our reach.

Chromosome Deletion↗
PubMed1996

Switch from monoallelic to biallelic human IGF2 promoter methylation during aging and carcinogenesis.

We have previously linked aging, carcinogenesis, and de novo methylation within the promoter of the estrogen receptor (ER) gene in human colon. We now examine the dynamics of this process for the imprinted gene for insulin-like growth factor II (IGF2). In young individuals, the P2-4 promoters of IGF2 are methylated exclusively on the silenced maternal allele. During aging, this promoter methylation becomes more extensive and involves the originally unmethylated allele. Most adult human tumors, including colon, breast, lung, and leukemias, exhibit increased methylation at the P2-4 IGF2 promoters, suggesting further spreading during the neoplastic process. In tumors, this methylation is associated with diminished or absent IGF2 expression from the methylated P3 promoter but maintained expression from P1, an upstream promoter that is not contained within the IGF2 CpG island. Our results demonstrate a remarkable evolution of methylation patterns in the imprinted promoter of the IGF2 gene during aging and carcinogenesis, and provide further evidence for a potential link between aberrant methylation and diseases of aging.

Adolescent↗
PubMed2001

Mouse plasmacytoma: an experimental model of human multiple myeloma.

BACKGROUND AND OBJECTIVES: There is no ideal animal model for human multiple myeloma (MM). All the models resemble the human disease in some respect, but none of them fulfils all the criteria of a perfect animal model. EVIDENCE AND INFORMATION SOURCES: The pristane oil (2,6,10,12-tetramethylpentadecane)-induced mouse plasmacytoma (MPC) model is the most widely used and accepted model and has provided the most data on plasmacytomagenesis so far. This model gives the opportunity to study the role of c-myc dysregulations, the mechanisms leading to cytogenetic changes involving Ig genes, the role of chronic inflammatory factors, the role of interleukin-6 (IL-6), insulin-like growth factor-I, prostaglandins, as well as signal transduction pathways in the neoplastic process. Therapeutic agents have been successfully tested. Although MPC growth is usually restricted to the peritoneal environment, intraperitoneal injection of MPC cell suspensions can reproduce the disseminated characteristics of the human disease in recipients. The IL-6 transgene and knockout models are important tools for clarifying the role of IL-6 in the pathogenesis of MM. Transgenic mice and retroviral gene transfer facilitate the study of oncogenes in neoplastic transformation. Spontaneous development of plasmacytomas in C57BL/ KaLwRij aging mice has several advantages, mainly because the disseminated growth, the typical bone lesions and renal involvement resemble, in part, the human disease. Furthermore, this model has already proved useful in studies on the effect of bisphosphonate in the treatment of bone disease in MM. The severe combined immunodeficiency (SCID) mouse model is also very attractive. A disseminated-like disease can be reproduced in this model. Multiple osteolytic bone lesions and bone marrow involvement are generated, and conventional drugs applied in the treatment of human multiple myeloma have proven to be effective. Nevertheless, the immune system of SCID mice basically differs from that of a MM patient. PERSPECTIVES: Taken together, all these models have contributed to our understanding of MM, but demonstrate the opportuness of developing a more appropriate model of the human disease.

Animals↗
PubMed1987

Unusual immunoglobulin DNA sequences from the nonexpressed chromosome of mouse normal B lymphocytes: implications for allelic exclusion and the DNA rearrangement process.

