Biomedical subjects

A G Nerlich

Publications and source records attributed to A G Nerlich.

61 records · Page 4Linked to original sources

PubMedDate not supplied

Malignant tumors in an ancient Egyptian population.

Since it is still an open debate whether malignant tumors are mainly influenced by environmental factors, the frequency of such malignant tumors in historic populations with different living conditions is of particular interest. In the present study, we investigated the occurrence of malignant tumors affecting bone tissue in a population of mumrnies and skeletons, which had been excavated from the large necropolis of Thebes-West, Upper Egypt. Our study material comprised a series of at least 415 individuals (thereof 325 adults) dating from approx. 1500-500 B.C. All individuals had been mummified, but were severely damaged and partially broken by grave robbers, so that often only parts of the mummies/skeletons were available for investigation. The available specimens were subjected to careful macroscopic examination, while isolated findings were radiologically analyzed. Using this approach, we identified at least 4 cases showing malignant tumors affecting the skeleton. In two cases, multiple mixed osteolytic-osteoblastic lesions suggested multiple metastases from carcinomas. Two further individuals presented with multiple osteolyses (vertebra, pelvis, skull) most suggestive of multiple myeloma. The observation of at least 4 cases of malignant tumors with osseous manifestation in a series of 325 adult individuals provides clear evidence that malignant tumors were not a rare event in the ancient Egyptian study population, particularly when the limitations of a study of tumors manifested only in osseous remnants are taken into consideration. A calculation of the age- and sex-adjusted tumor frequency in our material in comparison with a recent model for such a material by Waldron (1996) indicates that the rate of malignant tumors with bone affection in our series is higher than in an English population from 1901-1905, although lower than in a comparable present day population. This clearly indicates that important factors affecting malignant tumors were effective even in historic populations.

Adult↗

PubMedDate not supplied

Matrix metalloproteinases (MMPs) in breast cancer cell lines of different tumorigenicity.

In the present study we investigated the presence, amount and activity of matrix metalloproteinases (MMPs)-1, -2, -3, -7, -8, -9, -10, -11 and -13 and TIMP-1 in three well-defined breast cancer cell lines with different biological behaviour; i.e. poorly-invasive MCF-7 cells, invasively growing MDA-MB-231 cells and invasive and highly-metastatic MDA-MB-435 cells. The parallel immunocytochemical determination of the degree of cellular differentiation, as monitored by the immunocytochemical expression of cytokeratins (CK), confirmed differences in the tumor cell differentiation. Thereby, MCF-7 cells expressed more glandular CKs than MDA-MB-231 cells, while MDA-MB-435 cells were only labelled by pancytokeratin markers, but neither by glandular nor by squamous epithelial CKs. Conditioned media were analyzed for the presence of MMPs and TIMP-1 using Western blot with specific polyclonal antibodies and for gelatinolytic and caseinolytic activity by zymography. In addition, the cellular pool of several MMPs was investigated by immunocytochemistry. An enhanced cytoplasmatic staining for MMP-3 and -9, MMP-1, -10 and -11 was seen in the highly metastatic cells at almost equal levels, while MMP-2 revealed only a minor intracellular staining in all three cell lines. Western blots of conditioned media showed enhanced amounts of MMP-1, -3, -7, -10 and -11 in media of the two metastatic cell lines. Casein zymography correlated with the results of the MMP-1 Western blots. By means of gelatin zymography, MMP-2 and -9 were detectable in cell culture supematants of all the three cell lines, while gelatinolytic activity was elevated in the media of the more malignant MDA-MB-435 cells. Separate addition of EDTA or Pefa bloc SL partially inhibited the gelatinoltic activity indicating the presence of metallo- and serine proteinases, respectively; combined application of both inhibitors resulted in a complete suppression of activity. We provide evidence that the deviation expression in secretion of various MMPs in breast cancer cell lines of different tumorigenicity correlates with the biological behaviour of these cells, ie. the more malignant cells synthesize more MMPs than the less malignant ones. In addition, the secretion of MMP-1, -3, -7, -10 and -11 was enhanced in the malignant MDA-MB-231 and -435 cells when compared to the corresponding intracellular pool. This analysis confirms previous results obtained in a keratinocyte tumor cell model and provides evidence for a more general biological association between MMP-expression and tumor cell growth.

