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PubMed1997

Ambulatory long-term jejunal manometry in diabetic patients with cardiac autonomic neuropathy.

Concerning alteration of small bowel motility in diabetic patients with autonomic neuropathy controversial data were obtained with stationary manometry and over a limited period of time. The aim of our study was to examine ambulatory 24 h jejunal motility in 15 diabetic patients with cardiac autonomic neuropathy compared with data obtained in 50 healthy controls. Twenty-four hour motility was recorded in the proximal jejunum with a portable datalogger and tube-mounted miniature pressure sensors. Diurnal and nocturnal fasting motility and the motor response to a standardized evening meal of 600 kcal were evaluated by visual and computer-aided analysis. The following abnormalities were found during fasting motility (n = number of patients): absence of phase III over 24 h (n = 2), retrograde migration or simultaneous occurrence of phase III (n = 5). During postprandial motility irregular bursts with tonic baseline elevation (n = 3) and contraction frequencies below the range of controls (n = 8) occurred. Furthermore patients exhibited an inversion of the normal relationship between phase I and phase II during nocturnal MMC-cycles, and discrete clustered contractions were diminished (P < 0.01) in the fasting and digestive state. All patients showed at least one abnormal manometric finding. We conclude that small bowel motility in diabetic autonomic neuropathy is characterized by disturbances in the generation and aboral migration of phase III, an altered circadian variability of the MMC cycle and by postprandial hypomotility.

Adult↗
PubMed2006

Phosphatidylinositol 3-kinase/Akt regulates the balance between plasminogen activator inhibitor-1 and urokinase to promote migration of SKOV-3 ovarian cancer cells.

OBJECTIVES: Increased levels of urokinase-type plasminogen activator (uPA) are associated with shortened overall survival in ovarian cancer patients. Additionally, elevated levels of the serine protease inhibitor (serpin), plasminogen activator inhibitor-1 (PAI-1), a uPA inhibitor, have also been correlated with an unfavorable prognosis in ovarian cancer. Therefore, it is critical to understand the signaling pathways that regulate PAI-1 and uPA expression in cancer cell migration-invasion. METHODS: We studied the PI3K/Akt, Rho kinase/ROCK, p38 MAPK and MEK pathways and their modulation of PAI-1 and uPA expression and wound-induced cell migration in SKOV-3 ovarian cancer cells. The PI3K/Akt pathway was further examined using pharmacological inhibitors (LY294002 and wortmannin), Akt siRNA, constitutively active Akt adenovirus and treatment with IGF-1/insulin in the SKOV-3 cells. RESULTS: The PI3K/Akt pathway negatively regulates PAI-1 expression and positively correlates with migratory abilities and uPA expression in SKOV-3 cells. A reduction in active Akt results in an increase in PAI-1 expression coupled with a decrease in uPA expression to ultimately result in reduced cell migration and invasion. By contrast, an increase in Akt activity reduces PAI-1 expression and results in an increase in SKOV-3 wound-induced cell migration. Furthermore, IGF-1 and insulin stimulated SKOV-3 migration by altering the balance between uPA and PAI-1 to favor uPA, and the enhanced migration was attenuated by treatment with LY294002 indicating PI3K/Akt in this pathway. CONCLUSIONS: These results suggest an overall ovarian tumor-protective role for PAI-1, and that the PI3K/Akt signaling pathway regulates the ratio of PAI-1:uPA to either increase or decrease cell migration.

Cell Line, Tumor↗
PubMed1999

Antioxidants improve impaired insulin-mediated glucose uptake and prevent migration and proliferation of cultured rabbit coronary smooth muscle cells induced by high glucose.

