Evolution and development. Making jaws.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
T Schilling
Publications and source records attributed to T Schilling.
[The "needle man": more than 40,000 injections in 40 years].
HISTORY AND ADMISSION FINDINGS: A now 65-year-old man had undergone a subtotal thyroidectomy over 40 years ago, which postoperatively resulted in hypoparathyroidism. His doctor began daily intravenous injections of a calcium preparation (1880 mg to 3760 mg calcium per day, over 40000 injections during this period), a regimen continued subsequently by a total of more than 15 other doctors for over 40 years. On admission the patient complained of oral paresthesias and paresthesias of the limbs. INVESTIGATIONS: Low calcium and parathormone levels confirmed the diagnosis of hypoparathyroidism. TREATMENT AND COURSE: Normal levels of calcium were achieved after a short course of 1.25-dihydroxycalciferol. This was followed by the administration of cholecalciferol and calcium. The patient soon became symptom-free and calcium levels returned to normal. Late sequelae have been calcification of the basal ganglia, first signs of nephrocalcinosis and bilateral cataract. CONCLUSION: This case demonstrates that appropriate treatment of hypoparathyroidism [corrected] might not be given in every case.
Aged↗
Lysophospholipids induce membrane hyperpolarization in microglia by activation of IKCa1 Ca(2+)-dependent K(+) channels.
Effects of the lysophospholipids sphingosine-1-phosphate and lysophosphatidic acid were studied in cultured murine microglia using the patch-clamp and video imaging techniques. Both lysophospholipids induced transient membrane hyperpolarization and K(+) current activation. The lysophospholipid-induced K(+) current was blocked by charybdotoxin or iberiotoxin, but was unaffected by apamin. In recordings with 1 microM intracellular free Ca(2+), Ca(2+)-dependent K(+) currents of microglia showed a similar pharmacological profile to lysophospholipid-induced currents. The Ca(2+)-dependent K(+) channels activated in microglia by lysophospholipids are most likely encoded by the IKCa1 channel gene. The presence of IKCa1 mRNA in microglia was demonstrated by reverse transcriptase-polymerase chain reaction studies. Ca(2+) imaging experiments revealed increases in the intracellular free Ca(2+) concentration of microglia to a mean value of about 400 nM after application of 1 microM sphingosine-1-phosphate or 1 microM lysophosphatidic acid. We suggest that the transient membrane hyperpolarization seen in microglia following exposure to sphingosine-1-phosphate or lysophosphatidic acid is caused by activation of IKCa1 Ca(2+)-dependent K(+) channels. Increases in the concentration of intracellular free Ca(2+) evoked by the lysophospholipids are sufficient to activate microglial Ca(2+)-dependent K(+) channels.
Animals↗
[Analysis of factors affecting the prognosis of vertebral metastases].
The goal of this study was to evaluate factors for the prognosis of patients with metastatic spinal tumors. 139 patients with vertebral metastases were studied. The modified Tokuhashi Score (a preoperative score composed of six parameters) and single factors were analysed with statistical methods. The modified Tokuhashi Score showed a significant correlation (p = 0,0019) with survival time of patients. Additionally, only the Karnofsky Index as single parameter showed statistically significant correlation(p = 0.0016). Regarding the logistic regression, primary tumor, age, sex and Karnofsky Index were identified as prognostic factors for survival time. This trial could demonstrate that the Tokuhashi Score is a successful predicting tool for the assessment of prognosis of patients with vertebral metastases.
Adult↗
Endocrine effects of dopexamine vs. dopamine in high-risk surgical patients.