Breast Neoplasms↗

PubMedDate not supplied

Basement membrane components as differential markers for mesenchymal tumors of various origin.

We immunohistochemically analyzed the presence or absence of a pericellular basement membrane in benign and malignant soft tissue tumors of different origin--of peripheral nerve, smooth and striated muscle, fat tissue, connective tissue, blood and lymph vessels, cartilage and bone--to test the role of the expression of the BM components collagen IV, laminin, heparan sulfate proteoglycan (HSPG) and fibronectin as a differential diagnostic aid. All benign tumors revealed a BM feature corresponding to that of the normal tissue. Well differentiated sarcomas similarly showed a BM pattern close to that of the respective normal mesenchymal cells, so that these sarcomas were attributable to different histogenetic entities. Low differentiated sarcomas preserved in some, but not all, instances a typical BM pattern as well. Since the BM expression in most sarcomas of lesser degree of differentiation shows a distinctive BM pattern, we believe that the BM analysis of soft tissue sarcomas may be useful to establish a proper histogenetic classification of mesenchymal tumors.

Basement Membrane↗

PubMedDate not supplied

Gene expression and protein deposition of major basement membrane components and TGF-beta 1 in human breast cancer.

In the present study we used immunohistochemistry and in-situ hybridization for the localization of major basement membrane (BM) components and their mRNA, respectively, in order to determine the extent of BM production and deposition in normal mammary tissue as well as in invasive mamma carcinomas. While normal mammary tissue showed an intact epithelial BM, as evidenced by a continuous linear staining for collagen i.v., laminin, heparan sulfate proteoglycan (perlecan) and fibronectin, this staining was widely lost in the invasive carcinomas. Non-invasive intraductal areas of the carcinomas (carcinoma-in-situ) revealed focal fragmentation and duplication of the epithelial BM. Using in-situ hybridization, we observed only focally positive mRNA-expression for collagen i.v.-, perlecan- and fibronectin-mRNA in normal glands, while mRNA-signals were significantly enhanced in one case of fibroadenoma and particularly in invasive and non-invasive carcinomas, regardless of the degree of tumor cell differentiation. In these instances both tumor and stroma cells were positively labelled. In addition, we could demonstrate a significant increase in the level of TGF-beta 1-mRNA--as the most active cytokine for the induction of matrix component production--by carcinoma cells and to lesser extent by stroma cells. The discrepancy between significantly enhanced mRNA-synthesis and loss in protein deposition points either to an upregulated activity of matrix degrading proteinases (matrix-metalloproteinases) or a posttranslational block of protein synthesis or both.

Adult↗

PubMedDate not supplied

Prognostic aspects of the loss of epithelial basement membrane components in preinvasive and invasive laryngeal carcinomas.

The integrity of the epithelial basement membrane (BM) is an essential criterion or the biological behaviour of tumors. Previous studies on various types of carcinomas have demonstrated a good correlation between the amount of retained BM and the course of tumor growth. We therefore evaluated the prognostic significance of the tumor BM in laryngeal carcinomas. In this study, we analyzed 66 cases of laryngeal carcinomas using immunohistochemistry for the visualization of the major BM components collagen IV and VII, laminin-1, heparan sulfate proteoglycan (HSPG, perlecan) and fibronectin. The extent of retained BM-material was quantified morphometrically. A subsequent statistical analysis correlated the immunohistochemical findings with clinical and routine histological parameters, such as the mode of tumor infiltration. All carcinomas showed a defective epithelial BM. In addition, we observed a correlation between the degree of tumor cell-differentiation and the amount of BM material retained. The loss of BM, however, affected the various components differently with an "early" loss of collagen VII. In non-infiltrative dysplastic lesions focal BM disruptions were seen which affected the various BM components very similarly. When we statistically analyzed the correlation between the BM staining pattern and prognostically relevant parameters, collagen VII represented a marker for "early" stroma invasion. It also positively correlated with tumor size/stage, presence of lymph node metastasis and the recurrence of tumor growth. The collagen IV expression was positively correlated with the degree of tumor cell differentiation. The other parameters did not show further prognostically relevant data. Our observations provide significant information on the biological course of the disease. Thus, collagen VII may be a marker for "early" invasive tumor growth, as well as for lymphatic metastasis and local tumor recurrence, while the amount of collagen IV correlates with the tumor cell differentiation.

