Growth factor regulation of integrin-mediated cell motility

Summary Cell motility, a primary component of tumor cell invasion, is a continuum of sequential events in which the cell extends pseudopodia, forms nascent attachments, assembles and contracts the cytoskeleton, and finally, as it translocates forward, disengages distal adhesions. What triggers cells to move? Substratum contact mediated by integrin adhesion receptors is important, but other signals such as chemokinetic factors appear to be required for continued crawling. It is now apparent that integrins do not simply bind cells to matrix in a Velcrolike fashion, but also are potent signaling molecules. Initial engagement of integrins induces their condensation into focal contacts, forming anchors to the extracellular matrix and discrete signal-transducing complexes on the cytoplasmic surface. A number of growth factors, through either autocrine or paracrine pathways, can activate the cellular machinery that mobilizes the cell. Thus, these two classes of receptors - the integrin receptors that bind specific extracellular adhesion molecules, and growth factor receptors that bind their respective ligands - can regulate cell locomotion. Not surprisingly, there is cross-talk between integrin and growth factor receptors that occurs through their common intracellular signaling pathways. In this way, each receptor type can either amplify or attenuate the other's signal and downstream response. An example of growth factor-induced motility is the epithelial-mesenchymal transition induced by hepatocyte growth factor/scatter factor (HGF/SF). When bound to its receptor, the c-met proto-oncogene product, HGF/SF induces a phenotypic conversion that appears to be an important aspect of tumor progression in malignant carcinomas. The motogenic response produced by HGF/SF in carcinoma cells occurs in discrete steps in which integrins and focal adhesion kinase (p125^FAK) are first recruited to focal contacts. This is rapidly followed by cell spreading, disruption of focal adhesions and cell-cell contacts, and, finally, cell crawling. The precise mechanism by which growth factors such as HGF/SF and its receptor induce this motogenic response and modulate integrin function has not been clearly defined but appears to involve several signaling pathways. Understanding the process by which growth factor and integrin receptors interact and regulate motility may suggest novel targets for therapeutic intervention.     

The antiproliferative aspects of mortalin (review)

Cellular mortal and immortal phenotypes as defined by the limited and the infinite capacity of cells to divide are the characteristics of normal and cancerous cells in culture. Numerous strategies that have been employed to understand the mechanism(s) of normal as well as tumor cell growth have revealed that these are genetically controlled, however, the genes and the synchronized regulations remain largely undefined so far. The present report reviews the identification of mortalin, a novel member of murine hsp70 family of proteins, as a gene involved in pathways that determine divisional phenotype of cells in vitro. In the present study, the anti-proliferative activity of mortalin is demonstrated also in human skin fibroblasts (TIG-73PD) by microinjection of anti-mortalin antibody. Furthermore, studies on the mortalin immunofluorescence patterns in SV40-immortalized pre-crisis and post-crisis human cells have revealed that the change in the intracellular distribution of mortalin is linked to the change in the divisional phenotype of cells. Thus, the studies to resolve the molecular basis of association of the cytosolically distributed form of mortalin with cellular mortal phenotype would be important in understanding of the mechanism(s) that determine replicative potential of cells in culture.     

Benthic Community Structure and Biomarker Induction in Grass Shrimp in an Estuarine System

The impact of polycyclic aromatic hydrocarbons (PAHs) and lead contamination on benthic community structure and grass shrimp (Palaeomonetes sp.) biochemical markers were investigated in a bayou that has been heavily contaminated by PAHs and heavy metals. The benthic community had decreased species richness as well as decreased numbers of individuals along a contamination gradient. Grass shrimp collected in the field showed a contaminant-gradient increase in heat shock protein 63 and cytochrome P450 1A (as measured by ECOD metabolism). Grass shrimp had elevated ECOD metabolism when exposed in the laboratory to sediments from the most contaminated site. However, individual variation was too great for statistically significant changes. In addition, heat shock protein levels were not significantly elevated in laboratory exposed shrimp. Benthic community structure and wild-caught grass shrimp are clearly impacted in this bayou. Received: 4 December 1998/Accepted: 9 February 1999     

Evaluation of the accuracy of preoperative staging in thoracic esophageal cancer

Background. Exact clinical staging before treatment of esophageal cancer has become increasingly important in the evaluation and comparison of the results of different treatment modalities, including surgery, chemotherapy, and radiotherapy.

Methods. The accuracy of preoperative tumor staging by using an esophagography, esophagoscopy, percutaneous and endoscopic ultrasonography, and computed tomography was assessed in 224 patients with resectable esophageal cancer. The results of tumor staging by these tests were compared prospectively with the pathologic stage of the esophagectomy specimens with respect to the T and N categories defined by the International Union Against Cancer TNM classification.

Results. For the T category, the overall accuracy was 80%. For the N category, overall accuracy was 72%, with a sensitivity of 78%, a specificity of 60%, and a positive predictive value of 78%. Overall, the accuracy of stage grouping was 56%.