BACKGROUND: To explore the role of intracellular oxidative stress in high glucose-induced atherogenesis, we examined the effect of probucol and/or alpha-tocopherol on the migration and growth characteristics of cultured rabbit coronary vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: Chronic high-glucose-medium (22. 2 mmol/L) treatment increased platelet-derived growth factor (PDGF)-BB-mediated VSMC migration, [3H]thymidine incorporation, and cell number compared with VSMCs treated with normal-glucose medium (5.6 mmol/L+16.6 mmol/L mannose). Probucol and alpha-tocopherol significantly suppressed high glucose-induced increase in VSMC migration, cell number, and [3H]thymidine incorporation. Probucol and alpha-tocopherol suppressed high glucose-induced elevation of the cytosolic ratio of NADH/NAD+, phospholipase D, and membrane-bound protein kinase C activation. Probucol, alpha-tocopherol, and calphostin C improved the high glucose-induced suppression of insulin-mediated [3H]deoxyglucose uptake. Chronic high-glucose treatment increased the oxidative stress, which was significantly suppressed by probucol, alpha-tocopherol, suramin, and calphostin C. CONCLUSIONS: These findings suggest that probucol and alpha-tocopherol may suppress high glucose-induced VSMC migration and proliferation via suppression of increases in the cytosolic ratio of free NADH/NAD+, phospholipase D, and protein kinase C activation induced by high glucose, which result in reduction in intracellular oxidative stress.

Animals↗
PubMedDate not supplied

Thermal regulation of dendritic cell activation and migration from skin explants.

Dendritic cells (DCs) in the skin rapidly take up antigen and migrate out of the skin to draining lymph nodes for antigen presentation. As a result, these cells play an important role in generating specific immune responses against infectious agents that enter the skin and against antigens delivered as vaccines. Previous efforts revealed that fever-like elevations in body temperature enhance antigen-dependent immune responses initiated at the site of the skin and stimulate the migration of epidermal DCs to draining lymph nodes. Collectively, these data have led to the hypothesis that the activation of epidermal DCs is sensitive to physiological thermal stimuli. In this study, ear skin explants derived from BALB/c mice were either maintained at 37 degrees C or incubated at 40 degrees C for the first 6.5 h before being placed at 37 degrees C. This heating protocol altered the density and morphology of the epidermal DCs in a manner suggestive of an increased kinetics of activation-associated DC migration. Flow cytometric analysis of the emigrated cells also indicated that mild heating enhanced the migration kinetics of DCs and increased the DC expression of MHC class II and the activation marker CD86. Importantly, these migrated cells displayed higher stimulatory capacity in a mixed lymphocyte reaction compared to those of controls. Overall, these results suggest that mild thermal stimuli can enhance DC activation and function and that strategic applications of heat could enhance the potency of vaccines consisting of relatively weak antigens, such as cancer vaccines.

Animals↗
PubMed1989

Modulation of eicosanoid production and cell-mediated cytotoxicity by dietary alpha-linolenic acid in BALB/c mice.

The effects of dietary alpha-linolenic acid (18:3n-3) on fatty acid composition, eicosanoid production, and cell-mediated cytotoxic activity of immune cells before and after challenge with virus or poly I-C from BALB/c mice were studied. Weanling BALB/c mice were fed purified diets containing either 10%-by-weight corn oil or linseed oil providing a ratio of 18:3n-3 to 18:2n-6 of 1/32 or 2/1, respectively, for 6-10 weeks. Fatty acid analysis of splenocyte phospholipids showed an appreciable increase in the percentage of n-3, and a decrease in n-6, fatty acids in splenocytes from mice fed the linseed oil diet. Splenocyte prostaglandin E and peritoneal exudate cell leukotriene C production was significantly lower in the linseed oil-fed mice. In general, cell-mediated cytotoxic activity was similar for immune cells from linseed oil and corn oil-fed mice. However, 6 days after the viral challenge, splenocyte cell-mediated cytotoxic activity was significantly higher in linseed oil mice. This higher activity was associated with nonspecific cytotoxicity rather than that of viral-specific cytotoxic T-lymphocytes. Cell yields from the spleen and peritoneum were frequently significantly higher in linseed oil mice. Interactions between dietary 18:3n-3, eicosanoid production, and immune cell proliferation and/or migration are discussed. In summary, feeding mice a diet rich in 18:3n-3 elevates immune cell n-3 fatty acid content, reduces eicosanoid synthesis and, to a limited extent, enhances the cell-mediated cytotoxic response to a viral challenge.