Adult↗

PubMedDate not supplied

Morphological aspects of altered basement membrane metabolism in invasive carcinomas of the breast and the larynx.

In the present study we compared the localization of major basement membrane (BM) components and their mRNAs between invasive carcinomas of the breast (adenocarcinomas) and larynx carcinomas (squamous cell carcinomas, SCC), in order to determine the extent of BM production and deposition in malignant tumors of biologically different behaviour. Thus, breast carcinomas usually show a rapid locoregional/systemic spread, while the laryngeal SCCs normally show a more locally restricted growth pattern. While normal mammary glands and laryngeal mucosa revealed an intact epithelial BM as evidenced by a continuous linear staining for collagen IV, laminin-1, heparan sulfate proteoglycan (perlecan) and fibronectin-as well as collagen VII in the larynx mucosa-, this continuous staining was lost in the invasive carcinomas, however, affecting the two tumor types differently. In the breast carcinomas, a complete loss was seen even in well differentiated tumors affecting the various BM components similarly, while in the SCCs well differentiated carcinomas had retained significantly more BM material than poorly differentiated ones. In the SCCs, an "early" loss of collagen VII contrasted with a "later" loss of collagen IV, laminin, perlecan and fibronectin the extent of which was, however, associated with a decreasing degree of differentiation. In contrast to the protein findings, by use of the in-situ hybridization we observed a significant expression of mRNA for collagen IV, perlecan and fibronectin. The resulting pattern was comparable between both tumor types and not significantly related to the tumor cell differentiation. Both tumor cells and stroma cells were positively labelled with a more extensive labelling of the stroma cells. Our observations indicate a similar upregulation of the mRNAs for BM-components in breast and larynx carcinomas, but significant differences in the BM-protein deposition so that either major differences in presumed BM-proteolysis or further translational defects are suggested. Furthermore, it can be speculated that the far lesser amount of BM-material in the breast carcinomas may be linked to the more aggressive metastatic spread of those tumors, particularly when compared to the SCCs.

Basement Membrane↗

PubMedDate not supplied

Patients with diabetes-induced microangiopathy show a reduced frequency of carcinomas.

Contradictary results have been reported indicating both increased and reduced risks for malignancies in diabetic patients. This may possibly be due to difficulties in the clinical diagnosis of carcinomas and inaccuracies in the determination of diabetic conditions in the autopsy studies. Since glomerular microangiopathy is a typical feature of long-term diabetes, we performed a retrospective statistical analysis on 5000 consecutive, non-selected autopsy cases with particular reference to the presence/absence of microangiopathy in diabetic individuals. In our study group, we found a total incidence of 9.8% (n = 488) diabetic patients of which 213 (4.3%) had a histologically confirmed significant glomerulosclerosis and a total of 34% patients with verified carcinoma (n = 1699). The age- and sex ratios were matched between diabetic, non-diabetic and carcinoma patients. Systemic and coronary arteriosclerosis were significantly higher in diabetics than non-diabetics (p < 0.0001). Most interestingly, the rate of carcinomas in the diabetic group with nodular and diffuse glomerulosclerosis was 2.5- (p < 0.0001) and 1.9-fold (p < 0.0027), respectively, lower than in the non-diabetic group. In addition, the statistical evaluation showed in the glomerulosclerotic diabetic group significantly lower rates of metastasis. Our retrospective statistical analysis on an unselected series of autopsy cases thus provides evidence that diabetes mellitus with glomerulosclerosis is associated with a significantly lower frequency of carcinomas when compared to individuals without renal microangiopathy. Since TGF-beta is assumed to play a crucial role both in diabetes and carcinogenesis/tumor progression, our findings suggest an altered cell-matrix interaction in diabetes, possibly exerted by chronic TGF-beta overexpression.

Adolescent↗