Allelic exclusion of immunoglobulin gene products results in the expression of only one of two possible alleles in normal B lineage cells. Attempts to define the role of heavy chain gene rearrangements in this process have revealed the nonexpressed allele to be rarely in its germline context, but rather incompletely rearranged (D/J rearrangements) or completely rearranged (V/D/J rearrangements) and in a context that cannot be expressed as a protein. Nearly all DNA sequences of heavy chain genes from the nonexpressed allele have originated from plasmacytomas, virus-induced pre-B leukemias, and hybridomas--all clonal cell lines perhaps altered by the neoplastic process. In this communication, we present the first examples of isolation and DNA sequence analysis of heavy chain gene rearrangements from the nonexpressed allele of normal B lymphocytes. Splenic B lymphocytes from allotype heterozygous (BALB/c X C57BL/6J)F1 mice expressing the BALB/c IgD allotype were detected with a monoclonal antibody, H10-4.22, to the BALB/c delta chain genetic marker and were isolated with a FACS (fluorescence-activated cell sorter). lambda phage clones containing the JH gene region from the sorted cells were isolated, and those containing sequences derived from the C57BL/6J nonexpressed chromosome were identified by a restriction fragment length polymorphism. DNA sequences of seven rearranged clones from the nonexpressed allele are presented. Five of these rearrangements have unexpected compositions. Four of the five clones contain V/D/J rearrangements with no obvious impediments to expression generated by the rearrangements. The novel variable region gene in one of these V/D/J rearrangements is a member of a newly described VH gene family. The fifth clone has a 3.5 kb deletion removing all of the JH gene segments. The remaining two clones contain D/J rearrangements that are typical of the initial stage of variable region assembly. These findings suggest that the mechanisms that generate nontranslatable heavy chains do not exclusively account for allelic exclusion. Rather, several different mechanisms may contribute to the establishment of allelic exclusion in normal B lymphocytes.

Alleles↗
PubMed2001

Monoclonality in normal epithelium and in hyperplastic and neoplastic lesions of the breast.

The clonal nature of neoplastic lesions such as invasive breast cancer and ductal carcinoma in situ (DCIS) has been widely proven by several proliferative, genetic or other malignancy-associated markers. The aim of this study is to clarify whether benign hyperplastic lesions such as ductal hyperplasia of usual type (DH) and papilloma can be distinguished from neoplastic lesions such as DCIS by X-chromosome inactivation analysis. Clonal analysis was performed using a polymerase chain reaction-based assay for non-random X-chromosome inactivation of the human androgen receptor gene (HUMARA). Formalin-fixed and paraffin-embedded archival tissue of ten DCIS, sixteen DH, nine papillomas, and seven normal terminal ductal lobular units (TDLUs) was laser-microdissected to avoid contamination with surrounding tissue. All of the cases analysed revealed a monoclonal origin. Furthermore, in one of these cases, opposite X chromosomes were inactivated within the same breast. X-linked inactivation analysis clearly demonstrates that, at least in the breast, monoclonality is not restricted to neoplastic processes. The data support the hypothesis that the mammary gland is organized into distinct stem cell-derived monoclonal patches and that TDLUs are monoclonal in origin. Any proliferative lesion arising within such a pre-existing clonal patch should therefore be clonal, irrespective of whether it originates from one or more patch cells. Thus, X-chromosome inactivation analysis cannot be considered a valid method for distinguishing between neoplastic and hyperplastic breast lesions.

Breast↗
PubMed2004

Gene expression profiles of epithelial cells microscopically isolated from a breast-invasive ductal carcinoma and a nodal metastasis.

Expression profiles of breast carcinomas are difficult to interpret when they are obtained from tissue in toto, which may contain a large proportion of non-cancer cells. To avoid this problem, we microscopically isolated cells from a primary invasive ductal carcinoma of the breast and from an axillary node harboring a metastatic breast carcinoma, to obtain pure populations of carcinoma cells ( approximately 500) and used them for serial analysis of gene expression. The expression profiles generated from both populations of cells were compared with the profile of a disease-free mammary epithelium. We showed that the expression profiles obtained are exclusive of carcinoma cells with no contribution of non-epithelial cells. From a total of 16,939 unique tags analyzed, we detected 559 statistically significant changes in gene expression; some of these genes have not been previously associated with breast cancer. We observed that many of the down-regulated genes are the same in both cancers, whereas the up-regulated genes are completely different, suggesting that the down-regulation of a set of genes may be the basic mechanism of cancer formation, while the up-regulation may characterize and possibly control the state of evolution of individual cancers. The results obtained may help in characterizing the neoplastic process of breast cancer.