OBJECTIVES: To compare the endocrine effects of dopexamine and dopamine on prolactin (PRL), dihydroepiandrosterone sulfate (DHEAS), cortisol, thyrotropin (TSH), and peripheral thyroid hormone serum concentrations in surgical patients at risk of developing postoperative complications because of hypoperfusion of various organ systems. DESIGN AND SETTING: A prospective, randomized, placebo-controlled, blinded clinical trial in an adult surgical intensive care unit in a university hospital. PATIENTS: Thirty-two male surgical risk patients undergoing elective major abdominal surgery. INTERVENTIONS: Patients were randomized to receive placebo ( n=8), dopexamine (0.5 microg kg(-1) min(-1), n=8), dopexamine (1 microg kg(-1) min(-1), n=8) or dopamine (5 microg kg(-1) min(-1), n=8) on the first postoperative day. MEASUREMENTS AND RESULTS: All patients received either a placebo or catecholamine infusion for 24 h. Blood samples were obtained every 2 h for the next 2 days. PRL, DHEAS, cortisol, TSH, triiodothyronine, thyroxin, free triiodothyronine, and free thyroxin serum concentrations were determined by radioimmunoassay or luminescence immunoassay. Dopexamine (0.5 microg kg(-1) min(-1)) had no effects on serum concentrations of PRL or TSH. Higher doses of dopexamine (1 microg kg(-1) min(-1)) suppressed PRL secretion significantly, but not TSH. In contrast, infusion of dopamine (5 microg kg(-1) min(-1)) completely inhibited PRL and TSH secretion. DHEAS, cortisol, and thyroid hormone serum concentrations were not affected by either dopexamine or dopamine infusion. Measurements of hemodynamic parameters, peripheral oxygen saturation, diuresis, blood gases, and standard laboratory parameters were repeated hourly. Significant differences were not found between placebo, dopexamine (0.5 microg kg(-1) min(-1)) and dopamine (5 microg kg(-1) min(-1)) group. Dopexamine at 1 microg kg(-1) min(-1) increased the heart rate significantly. CONCLUSIONS: Routine postoperative optimizing of men undergoing abdominal surgical procedures with dopexamine at higher doses or dopamine induces at least partial hypopituitarism, which may possibly affect postoperative morbidity.
Abdomen↗
Prognostic value of codon 918 (ATG-->ACG) RET proto-oncogene mutations in sporadic medullary thyroid carcinoma.
We have determined the frequency of 918 RET proto-oncogene mutations (ATG-->ACG) in primary MTC tumors and metastases and correlated the presence or absence of this mutation with the clinical outcome of patients suffering from sporadic medullary thyroid carcinoma (MTC). A total of 197 samples, consisting of both primary tumors and lymph node metastases from 34 patients with sporadic MTC, were collected for PCR analysis of the RET 918 mutation. In 75 of the samples (38%), codon 918 (ATG-->ACG) mutations could be detected. The mutations showed a heterogeneous distribution: 21/34 patients (62%) had mutations in at least 1 tumor sample, and in 13 patients (38%) the mutation was present in all examined samples. Patients were considered 918mt when at least 1 tumor sample showed the RET 918 mutation. These 918mt and 918 wild-type (918wt) patients did not differ significantly concerning sex, age at diagnosis, TNM stage at diagnosis, number of examined tumor samples or follow-up time. However, 918mt patients showed more aggressive development of distant metastases during follow-up (p = 0.032, Fisher's exact test) with decreased metastases-free survival (p < 0.005, log-rank test). Furthermore, 918mt patients had a significantly lower survival rate than 918wt patients (p = 0.048, log-rank test). These data show that the RET codon 918 mutation has a prognostic impact on patients with sporadic MTC which may influence follow-up treatment.
Adult↗
Predictive genetic screening and clinical findings in multiple endocrine neoplasia type I families.
Germline mutations of the MEN1 gene have been identified as the causative genetic defect of multiple endocrine neoplasia type I (MEN-I), an autosomal dominantly inherited condition. To establish the basis for predictive family screening we evaluated the spectrum of MEN1 gene mutations in MEN-I patients treated at our institution. Relatives at risk were subjected to predictive genetic screening after genetic counseling. Gene carriers were subjected to extensive clinical screening for MEN-I, including biochemical tests for basal hormone concentrations in blood and urine, a standardized meal stimulation test and imaging procedures (ultrasonography, computed tomography, magnetic resonance imaging). Among index patients of 15 independent MEN-I kindreds, 14 heterozygous MEN1 germline mutations were identified by single-strand conformational variant analysis (SSCV) and direct DNA sequence analysis. Of 51 individuals at risk, 26 predictively tested relatives with the wild-type MEN1 gene could be excluded from further screening procedures because they had not inherited the disease. In all previously presumed unaffected relatives with the mutant gene, our extensive clinical screening program revealed at least one manifestation of MEN-I. Furthermore, 22 additional diagnoses could be established in identified MEN-I patients. We show that mutation analysis enables predictive genetic screening for MEN-I families, providing a valuable tool for genetic counseling and clinical management. An extensive clinical screening program focusing on genetically proven individuals at risk allows detection of MEN-I manifestations at an early, asymptomatic stage of the disease. Controlled, prospective studies are now required to prove whether timely appropriate treatment on the basis of predictive screening might help improve disease-related quality of life and prolong life expectancy in MEN-I kindreds.