Animals↗
PubMed2004

Massive tears of the rotator cuff treated with a deltoid flap.

We retrospectively reviewed the charts of 29 patients younger than 65 years at surgery treated with deltoid flap reconstruction for massive postero-superior rotator cuff tears. All tears involved supraspinatus and infraspinatus tendons and were associated with tendon stump retraction to the glenoid rim, a preservable long biceps tendon, and an intact subscapularis tendon. Mean follow-up was 10.5 years. Patient satisfaction rate was 89%. Mean global Constant score improved from 43 to 71.5 points, mean pain score from 6.3 to 13.2, mean anterior flexion from 100 to 157 degrees, and force in elevation from 2.3 to 3 kg. Two thirds of patients had no humeral head migration. Of the 18 patients whose flap was examined by magnetic resonance imaging, 15 had no tear and 12 had a flap signal of muscle intensity; mean flap thickness was 5 mm. Pre-operative factors associated with poorer outcomes were upwards humeral head migration with a subacromial space smaller than 6 mm, presence of glenohumeral osteoarthritis, and supraspinatus amyotrophy greater than 40%. Deltoid flap reconstruction is a valid option in this patient population.

Aged↗
PubMed2003

Elevated proto-oncogene and collagen mRNA expression in PVR retinas.

PURPOSE: Retinal detachment is often accompanied by proliferation and migration of retinal cells and by increased synthesis of structural proteins, known as proliferative vitreoretinopathy (PVR). Herein we investigate the messenger RNA (mRNA) expression of proto-oncogenes responsible for cell proliferation and of structural proteins that have a role in membrane formation. METHODS: Retinal samples were obtained from patients undergoing vitreoretinal surgery for the treatment of retinal detachment complicated by PVR. Normal human control retinas were obtained from cornea donors. The mRNA expression of the proto-oncogenes c- myc, c- fos and the proliferation marker Ki67, as well as of collagen type III and type IV, were investigated using the ribonuclease protection assay. RESULTS: Ki67 mRNA expression was not detectable in either sample type, but c- fos and c- myc mRNA expression was found in normal and PVR retinas. Whereas the expression of c- myc showed a marginal increase, the up-regulation in c- fos expression was strongly significant (5.07-fold). The mRNA of collagen type III was detectable at widely varying levels in all the PVR retinas but was found in only 2 of the 16 analysed normal samples. Collagen type IV mRNA was expressed in both PVR and control samples but was higher (2.21-fold) in the PVR retinas. CONCLUSIONS: These results indicate that an up-regulation of the proto-oncogene c- fos occurs in human PVR retinas. An increase in mRNA expression of collagen types III and IV takes place simultaneously. These changes in mRNA expression appear to be mainly connected to the initiation of cell proliferation, dedifferentiation and formation of tractional membranes.

Adolescent↗
PubMed1985

Temporal changes in 12-HETE formation in two models of canine myocardial infarction.