Conclusions. Either the T or N categories can be predicted reliably by clinical staging techniques. However, the preoperative stage grouping might not be valid in resectable, localized esophageal cancer.     

Tumor scintigraphy by the method for subtracting the initial image with technetium-99m labeled antibody

The method for subtracting the initial image from the localization image was evaluated for radioimmunoscintigraphy of tumors with technetium-99m (Tc-99m) labeled antibodies. Monoclonal antibodies were parental mouse and mouse-human chimeric antibodies to carcinoembryonic antigen (CEA), designated F11-39 and ChF11-39, respectively, both of which have been found to discriminate CEA in tumor tissues from the CEA-related antigens. After reduction of the intrinsic disulfide bonds, these antibodies were labeled with Tc-99m. In vivo studies were performed on athymic nude mice bearing the human CEA-producing gastric carcinoma xenografts. Though biodistribution results showed selective and progressive accumulation of Tc-99m labeled antibodies at the tumor site, high radioactivity in blood was inappropriate for scintigraphic visualization of the tumors within a few hours. We examined the subtraction of the initial Tc-99m image from the Tc-99m localization image after a few hours. Subtracted images of the same count reflected the in vivo behavior of the Tc-99m radioactivity. The subtracted scintigrams revealed excellent tumor images with no significant extrarenal background. Visualization of the tumor site was dependent on antigen-specific binding and nonspecific exudation. These results demonstrate that a method of subtraction of the initial image may serve as a potentially useful diagnostic method for an abnormal site for agents with a low pharmacokinetic value.     

Contribution of peripheral chemoreception to the depression of the hypoxic ventilatory response during halothane anesthesia in cats

BACKGROUND: The effects of inhalational anesthetics on the hypoxic ventilatory response are complex. This study was designed to determine the contribution of peripheral chemoreception to the depression of hypoxic ventilatory response seen with halothane anesthesia. METHODS: Cats were anesthetized with pentobarbital sodium and alpha-chloralose and artificially ventilated. Respiratory output was evaluated by phasic inspiratory activity of the phrenic nerve. In 12 cats, this activity was measured during inhalation of an hypoxic gas mixture with halothane, 0, 0.1, and 0.8%, with intact or denervated carotid bodies. In 10 cats, a carotid body was isolated from the systemic circulation and perfused with hypoxic Krebs-Ringer solution equilibrated with halothane, 0, 0.1, and 0.8%. RESULTS: The hypoxic ventilatory response was depressed in a dose-dependent manner during halothane anesthesia. In carotid body perfusion studies, the response was significantly depressed only with halothane, 0.80%. CONCLUSION: The hypoxic ventilatory response is depressed by a high dose of halothane through a peripheral effect at the carotid body.     

Mediastinal lymph node metastasis of colon cancer: Report of a case

We herein describe a patient with mediastinal lymph node metastases which occurred after both a primary sigmoid colon cancer and metachronous ovarian metastasis had been resected. The most likely route of metastases to the mediastinum in this case is the paravertebral venous plexus probably connected to the ovarian metastasis, or so-called remetastasis. This case illustrates that the mediastinum is thus a possible metastatic site in patients with colon cancer. Surgeons should therefore pay attention to the mediastinum as well as the lung fields when checking chest X-ray films during a follow-up of patients after a resection of colon cancer.     

Comparison of the axonal and glial reactions between the caudal and rostral border in the cryoinjured dorsal funiculus of the rat spinal cord

Axonal and glial reactions to traumatic injury were compared between the caudal and rostral border of the lesion after freeze-injury to the C3 dorsal funiculus by attaching a liquid nitrogen-cooled copper probe to the dorsum of the rat spinal cord. The axonal and glial changes were examined up to 60 days postoperative by light and electron microscopy and immunohistochemistry for neurofilaments. Regenerative axonal changes and the appearance of numerous undifferentiated cells were found at the caudal border 7 days after cryoinjury. In contrast, such axonal and cellular reactions were scarce at the rostral border. Undifferentiated cells clearly manifested their phenotypes by differentiating into oligodendrocytes or astrocytes 11 days postinjury. The results indicated that glial cell reactions occurred in association with regenerative axonal changes at the proximal stump of the injured nerve fibers, suggesting that regenerating and demyelinated naked axons could be responsible for the appearance of the immature glial cells.     

Middle cerebral artery flow velocity and cerebral oxygenation during abdominal aortic surgery

Cerebral perfusion was evaluated in twelve patients undergoing elective infra-renal abdominal aortic aneurysmectomy by transcranial Doppler ultrasonography-determined middle cerebral artery mean flow velocity, near-infrared spectroscopy-assessed cerebral oxygen saturation and systemic haemodynamic variables. The middle cerebral artery mean flow velocity and cerebral oxygen saturation decreased during cross-clamping of the aorta, and both increased upon declamping of the aorta with the oxygen saturation change lagging behind the change in the flow velocity. The changes in cerebral flow velocity and oxygen saturation paralleled the deviations in cardiac output and end-tidal carbon dioxide tension.