[Show abstract][Hide abstract] ABSTRACT: During the last decade skin biopsy has been confirmed as a tool to provide diagnostic information on some peripheral neuropathies. Most studies were focused on intraepithelial nerve fibers and few studies have investigated large myelinated fibers or whether corpuscles in human skin change quantitatively or qualitatively in pathologies of the peripheral or central nervous system. The main objective of this article is to provide a comprehensive review of Meissner's corpuscles including their distribution, density and age changes, development, molecular composition, cellular anatomy and physiology. We also describe their involvement in several pathologies and suggest including this dermal structure in the routine study of skin biopsies, looking for changes to be used as potential markers for several disorders. Finally the article draws the main aspects of how to study Meissner's corpuscles in skin biopsies and gives a view on future perspectives for implementing their use in clinical practice.
[Show abstract][Hide abstract] ABSTRACT: Pleiotrophin (PTN) is an extracellular matrix-associated growth factor and chemokine expressed in mesodermal and ectodermal cells. It plays an important role in osteoblast recruitment and differentiation. There is limited information currently available about PTN expression during odontoblast differentiation and tooth formation, and thus the authors aimed to establish the spatiotemporal expression pattern of PTN during mouse odontogenesis. Immortalized mouse dental pulp (MD10-D3, MD10-A11) and odontoblast-like (M06-G3) and ameloblast-like (EOE-3M) cell lines were grown and samples prepared for immunocytochemistry, Western blot, and conventional and quantitative PCR analysis. Effects of BMP2, BMP4, and BMP7 treatment on PTN expression in odontoblast-like M06-G3 cells were tested by quantitative PCR. Finally, immunohistochemistry of sectioned mice mandibles and maxillaries at developmental stages E16, E18, P1, P6, P10, and P28 was performed. The experiments showed that PTN, at both the mRNA and protein level, was expressed in all tested epithelial and mesenchymal dental cell lines and that the level of PTN mRNA was influenced differentially by the bone morphogenetic proteins. The authors observed initial expression of PTN in the inner enamel epithelium with prolonged expression in the ameloblasts and odontoblasts throughout their stages of maturation and strong expression in the terminally differentiated and enamel matrix-secreting ameloblasts and odontoblasts of the adult mouse incisors and molars.
Journal of Histochemistry and Cytochemistry 02/2012; 60(5):366-75. · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diverse proteins of the denegerin/epithelial sodium channel (DEG/ENa(+) C) superfamily, in particular those belonging to the acid-sensing ion channel (ASIC) family, as well as some members of the transient receptor protein (TRP) channel, function as mechanosensors or may be required for mechanosensation in a diverse range of species and cell types. Therefore, we investigated the putative mechanosensitive function of human odontoblasts using immunohistochemistry to detect ENa(+) C subunits (α, β, and γ) and ASIC (1, 2, 3, and 4) proteins, as well as TRPV4, in these cells. Positive and specific immunoreactivity in the odontoblast soma and/or processes was detected for all proteins studied except α-ENa(+) C. The intensity of immunostaining was high for β-ENa(+) C and ASIC2, whereas it was low for ASIC1, ASIC3, γ-ENa(+) C, and TRPV4, being absent for α-ENa(+) C and ASIC4. These results suggest that human odontoblasts in situ express proteins related to mechanosensitive channels that probably participate in the mechanisms involved in teeth sensory transmission.
Microscopy Research and Technique 05/2011; 74(5):457-63. · 1.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Amyloid-β (Aβ) immunotherapy has recently begun to gain considerable attention as a potentially promising therapeutic approach to reducing the levels of Aβ in the Central Nervous System (CNS) of patients with Alzheimer's Disease (AD). Despite extensive preclinical evidence showing that immunization with Aβ(1-42) peptide can prevent or reverse the development of the neuropathological hallmarks of AD, in 2002, the clinical trial of AN-1792, the first trial involving an AD vaccine, was discontinued at Phase II when a subset of patients immunized with Aβ(1-42) developed meningoencephalitis, thereby making it necessary to take a more refined and strategic approach towards developing novel Aβ immunotherapy strategies by first constructing a safe and effective vaccine. This review describes the rational basis in modern clinical trials that have been designed to overcome the many challenges and known hurdles inherent to the search for effective AD immunotherapies. The precise delimitation of the most appropriate targets for AD vaccination remains a major point of discussion and emphasizes the need to target antigens in proteins involved in the early steps of the amyloid cascade. Other obstacles that have been clearly defined include the need to avoid unwanted anti-Aβ/APP Th1 immune responses, the need to achieve adequate responses to vaccination in the elderly and the need for precise monitoring. Novel strategies have been implemented to overcome these problems including the use of N-terminal peptides as antigens, the development of DNA based epitope vaccines and vaccines based on passive immunotherapy, recruitment of patients at earlier stages with support of novel biomarkers, the use of new adjuvants, the use of foreign T cell epitopes and viral-like particles and adopting new efficacy endpoints. These strategies are currently being tested in over 10,000 patients enrolled in one of the more than 40 ongoing clinical trials, most of which are expected to report final results within two years.