Arachidonic acid (AA) metabolism by infarcted canine myocardium was studied and correlated with matched histologic analyses following permanently occluded or reperfused infarction. Histologic analysis of tissues from reperfused infarcts showed a marked acceleration of inflammatory cell invasion and of granulation tissue formation when compared to the occlusive infarct. In the reperfused infarct, polymorphonuclear leukocytes (PMNs) were very prominent at one day after infarction while in the occlusive infarcts the neutrophilic invasion was less intense but more sustained. At one day following reperfused infarction the major arachidonate product, which co-migrated by thin layer chromatography with the mono-hydroxyeicosatetraenoic acids (HETEs), was significantly elevated (254 +/- 49 pmoles/gm wet weight, n = 3) when compared to normal tissue (48 +/- 6 pmoles/gm n = 19). This occurred at a time when the number of PMNs was maximal in the infarcted tissue. Addition of the calcium ionophore A23187 caused a further marked stimulation in HETE production in the one day reperfused infarct but not at the other time points studied. The production of HETE was not significantly different in the infarcted tissue than in the normal tissue at three and seven days following reperfused infarction or at one, three, or seven days after occlusive infarction. The identity of this HETE product was investigated using reverse phase high performance liquid chromatography (RP-HPLC) and gas chromatography-mass spectrometry (GC-MS) and found to be predominantly 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) with a small amount of 15-HETE. Thus the production of 12-HETE parallels the number of neutrophils invading the infarcted area of the heart.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed2004

Ghrelin stimulates motility in the small intestine of rats through intrinsic cholinergic neurons.

BACKGROUND AND PURPOSE: Ghrelin is a peptide discovered in endocrine cells of the stomach. Since ghrelin mRNA expression and plasma levels are elevated in the fasting state, we investigated the effects of ghrelin on the interdigestive migrating myoelectric complex (MMC) in the small intestine in vivo and compared with motor effects of ghrelin in vitro. METHODS: Sprague-Dawley rats were supplied with a venous catheter and bipolar electrodes in the duodenum and jejunum for electromyography of small intestine in awake rats. In organ baths, isometric contractions of segments of rat jejunum were studied. RESULTS: Ghrelin dose-dependently shortened the MMC cycle length at all three recording points. At the duodenal site, the interval shortened from 17.2+/-2.0 to 9.9+/-0.8 min during infusion of ghrelin (1000 pmol kg(-1) min(-1)) and at the jejunal site from 17.5+/-2.2 to 10.5+/-0.8 min. Ghrelin contracted the muscle strips with a pD2 of 7.97+/-0.47. Atropine (10(-6) M) in vitro and (1 mg kg(-1)) in vivo blocked the effect of ghrelin. CONCLUSION: Ghrelin stimulates interdigestive motility through cholinergic neurons. Ghrelin also stimulates motility, in vitro, suggesting that ghrelin receptors are present in the intestinal neuromuscular tissue and mediate its effects via cholinergic mechanisms.

Animals↗
PubMed2000

Neuronal-glial interactions and behaviour.

Both neurons and glia interact dynamically to enable information processing and behaviour. They have had increasingly intimate, numerous and differentiated associations during brain evolution. Radial glia form a scaffold for neuronal developmental migration and astrocytes enable later synapse elimination. Functionally syncytial glial cells are depolarised by elevated potassium to generate slow potential shifts that are quantitatively related to arousal, levels of motivation and accompany learning. Potassium stimulates astrocytic glycogenolysis and neuronal oxidative metabolism, the former of which is necessary for passive avoidance learning in chicks. Neurons oxidatively metabolise lactate/pyruvate derived from astrocytic glycolysis as their major energy source, stimulated by elevated glutamate. In astrocytes, noradrenaline activates both glycogenolysis and oxidative metabolism. Neuronal glutamate depends crucially on the supply of astrocytically derived glutamine. Released glutamate depolarises astrocytes and their handling of potassium and induces waves of elevated intracellular calcium. Serotonin causes astrocytic hyperpolarisation. Astrocytes alter their physical relationships with neurons to regulate neuronal communication in the hypothalamus during lactation, parturition and dehydration and in response to steroid hormones. There is also structural plasticity of astrocytes during learning in cortex and cerebellum.

Animals↗
PubMed2004

Cytokinins play opposite roles in lateral root formation, and nematode and Rhizobial symbioses.