DNA Mutational Analysis↗
Tissue-specific gene expression in medullary thyroid carcinoma cells employing calcitonin regulatory elements and AAV vectors.
Calcitonin (CT), the major secretory product of the C cell, is also expressed in C-cell-derived neoplasia. To investigate the role of the CT gene regulatory sequence in tissue-specific gene expression, the genes coding for the herpes simplex virus thymidine kinase (HSVtk) and for the enhanced green fluorescent protein (EGFP) regulated by the CT promoter (rAAV/CT266tkneo), the CT promoter/enhancer element (rAAV/CTenhtkneo), or the cytomegalovirus (CMV) promoter (rAAV/CMVtkneo) were transduced by recombinant adenoassociated viral (AAV) vectors into the medullary thyroid carcinoma (MTC) cell lines TT and hMTC and into HeLa cells as controls. In TT cell lines and hMTC cell lines transiently infected by the rAAV/CT266tkneo viruses, a significant increase in (3)H ganciclovir uptake was observed. Upon ganciclovir treatment, TT cells infected by rAAV/CT266tkneo revealed a significant growth inhibition, which was less tissue-specific because HeLa cells were also affected by these particles (74.5%). In contrast, a minor but more tissue-specific growth inhibition (33.6%) was observed for TT cells after transient infection with the rAAV/CTenhtkneo particles. Employing EGFP controlled by CMV promoter and the individual CT regulatory sequences for transduction by rAAV particles, similar results were obtained indicating that both the CT promoter and enhancer element are required for tissue-specific gene expression in MTC.
Calcitonin↗
Astrocyte-released cytokines induce ramification and outward K+ channel expression in microglia via distinct signalling pathways.
Differentiation of microglial cells is characterized by transformation from ameboid into ramified cell shape and up-regulation of K+ channels. The processes of microglial differentiation are controlled by astrocytic factors. The mechanisms by which astrocytes cause developmental changes in morphological and electrophysiological properties of microglia have remained unclear. We show here that the cytokines transforming growth factor-beta (TGF-beta), macrophage colony-stimulating factor (M-CSF) and granulocyte/macrophage colony-stimulating factor (GM-CSF) are released by astrocytes at concentrations sufficient to induce ramification and up-regulation of delayed rectifier (DR) K+ channels in microglia. Transformation from ameboid into ramified morphology induced in microglia by exposure to astrocyte-conditioned medium (ACM) was inhibited by neutralizing antibodies against TGF-beta, M-CSF or GM-CSF, whilst ACM-induced DR channel expression was exclusively inhibited by antibodies against TGF-beta. Although both ramification and DR channel up-regulation occurred simultaneously, DR channel blockade by charybdotoxin failed to inhibit microglial ramification. The ACM-induced ramification of microglia was inhibited by the tyrosine kinase inhibitor genistein, whereas DR channel up-regulation did not occur in the presence of the serine/threonine kinase inhibitor H7. Our data suggest that astrocytes modulate processes of microglial differentiation in parallel but via distinct signalling pathways.
Animals↗
Impact of modified radical neck dissection on biochemical cure in medullary thyroid carcinomas.
BACKGROUND: This study evaluated the outcome of total thyroidectomy and modified radical neck dissection in primary treatment of patients with medullary thyroid carcinoma (MTC). METHODS: Thirty-six patients with sporadic (n = 16) and hereditary (n = 20) MTC underwent thyroidectomy and systematic central and lateral lymph node dissection (unilateral, 23; bilateral, 13) between 1994 and 2000. Postoperative serum calcitonin levels were correlated with immediate or delayed surgery, tumor categories, and lymph node metastases. RESULTS: Sixteen of 36 (44%) patients with clinically evident MTC treated with central and lateral neck dissection exhibited normal basal and stimulated calcitonin levels at a median follow-up of 3.7 years. Lymph node involvement was detected in 75% of these patients and correlated with the TNM stages. Biochemical cure was achieved according to the T categories in 83% of the patients in stage T1, 42% in stage T2, and none of the patients in stage T4 (P = .011). Basal and stimulated calcitonin levels were found to be normal in 89% of the patients without lymph node involvement and in 30% of the patients with lymph node metastases (P = .005). CONCLUSIONS: Screening for MTC and primary treatment with total thyroidectomy and modified radical neck dissection are essential for biochemical cure of MTC.
Adolescent↗
Engineering of human vascular aortic tissue based on a xenogeneic starter matrix.