Current pharmaceutical design 03/2011; 17(5):508-20. · 4.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Brain-derived neurotrophic factor (BDNF) signaling through TrkB regulates different aspects of neuronal development, including survival, axonal and dendritic growth, and synapse formation. Despite recent advances in our understanding of the functional significance of BDNF and TrkB in the retina, the cell types in the retina that express BDNF and TrkB, and the variations in their levels of expression during development, remain poorly defined. The goal of the present study is to determine the age-dependent changes in the levels of expression and localization of BDNF and TrkB in the zebrafish retina. Zebrafish retinas from 10 days post-fertilization (dpf) to 180 dpf were used to perform PCR, Western blot and immunohistochemistry. Both BDNF and TrkB mRNAs, and BDNF and full-length TrkB proteins were detected at all ages sampled. The localization of these proteins in the retina was very similar at all time points studied. BDNF immunoreactivity was found in the outer nuclear layer, the outer plexiform layer and the inner plexiform layer, whereas TrkB immunoreactivity was observed in the inner plexiform layer and, to a lesser extent, in the ganglion cell layer. These results demonstrate that the pattern of expression of BDNF and TrkB in the retina of zebrafish remains unchanged during postembryonic development and adult life. Because TrkB expression in retina did not change with age, cells expressing TrkB may potentially be able to respond during the entire lifespan of zebrafish to BDNF either exogenously administered or endogenously produced, acting through paracrine mechanisms.
Journal of Anatomy 09/2010; 217(3):214-22. · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acid-sensing ion channels (ASICs) are the members of the degenerin/epithelial sodium channel (Deg/ENaC) superfamily which mediate different sensory modalities including mechanosensation. ASICs have been detected in mechanosensory neurons as well as in peripheral mechanoreceptors. We now investigated the distribution of ASIC1, ASIC2, and ASIC3 proteins in human cutaneous Pacinian corpuscles using immunohistochemistry and laser confocal-scanner microscopy. We detected different patterns of expression of these proteins within Pacinian corpuscles. ASIC1 was detected in the central axon co-expressed with RT-97 protein, ASIC2 was expressed by the lamellar cells of the inner core co-localized with S100 protein, and ASIC3 was absent. These results demonstrate for the first time the differential distribution of ASIC1 and ASIC2 in human rapidly adapting low-threshold mechanoreceptors, and suggest specific roles of both proteins in mechanotransduction.
Cellular and Molecular Neurobiology 03/2010; 30(6):841-8. · 2.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pleiotrophin (PTN), a neurotrophic factor with important roles in survival and differentiation of dopaminergic neurons, is up-regulated in the nucleus accumbens after amphetamine administration suggesting that PTN could modulate amphetamine-induced pharmacological or neuroadaptative effects. To test this hypothesis, we have studied the effects of amphetamine administration in PTN genetically deficient (PTN -/-) and wild type (WT, +/+) mice. In conditioning studies, we found that amphetamine induces conditioned place preference in both PTN -/- and WT (+/+) mice. When these mice were re-evaluated after a 5-day period without amphetamine administration, we found that WT (+/+) mice did not exhibit amphetamine-seeking behaviour, whereas, PTN -/- mice still showed a robust drug-seeking behaviour. In immunohystochemistry studies, we found that amphetamine (10 mg/kg, four times, every 2 hours) causes a significant increase of glial fibrillary acidic protein positive cells in the striatum of amphetamine-treated PTN -/- mice compared with WT mice 4 days after last administration of the drug, suggesting an enhanced amphetamine-induced astrocytosis in the absence of endogenous PTN. Interestingly, we found in concomitant in vitro studies that PTN (3 µM) limits amphetamine (1 mM)-induced loss of viability of PC12 cell cultures, effect that could be related to the ability of PTN to induce the phosphorylation of Akt and ERK1/2. To test this possibility, we used specific Akt and ERK1/2 inhibitors uncovering for the first time that PTN-induced protective effects against amphetamine-induced toxicity in PC12 cells are mediated by the ERK1/2 signalling pathway. The data suggest an important role of PTN to limit amphetamine-induced neurotoxic and rewarding effects.
[Show abstract][Hide abstract] ABSTRACT: To analyze the immunohistochemical profile of the human pancreatic pacinian corpuscles in comparison with that of the cutaneous pacinian corpuscles. In addition, we studied a Pacinilike corpuscle found in the adventitia of a pancreatic artery.
We used immunohistochemistry to detect specific antigens for corpuscular constituents, specific antibodies for the identification of Adelta- and C-sensory fibers and for the detection of several growth factor receptors, and some members of the degenerin/epithelial Na channel superfamily of proteins.