Breast↗
PubMed1991

Breast cancer-associated protein pS2 expression in tumors of the biliary tract.

Expression of pS2 (an estrogen-induced gene isolated from breast carcinoma MCF7 cells) and of the human spasmolytic peptide (hSP) gene was analyzed in 21 human biliary tract and gallbladder carcinomas and 16 non-neoplastic gallbladders at the protein level (immunochemistry) and, in a series of these cases, at the RNA level (Northern blots). Eighteen carcinomas and 14 non-neoplastic mucosae with inflammatory alterations showed pS2 activity by immunostaining or Northern blotting. In addition, in samples with pS2 expression, hSP RNA was demonstrated. In the corresponding non-neoplastic and healthy mucosae, pS2 was negative, as judged by immunostaining. Northern blots showed weak (basal) level of activity for pS2 and hSP. The genes' increased expression in correlation to inflammatory and neoplastic processes, by now observed in several carcinomas and idiopathic inflammatory bowel disease, hints to their essential role in such diseases.

Biliary Tract Neoplasms↗
PubMedDate not supplied

The human lck cDNA clone YT16 is a transforming oncogene.

The lck gene belongs to the src gene family and it is implicated in processes of lymphomagenesis. A full-:length lck-encoding cDNA clone, termed YT16 was isolated from a subtractive cDNA library, which was specific for expressed genes of the human Jurkat T-cell lymphoma. Sequence analysis of this molecular clone revealed major structural alterations compared to other tyrosine kinases classified as src-related genes. Firstly, a region within thw YT16 sequence surrounding the conserved ATP-binding site was modified by several short frameshift mutations. Secondly, the regulatory important tyrosine-505 residue was substituted by a threonine at this aligned position. The latter mutation was expected to result in a constitutional hypophosphorylated and thus permanently activated protein tyrosine kinase. These significant genetic alterations within the coding region of YT16 prompted us to investigate its biological relevance in vivo. To this end, we expressed YT16-specific sequences in NIH 3T3 fibroblasts and looked for morphological transformation of transfected cells. Here we report, that transformation of NIH 3T3 cells is obtained, provided that inhibitory untranslated sequences are removed from the YT16 cDNA clone. These results lend support to the notion, that structurally altered lck genes, in this study represented by the YT16 clone, may contribute to neoplastic processes in lymphoid cells.

3T3 Cells↗
PubMedDate not supplied

Genomic instability in squamous cell carcinoma of the head and neck.

The role of genomic instability in the development of squamous cell carcinoma (SCCHN) has become apparent with the publication of three major allelotype analysis of this disease, as well as many publications which have concentrated on specific target regions. The measurement of accumulated genetic alterations or fractional allele loss, as determined by allelotype analysis, provides a useful molecular indicator of tumour behaviour. In one major study, a positive correlation was found between FAL > median value and lymph node metastasis and also with a poor clinical outcome. In addition the recognition of microsatellite instability as a marker of DNA repair defects has provided a further molecular marker of the disease process and that loss of heterozygosity analysis and microsatellite instability appear to be independent genetic events in the development of SCCHN. Furthermore, the recognition of a number of novel target regions in SCCHN on chromosome arms, 1 p, 3p, 8p, 9p, 13q, 17p and 18q and our understanding of the role of certain oncogenes and tumour suppressor genes and their interaction with human papillomavirus has provided further elucidation of the neoplastic process. Even though this review describes a number of molecular events in SCCHN, the sequence of events still eludes the scientific community at present.

Alleles↗
PubMed1999

Functional roles of chromosomes 11 and 17 in the transformation of human breast epithelial cells in vitro.