BACKGROUND: The goal for tissue engineering of vascular grafts is the replacement of a diseased vessel with a functional and stable graft. We now introduce a new concept for the tissue engineering of vessels. The idea was to humanize a previously acellularized, but structurally intact, xenogeneic vessel by repopulation with human autologous cells. To this purpose, a gentle nondenaturing and nondeterging acellularization procedure for xenogeneic aortas was developed. This structure was reseeded with pre-expanded peripheral vascular endothelial cells (EC) and myofibroblasts using specifically designed bioreactors. METHODS: Aortas from 15-30 kg female landrace pigs were acelullarized with a 0.1% trypsin solution for between 24 and 96 hr. Human vascular cells were harvested from saphenous vein biopsy specimens. Acellularized vessels were reseeded with EC and myofibroblasts. Cell viability after reseeding was assayed by fluorescence staining. Morphologic features of the acellularized matrix and tissue engineered vessel was assayed by transmission and scanning electron microscopy and histologic analysis. Nitric oxide-synthetase activity was investigated by mass spectrometric analysis of bioreactor supernatants. The in vivo immune response was tested by subcutaneous implantation of acellularized porcine aortic tissue in a rat model. RESULTS: The acellularization procedure resulted in an almost complete removal of the original resident cells, and the 3-D matrix was loosened at interfibrillar zones. However, the 3-D arrangement of the matrix fibers was grossly maintained. The 3-D matrix was covered with a fully confluent human endothelial cell layer obtained by continuous stress challenge in the bioreactor. Myofibroblasts migrated into positions formerly occupied by the xenogeneic cells. Nitric oxide synthetase activity was maintained in the bioartificial graft. T-lymphocyte and CD18 positive leukocyte infiltrate were greatly reduced after acellularization of porcine aortic specimens after implantation in the rat. CONCLUSIONS: Porcine vessels were acellularized and consecutively fully repopulated with human EC and myofibroblasts. This approach may eventually lead to the engineering of vessels immunologically acceptable to the host using a relatively short preparation period of 2-3 weeks. We expect matrix turnover in vivo leading to a gradual assimilation of the matrix structure by the host mediated by the hosts autologous cells.
Animals↗
Increased risk of restenosis after placement of gold-coated stents: results of a randomized trial comparing gold-coated with uncoated steel stents in patients with coronary artery disease.
BACKGROUND: Gold is a highly biocompatible material. Experimental evidence suggests that coating the stent with a gold layer may have a beneficial influence. In this randomized trial, we assessed whether gold-coated stents were associated with a better clinical and angiographic outcome after coronary placement. METHODS AND RESULTS: Patients with symptomatic coronary artery disease were randomly assigned to receive either a gold-coated Inflow stent (n = 367) or an uncoated Inflow stainless steel stent (n = 364) of identical design. Follow-up angiography was routinely performed at 6 months. The primary end point of the study was the occurrence of any adverse clinical event (death, myocardial infarction, or target-vessel revascularization) during the first year after stenting. At 30 days, there was no significant difference in the combined incidence of adverse events, with 7.9% in the gold-stent group versus 5.8% in the steel-stent group (P = 0.25). The incidence of angiographic restenosis (> or =50% diameter stenosis) was 49.7% in the gold-stent group and 38.1% in the steel-stent group (P = 0.003). One-year survival free of myocardial infarction was 88.6% in the gold-stent group and 91.8% in the steel-stent group (P = 0.14). One-year event-free survival was significantly less favorable in the gold-stent group (62.9% versus 73.9% in the steel-stent group; P = 0.001). CONCLUSIONS: Coating steel stents with gold had no significant influence on the thrombotic events observed during the first 30 days after the intervention. However, gold-coated stents were associated with a considerable increase in the risk of restenosis over the first year after stenting.
Aged↗
Management of nonfunctioning islet cell carcinomas.