We used the cytokinin-responsive Arabidopsis response regulator (ARR)5 gene promoter fused to a beta-glucuronidase (GUS) reporter gene, and cytokinin oxidase (CKX) genes from Arabidopsis thaliana (AtCKX3) and maize (ZmCKX1) to investigate the roles of cytokinins in lateral root formation and symbiosis in Lotus japonicus. ARR5 expression was undetectable in the dividing initial cells at early stages of lateral root formation, but later we observed high expression in the base of the lateral root primordium. The root tip continues to express ARR5 during subsequent development of the lateral root. These results suggest a dynamic role for cytokinin in lateral root development. We observed ARR5 expression in curled/deformed root hairs, and also in nodule primordia in response to Rhizobial inoculation. This expression declined once the nodule emerged from the parent root. Root penetration and migration of root-knot nematode (RKN) second-stage larvae (L2) did not elevate ARR5 expression, but a high level of expression was induced when L2 reached the differentiating vascular bundle and during early stages of the nematode-plant interaction. ARR5 expression was specifically absent in mature giant cells (GCs), although dividing cells around the GCs continued to express this reporter. The same pattern was observed using a green fluorescent protein (GFP) reporter driven by the ARR5 promoter in tomato. Overexpression of CKX genes rendered the transgenic hairy roots resistant to exogenous application of the cytokinin [N6-(Delta2 isopentenyl) adenine riboside] (iPR). CKX roots have significantly more lateral roots, but fewer nodules and nematode-induced root galls per plant, than control hairy roots.

Animals↗
PubMed2003

Focal adhesion kinase in cancer.

Focal adhesion kinase (FAK) is a non-receptor cytoplasmic tyrosine kinase that transmits signals important in modulating several cell functions, including proliferation, migration, and survival. Several different types of malignant tumors have been reported to express elevated levels of FAK protein in vivo, potentially pointing to a role for FAK in either the progression of tumor cells to malignancy or the pathogenesis of cancer. Considerable knowledge has been gained regarding FAK signaling in non-neoplastic cells, such as fibroblasts, while much less is known regarding FAK signaling in malignant cells. Several studies to date suggest that the regulation of FAK activity and signaling may be different in malignant cells. In this review, we summarize what is known regarding the function and signaling of FAK in cancer cells, and highlight areas that need further study. Evidence is emerging that aberrant FAK expression, activity, and signaling can potentially promote the progression of several types of tumors in vivo through its effects on cell function.

Animals↗
PubMed2002

Modulation of endotoxin-induced cardiopulmonary dysfunction by S-nitroso-albumin.

Nitric oxide (NO) is an endogenous vasodilator and modulator of inflammation. During endotoxemia, the beneficial effects of NO are overwhelmed by the inflammatory cascade, resulting in a functional depletion of NO. S-nitroso-albumin (S-NO-alb) exists as a novel and highly stable NO thiol complex that slowly releases NO into the vascular micro-environment. Using a porcine model, we examined the ability of intravenous S-NO-alb to modulate cardiopulmonary dysfunction characteristic of endotoxemia. Pigs were anesthetized, instrumented for standard cardiopulmonary function measurements, and randomly assigned to receive: (i) albumin + saline; (ii) albumin + LPS; or (iii) S-NO-alb + LPS. Cardiopulmonary parameters were evaluated every 30 min and ex vivo phorbol myristate acetate (PMA)-stimulated superoxide release was serially determined as a marker of in vivo neutrophil priming. Lung myeloperoxidase (MPO) activity was measured as a marker of neutrophil migration into the lung. LPS-induced cardiopulmonary dysfunction was characterized by a sustained elevation in mean pulmonary arterial pressure, pulmonary vascular resistance, and peak intratracheal pressure, as well as a reduction in cardiac index, stroke volume index and PaO(2) over 6 h. Pretreatment with S-NO-alb attenuated LPS-induced cardiopulmonary dysfunction without adversely affecting systemic hemodynamics. Moreover, S-NO-alb blunted the LPS-induced hypoxemic response and reduced neutrophil activation. S-NO-alb did not, however, attenuate LPS-induced increases in lung MPO. Our results suggest that S-NO-alb can selectively modulate endotoxin-induced pulmonary dysfunction, attenuate neutrophil priming and block the early mortality (40%) in this model.