Genomic alterations in primary breast cancer play a role in the initiation and progression of the disease. We have analyzed the molecular events involved in the initiation and progression of the neoplastic process in an in vitro experimental system. Immortalization of human breast epithelial cells (HBEC) is associated with 3:9 translocation, p53 mutation and microsatellite instability (MSI) of chromosomes 11p13, and 17p. BP1-E cells, derived from the immortalized MCF-10F cells transformed by the carcinogen benzo(a)pyrene (BP), express in vitro growth advantage, anchorage independence, enhanced chemoinvasiveness, loss of ductulogenic capabilities and tumorigenesis in a heterologous host. This neoplastic progression is also associated with mutations and/or amplification of c-H-ras, int-2, c-neu, c-myc and MDM2, MSI at 11q25 and 13q12-q13 and loss of heterozygosity at 17p. In order to test whether chromosomes 11 or 17 play a functional role in the phenotypic expression of transformation of BP1E cells, we utilized microcell-mediated chromosome transfer (MMCT) technique for inserting the corresponding normal chromosomes to these transformed cells. BP1E cells were transfected with PsV2neo plasmid and fused with microcells obtained from the mouse cell line A9, containing a normal chromosome 11 or 17 (A9-11neo and A9-17neo cells, selected in G418 and cloned. Sixteen primary microcell hybrids from each chromosome transfer, designated BP1E-11neo and BP1E-17neo survived selection in G-418 containing medium. A single clone from each group, BP1E-11neo #145 and BP1E-17neo D100, survived subcloning and were utilized for a detailed panel of analyses. The presence of a donor chromosome was confirmed by dual color fluorescence in situ hybridization (FISH), southern blot analysis of the marker vector pSV2neo, and microsatellite polymorphism analysis. The transfer of the normal chromosomes 11 and 17 resulted in a 50% and 90% inhibition of cell growth respectively, and reduced both colony efficiency and colony size. Telomerase activity was significantly reduced only by chromosome 17 insertion, providing a possible explanation for the more significant senescence observed in BP1E-17neo D100 cells. Microsatellite polymorphism analysis revealed that three loci, 11q13-23, 11q23.1, and 11q23.3 (markers D11S911, DRD2, and D11S29) were retained in BP1E-11neo #145 cells, and two, 17q24.2-25.2, 17q25.2 (markers D17S515 and D17S785 were retained in BP1E-17neo D100 cells. We conclude that the specific regions of normal chromosomes 11 and 17 transferred play a functional role in the expression of immortal and transformed phenotypes of HBEC in vitro.

Blotting, Southern↗
PubMed2003

Occlusive ileus as a complication of large intestinal diverticulosis (contribution of two cases).

After a short literature review of diverticulosis of the colon and its complications, the authors give a thorough description of two cases treated by them for sigmoid colon diverticulosis complicated with occlusive ileus. The patients were males aged 68 and 74 years. In both cases the authors had difficulties in making the precise intraoperative diagnosis. Since exclusion of malignancy was impossible (in emergency conditions immediate histological verification was not possible). Hartman's operation ensuring oncological radicalism was performed. The intestinal passage was restored at the second stage of operation. The final histological verification detected chronic inflammatory process due to diverticulosis that had lead to stenosis and occlusion of the intestinal lumen. On the basis of the two cases described herein and the available literature data, the authors accept Hartman's operation as a method of choice in the treatment of occlusive ileus resulting from large intestinal diverticulosis in elderly patients in impaired general condition. If feasible in emergency conditions immediate histological examination should be used to exclude neoplastic process of the colon.

Aged↗
PubMed2002

Deregulation of polyamine biosynthesis alters intrinsic histone acetyltransferase and deacetylase activities in murine skin and tumors.