Tumors arising from the pancreatic islet cells are rare and represent a heterogeneous group of benign or malignant lesions. Most tumors present with well characterized syndromes, whereas others appear to be nonfunctioning. The clinical features of 11 men and 7 women with nonfunctioning islet cell carcinomas operated on between 1983 and 1998 were reviewed. The median patient age was 53.5 years (range 26-74 years). The most frequent presenting symptoms were abdominal pain (13 patients), weight loss (7 patients), and obstructive jaundice (4 patients). Gut hormone profiles were normal in all patients. Abdominal sonography and computed tomography localized the tumor in 17 patients, and correct prediction of an endocrine tumor was achieved in 12 patients. Six of seven patients showed a hypervascular tumor upon angiography, and seven of eight patients preoperatively had positive somatostatin receptor scintigraphy. At operation, regional or distant metastases were present in 15 (83%) and 6 (33%) patients, respectively. Eleven patients underwent potentially curative resections, and the remaining seven patients were managed palliatively by resection (four patients) or bypass procedures (three patients). Three patients had up to three more resection for metastases. Eight patients received postoperative octreotide, interferon alpha therapy, or both. The overall cumulative 5- and 10-year survival rates were 65.4% and 49.1%, respectively. Of the 11 patients who underwent curative resection, 10 were alive after a median follow-up of 63 months (range 7-180 months), but only 5 are free from disease. Although surgical cure is rare in nonfunctioning islet cell carcinomas, significant long-term palliation can be achieved in a large proportion of patients with an aggressive surgical approach and, when indicated, additional medical therapy.
Adult↗
Microanatomical compartments of clonal and reactive T cells in mycosis fungoides: molecular demonstration by single cell polymerase chain reaction of T cell receptor gene rearrangements.
Mycosis fungoides (MF) is a cutaneous T cell lymphoma, clinically characterized by patches, plaques and tumors occurring in successive stages of the disease. In early MF, an infiltrate consisting of mainly reactive T cells is seen in the papillary dermis while tumor cells are mostly confined to the epidermis. By contrast, later stages show nodular infiltrates formed mostly of tumor cells in the dermis while the epidermis is relatively devoid of tumor cells; however, knowledge of the localization of clonal T cells has been based on histomorphologic features and immunohistochemical stainings visualizing certain V-beta subfamilies of the T cell receptor (TCR). As these techniques do not allow for an unequivocal identification of clonal tumor cells, we used micromanipulation and single cell PCR amplifying the TCR chain gene rearrangement. A total number of 387 single T cells was isolated from six skin biopsies in five patients in patch, plaque, and tumor stages. Of these, 180 T cells were picked from the epidermis and 207 from the dermal infiltrate. The rearranged TCR-gamma DNA could be sequenced from 181 of 387 T cells. In three of six patients representing all three stages, epidermal T cells with a clonal rearrangement could be amplified. In early plaque stage a higher degree of epidermal T lymphocytes was found than in initial patch, later plaque, and tumor stages with an inverse distribution found for reactive T lymphocytes. In two patients a biallelic rearrangement was demonstrated that had not been detected in prior PCR analysis from blood and skin samples. These data show that clonal (neoplastic) and non-clonal (reactive) T lymphocytes in MF preferentially infiltrate different microanatomical compartments of the skin, depending on the stage of disease. The microanatomically distinct localization of reactive and clonal T cells suggests that the absence of direct contact between tumor and host-defense lymphocytes may contribute to tumor persistence and progression in epidermis, peripheral blood, and deep dermal tumor cell nests, respectively.
Aged↗
Pancreaticoduodenal endocrine tumors in multiple endocrine neoplasia type 1: surgery or surveillance?
BACKGROUND: The management of pancreaticoduodenal endocrine tumors (PETs) remains controversial in multiple endocrine neoplasia type 1 (MEN 1). METHODS: Twenty-one patients with MEN 1 and PETs were analyzed for outcome of surgery and surveillance with special regard to the genotype based on MEN1 gene mutation analysis. RESULTS: Nine patients had gastrinomas, 5 had nonfunctioning tumors, 4 had insulinomas, 2 had insulinomas and gastrinomas, and 1 had a VIPoma. Seven patients (33%) had malignant tumors. Sixteen patients (76%) were initially treated by pancreatic resections or tumor enucleations or both. Six patients underwent reoperations for recurrences or lymph node metastases or both. Fifteen of the 16 operated patients are alive, and 12 have no evidence of disease after a median follow-up of 78 months (range, 1-198 months). Five patients with gastrinomas or nonfunctioning tumors, but no symptoms, underwent surveillance; 1 of them developed lymph node metastases. Patients with truncating mutations in the N- or C-terminal region (exons 2, 9, or 10) of the MEN1 gene had a significantly higher rate of malignant tumors (55% vs 10%; P <.05) than patients with other mutations. CONCLUSIONS: An aggressive surgical approach is justified for PETs in patients with MEN 1. However, MEN1 gene mutations in exons 3 to 8 seem to be associated with mild behavior of PETs, possibly allowing surveillance in asymptomatic patients.
Adult↗
Upregulation of Kv1.3 K(+) channels in microglia deactivated by TGF-beta.