Animals↗
PubMedDate not supplied

Orbital implants and prostheses: postoperative computed tomographic appearance.

Computed tomographic (CT) scans of 19 patients with 10 right and nine left orbital implants were reviewed. Except for orbital soft-tissue swelling due to recent surgery or infection, CT scans obtained with both the implant and prosthesis in place showed relative symmetry of the postoperative side and the native globe. Benign air collections were often associated with either the implant or prosthesis interface or with seating of the prosthesis in the conjunctival fornices. Six patients had either cartilage, silicone, or glass beads placed surgically along the orbital floor to elevate the implants, four having had prior depressed orbital floor fractures. CT identified implant migration in five patients. The orbital prosthesis, usually constructed of solid methylmethacrylate, is fitted over the implant and simulates the appearance of the eye of the contralateral side. The operative anatomy and its relation to the CT appearance of the implant and external prosthesis are reviewed.

Cartilage↗
PubMed1997

[Simultaneous presence of macroamylase and macrolipase in a patient].

Here we report a case demonstrating simultaneous macroamylasemia and macrolipasemia. The patient showed persistently elevated serum amylase and lipase activities. On thin-layer gelfiltration, normal serum amylase migrated as a round spot behind albumin. However, serum amylase from this patient migrated slightly ahead of albumin. This finding indicated that serum amylase from this patient had a molecular weight greater than that of normal amylase. Lipase of normal serum was eluted from a Sephacryl S-300 column after the 4S protein. Lipase in the serum from this patient was eluted from the column slightly behind the 19S protein. This finding indicated that serum lipase from this patient also had a molecular weight greater than that of normal lipase. The conversion of macroamylase and macrolipase was observed when the normal serum was mixed with the patient's serum. To determine the isotypes of immunoglobulin (Ig) that was bound to amylase and lipase in the patient's serum, we investigated the effect of adding various anti-human Ig sera to the patient's serum. Amylase activity was precipitated only with anti-IgA lambda and lipase activity was precipitated both with anti-IgA lambda and anti-IgA kappa (anti-IgA kappa > anti-IgA lambda). Taken together, these data indicate that the material that enhanced amylase and lipase activities in the patient's serum was monoclonal IgA; IgA lambda for amylase and both IgA lambda and IgA kappa for lipase.

Amylases↗
PubMed1976

Ascorbic acid prevents corneal ulceration and perforation following experimental alkali burns.

Depressed aqueous humor glucose and ascorbic acid levels returned to control values within 14 days following a 20 sec, 6 mm. diameter, 1N sodium hydroxide burn of the rabbit cornea. These corneas did not ulcerate or perforate. After a 20 sec., 12 mm. diameter, 1N sodium hydroxide burn, aqueous humor glucose levels returned to normal values, but ascorbic acid levels remained significantly depressed for up to 30 days. These corneas became markedly ulcerated in about 60 per cent of animals and frequently perforated. Following 12 mm. alkali burns, rabbits treated daily with 1.5 Gm. of subcutaneous ascorbic acid rarely developed corneal ulcerations and the corneas did not perforate. It is suggested that exogenous maintenance of adequate aqueous humor levels of ascorbic acid overcomes the relatively scorbutic state of the anterior segment induced by a 12 mm. alkali burn, thereby impairing the development of corneal ulceration and perforation. Elevated aqueous humor levels of ascorbic acid had no influence on corneal epithelial cell migration patterns following alkali burns.

Alkalies↗
PubMed2000

Differential effects of UVA1 and UVB radiation on Langerhans cell migration in mice.