The essential requirement for polyamines for normal cell growth and differentiation may be partly attributed to their influence on gene expression, a process regulated by the acetylation state of nucleosomal histones. We used transgenic mice to examine the effects of constitutive expression of ornithine decarboxylase (ODC), a key rate-limiting enzyme in polyamine biosynthesis, on histone acetylation in epithelial cells in skin. As compared with the skin of normal littermate mice, both intrinsic histone acetyltransferase (HAT) and deacetylase activities are elevated in ODC transgenic skin. Skin tumors that form spontaneously in ODC/Ras double transgenic mice exhibit exceptionally high HAT activity having a distinct specificity for Lys-12 in the tail domain of histone H4, which may have implications for gene transcription. However, acetylation of histones by HAT enzymes was impeded in cultured ODC transgenic keratinocytes, and there were only modest changes in levels of acetylated histones in the skin of ODC transgenic mice. Treatment with the ODC enzyme inhibitor alpha-difluoromethylornithine, which results in regression of ODC/Ras tumors, reverses the effects on HAT and deacetylase enzyme function, implicating polyamine biosynthesis in the regulation of histone acetylation. Polyamines do not directly stimulate the enzymatic activity of either p300 or p300/CREB-binding protein (CBP)-associated factor, members of two distinct classes of HAT enzymes, implying that the elevated CBP/p300-associated HAT activity detected in ODC transgenic skin is attributable to indirect influence of polyamines. These results suggest that multiple mechanisms exist by which endogenous polyamines influence chromatin in mammals. Furthermore, they suggest that the elevated polyamine levels inherent in many solid tumors alter chromatin structure, likely affecting gene expression and promoting the neoplastic process.

Acetylation↗
PubMed2006

Cellular and molecular aspects of gastric cancer.

Gastric cancer remains a global killer with a shifting burden from the developed to the developing world. The cancer develops along a multistage process that is defined by distinct histological and pathophysiological phases. Several genetic and epigenetic alterations mediate the transition from one stage to another and these include mutations in oncogenes, tumour suppressor genes and cell cycle and mismatch repair genes. The most significant advance in the fight against gastric cancer came with the recognition of the role of Helicobacter pylori (H pylori) as the most important acquired aetiological agent for this cancer. Recent work has focussed on elucidating the complex host/microbial interactions that underlie the neoplastic process. There is now considerable insight into the pathogenesis of this cancer and the prospect of preventing and eradicating the disease has become a reality. Perhaps more importantly, the study of H pylori-induced gastric carcinogenesis offers a paradigm for understanding more complex human cancers. In this review, we examine the molecular and cellular events that underlie H pylori-induced gastric cancer.

Cell Cycle Proteins↗
PubMed1998

Cell-adhesion-dependent influences on genomic instability and carcinogenesis.

Adhesion-dependent cell signaling is known to be important in carcinogenesis. It is postulated that several types of adhesion molecules act as tumor suppressor genes by enforcing cell-substrate and cell-cell adhesion thereby preventing the migration of cells and their invasion into surrounding tissues. Recent evidence, however, suggests that disruption of adhesion systems can both initiate neoplastic transformation and contribute a rate-limiting step to progression. Adhesion may modulate neoplastic processes by altering pathways that control genomic stability. Analysis of the adhesion-controlled inactivation of the p53 protein and the concomitant relaxation of cell cycle checkpoint control could identify the critical contributions of adhesion-mediated influences to carcinogenesis.

Cell Adhesion↗
PubMed1991

Cellular differentiation and morphologic heterogeneity in polymorphous low-grade adenocarcinoma of minor salivary gland.

Histologic diversity is intrinsic to salivary gland tumors, but it is a particular feature of polymorphous low-grade adenocarcinoma as denoted by the terminology. Application of immunohistochemistry and electron microscopy to three examples allowed the study of some aspects of tumor cell differentiation in this minor salivary gland lesion. In one case where the tumor cells were cytologically of one type, immunohistochemistry clearly identified both luminal and nonluminal tumor cells, but the latter showed no evidence of myoepithelial cell differentiation. A second case revealed differentiation only of luminal-type tumor cells, while a third example was largely differentiated as myoepithelial cells but again immunohistochemistry confirmed focal formation of duct-like structures by luminal epithelium. These cases show a considerable range of tumor cell heterogeneity as well as variations in their organization. This variation in differentiation characteristics underlies the histology of polymorphous low-grade adenocarcinomas, and likely occurs in other salivary gland tumors. To establish specific and reliable diagnostic criteria for such tumors requires awareness of this neoplastic process. The limited malignant potential and excellent survival of patients with polymorphous low-grade adenocarcinoma is apparently little affected by patterns of differentiation in this particular neoplasm.

Actins↗