Microglial activation is accompanied by changes in K(+) channel expression. Here we demonstrate that a deactivating cytokine changes the electrophysiological properties of microglial cells. Upregulation of delayed rectifier (DR) K(+) channels was observed in microglia after exposure to transforming growth factor-beta (TGF-beta) for 24 h. In contrast, inward rectifier K(+) channel expression was unchanged by TGF-beta. DR current density was more than sixfold larger in TGF-beta-treated microglia than in untreated microglia. DR currents of TGF-beta-treated cells exhibited the following properties: activation at potentials more positive than -40 mV, half-maximal activation at -27 mV, half-maximal inactivation at -38 mV, time dependent and strongly use-dependent inactivation, and a single channel conductance of 13 pS in Ringer solution. DR channels were highly sensitive to charybdotoxin (CTX) and kaliotoxin (KTX), whereas alpha-dendrotoxin had little effect. With RT-PCR, mRNA for Kv1.3 and Kir2.1 was detected in microglia. In accordance with the observed changes in DR current density, the mRNA level for Kv1.3 (assessed by competitive RT-PCR) increased fivefold after treatment of microglia with TGF-beta.
Animals↗
Regulation of PTHrP and PTH/PTHrP receptor by extracellular Ca2+ concentration and hormones in the breast cancer cell line 8701-BC.
It was previously reported that 8701-BC breast tumour cells express the gene for parathyroid hormone-related peptide (PTHrP) and PTH/PTHrP receptor (PTHrP-R) and release immunoreactive PTHrP (iPTHrP) into the extracellular medium. Since the regulation of PTHrP and PTHrP-R by breast cancer cells has been poorly investigated so far, we have chosen the 8701-BC cell line as a model system to investigate whether alterations in the extracellular Ca2+ concentration ([Ca2+]e) and treatment with some well-known differentiation agents for breast cells, such as dimethyl sulfoxide, hydrocortisone, progesterone, prolactin, all-trans retinoic acid and transforming growth factor-beta1 might (i) modulate quantitatively the release of iPTHrP, (ii) affect the PTHrP promoter usage and mRNA splicing patterns, and (iii) modify the expression of PTHrP-R. The data obtained indicate that 8701-BC cells are potentially able to utilise different start sites and mRNA splicing patterns for PTHrP transcription, and respond to variations of [Ca2+]e and to the addition of two hormones, hydrocortisone and progesterone, with modifications in the extracellular amount of iPTHrP. Moreover, expression of PTHrP-R is also modulated by changes of [Ca2+]e or treatment with hydrocortisone. This indicates that the 8701 -BC cell line is a suitable in vitro model for further studies on the complex molecular regulation of the PTHrP/PTHrP-R pair in breast cancer.
Breast Neoplasms↗
Extracellular matrix regulation of PTHrP and PTH/PTHrP receptor in a human breast cancer cell line.
It was previously reported that 8701-BC breast cancer cells express the gene for parathyroid hormone-related peptide (PTHrP) and its cognate receptor (PTHrP-R), and release immunoreactive PTHrP in the extracellular medium; it was also found that PTHrP, in turn, exerts a role on the proliferative and invasive behavior in vitro of the same cell line. On the other hand, evidence has been produced that adhesion of 8701-BC cells onto different collagen substrates influences in various ways a number of phenotypic expressions, such as cell growth, motility, invasion of reconstituted basement membrane and production of lytic enzymes of the extracellular matrix (ECM). In light of these previous data, we have examined whether substrates of either reconstituted basement membrane or representative collagen components of the breast tumor stroma (type I, V and OF/LB) might (i) regulate the PTHrP promoter usage and mRNA splicing patterns, (ii) modulate quantitatively the extracellular release of immunoreactive PTHrP (iPTHrP), and (iii) affect the expression of PTHrP-R. The results obtained give evidence that (i) 8701-BC cells are able to utilize different start sites and mRNA splicing patterns for PTHrP transcription; (ii) 'structural' components of the stroma, such as collagens, are by themselves capable of controlling both the expression pattern of the PTHrP gene and the extent of extracellular release of iPTHrP, and (iii) PTHrP-R expression can be up- or down-regulated in response to the ECM substrate present. These data demonstrate that PTHrP and PTHrP-R expression by 8701-BC neoplastic cells can be modulated by ECM molecules, indirectly supporting the active participation of stromal collagen composition in the regulation of PTHrP-controlled circuits which may play a role in carcinogenesis.
Breast Neoplasms↗