The UVB (280-315 nm)- and UVA1 (340-400 nm)-induced migration of Langerhans cells (LC) from the epidermis and accumulation of dendritic cells (DC) in the lymph nodes draining the exposed skin site of C3H/HeN mice have been investigated. One minimum erythemal dose (MED) of UVB (1.5 kJ/m2) and of UVA1 (500 kJ/m2) were chosen, which have been shown previously to suppress delayed hypersensitivity (DTH). UVB irradiation resulted in a reduction in epidermal LC numbers, local to the site of the exposure, which was most apparent 12 h after exposure, but, in contrast, UVA1 had no significant effect even at 72 h after exposure. UVA1 did not exert any protection against the UVB-mediated depletion in LC numbers. The reduction in local LC following UVB exposure was prevented by systemic (intraperitoneal) treatment of mice with neutralising antibodies to either tumor necrosis factor (TNF)-alpha or interleukin (IL)-beta 2 h prior to the irradiation. It has been reported previously that UVB exposure caused an increase in the number of dendritic cells (DC) in the lymph nodes draining the irradiated skin site. In the present study we have shown that UVA1 had a similar effect. Pretreatment of the mice with neutralising antibodies to IL-1beta (by intraperitoneal injection) substantially inhibited DC accumulation induced by both UV regimens. However, anti-TNF-alpha antibodies affected only the UVB-induced increase, and did not alter the elevation in DC numbers observed following UVA1 exposure. These results indicate that UVB causes the migration of LC from the epidermis and an accumulation of DC in the draining lymph nodes by a mechanism that requires both TNF-alpha and IL-1beta. In contrast, UVAI does not cause LC migration from the epidermis and the accumulation of DC in the draining lymph nodes observed following UVA1 exposure requires IL-1beta, but not TNF-alpha. It is likely therefore that UVA1 acts through a different mechanism from UVB and may target a cutaneous antigen presenting cell other than LC, such as the dermal DC.

Animals↗
PubMed1996

Restricted expression and function of laminin 1-binding integrins in normal and malignant oral mucosal keratinocytes.

Squamous cell carcinoma of the oral cavity spreads by initial invasion of the laminin-rich basement membrane. We examined the adhesion and motility of human oral SCC cells and normal mucosal keratinocytes and found that the SCC cells readily attached and migrated on laminin 1 substrates but migrated poorly on collagen type I and fibronectin. The normal keratinocytes, however, adhered poorly to and were non-motile on laminin 1 yet readily and preferentially attached and migrated on fibronectin and collagen type I. Analysis with blocking anti-integrin antibodies showed that the SCC cells used the alpha 6 beta 1 complex to attach and migrate on laminin 1 and that this activity was confined to the E8 long arm fragment of laminin. Affinity chromatography on laminin-Sepharose columns revealed that the SCC cells, but not normal keratinocytes, expressed high levels of the alpha 6 beta 1 laminin 1 receptor. Metabolic pulse-chase analysis indicated that in contrast to the SCC cells, keratinocytes did not have a stable pool of beta 1 subunit precursor. Preferential pairing of alpha 6 with beta 4 and the deficiency in pre-beta 1 levels appear to account for the failure of keratinocytes to form significant alpha 6 beta 1 complex. Additionally, the presence of laminin 1 in co-coating experiments blocked keratinocyte adhesion to other immobilized ligands, such as collagen type I or fibronectin. This anti-adhesive effect seemed to reflect a general paralysis of cell adhesive function, since laminin 1 also diminished the adhesion of keratinocytes to substrates coated with immobilized anti-integrin subunit antibody. The inhibitory activity of laminin 1 resided in the E1' and E8 fragments, and not in the E3, E4 or G domains. Collectively, our results indicate that laminin 1 is a restrictive ligand for normal keratinocytes, apparently because of their failure to assemble and express the alpha 6 beta 1 complex or other functional laminin receptors and their sensitivity to the anti-adhesive activity of laminin itself. The elevated expression of alpha 6 beta 1 following malignant conversion of muscosal keratinocytes promotes their migration on laminin, a process important during invasion and metastasis.

Binding, Competitive↗