Approximately 62% of pancreatic pacinian corpuscles have 2 to 10 axonic profiles each enclosed by its own inner core: 1 or 2 of these axonic profiles displayed RT-97 immunoreactivity (specific marker of mechanical axons). The cutaneous pacinian corpuscles showed not more than 2 axonic profiles with identical immunohistochemical characteristics. The expression of glial fibrillary acidic protein, epithelial membrane antigen, and tyrosine receptor kinase B was different between pancreatic and cutaneous pacinian corpuscles; the pattern of distribution of degenerin/epithelial Na channel proteins was identical in both cases. The arterial Pacinilike corpuscles displayed a specific immunohistochemical profile.
Pancreatic pacinian corpuscles slightly differ from the cutaneous ones, and these differences could be related to topography, growth factor requirements, or function of pacinian corpuscles in the pancreas.
[Show abstract][Hide abstract] ABSTRACT: Cutaneous Meissner corpuscles depend for development and survival exclusively on the NT system TrkB/BDNF/NT-4 unlike other types of sensory corpuscles and nerve endings, which have very complex neuronal and growth factor dependence. However, the pattern of expression of TrkB in human Meissner corpuscles is not known. The experiments in these studies were designed to pursue further findings that suggest that BDNF and NT-4 have critical roles in the development and maintenance of Meissner corpuscles by analyzing the pattern of expression of TrkB, their high-affinity receptor, in human glabrous skin. These experiments showed that TrkB is expressed in different patterns by the lamellar cells of Meissner corpuscles and not by the axon. The studies also show that while the percentage of Meissner corpuscles that express TrkB remains constant from birth till 50-year old cases, it decreases approximately 3-fold in subjects older than 50 years. These results are important since the study of Meissner corpuscles from cutaneous biopsies to diagnose some neurological diseases has rapidly become of high interest and therefore the proteins expressed in these corpuscles are potential diagnostic tools.
[Show abstract][Hide abstract] ABSTRACT: Null mutations of genes from the NGF family of NTs and their receptors (NTRs) lead to loss/reduction of specific neurons in sensory ganglia; conversely, cutaneous overexpression of NTs results in skin hyperinnervation and increase or no changes in the number of sensory neurons innervating the skin. These neuronal changes are paralleled with loss of specific types of sensory nerve formations in the skin. Therefore, mice carrying mutations in NT or NTR genes represent an ideal model to identify the neuronal dependence of each type of cutaneous sensory nerve ending from a concrete subtype of sensory neuron, since the development, maintenance, and structural integrity of sensory nerve formations depend upon sensory neurons. Results obtained from these mouse strains suggest that TrkA positive neurons are connected to intraepithelial nerve fibers and other sensory nerve formations depending from C and Adelta nerve fibers; the neurons expressing TrkB and responding to BDNF and NT-4 innervate Meissner corpuscles, a subpopulation of Merkell cells, some mechanoreceptors of the piloneural complex, and the Ruffini's corpuscles; finally, a subpopulation of neurons, which are responsive to NT-3, support postnatal survival of some intraepithelial nerve fibers and Merkel cells in addition to the muscle mechanoreceptors. On the other hand, changes in NTs and NTRs affect the structure of non-nervous structures of the skin and are at the basis of several cutaneous pathologies. This review is an update about the role of NTs and NTRs in the maintenance of normal cutaneous innervation and maintenance of skin integrity.
Microscopy Research and Technique 10/2009; 73(5):513-29. · 1.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pacinian corpuscles are innervated by large myelinated Aalpha-beta axons from the large- and intermediate-sized sensory neurons of dorsal root ganglia. These neurons express different members of the degenerin/epithelial Na(+) channel (DEG/ENa(+)C) superfamily of proteins with putative mechanosensory properties, whose expression is regulated by the TrkB-BDNF system. Thus, we hypothesized that BDNF and/or NT-4 signalling through activation of TrkB may regulate the expression of molecules supposed to be necessary for the mechanosensory function of Pacinian corpuscles. To test this hypothesis we analyzed the expression and distribution of ENa(+)C subunits and acid-sensing ion channel 2 (ASIC2) in Pacinian corpuscles from 25 days old mice deficient in TrkB, BDNF and NT-4. Pacinian corpuscles in these animals are normal in number, structure, and expression of several immunohistochemical markers. Using immunohistochemistry we observed that the beta-ENa(+)C and gamma-ENa(+)C subunits, but not the alpha-ENa(+)C subunit, were expressed in wild-type animals, and they were always found in the central axon. ASIC2 immunoreactivity was found in both the central axon and the inner core cells. The absence of TrkB or BDNF abolished expression of beta-ENa(+)C and ASIC2, whereas expression of gamma-ENa(+)C did not change. Expression of beta-ENa(+)C and gamma-ENa(+)C subunits in NT-4 deficient mice was found in the axons but also in the inner core cells whereas levels of expression of ASIC2 were increased in these animals. This study suggests that expression in Pacianian corpuscles of some potential mechanosensory proteins is regulated by BDNF, NT-4 and TrkB.
[Show abstract][Hide abstract] ABSTRACT: Normal development of the lung requires coordinated activation of cascades of signaling pathways initiated by growth factors signaling through their receptors. TrkB and its ligands, brain-derived neurotrophic factor (BDNF) and neurotrophin-4, belong to the neurotrophin family of growth factors, which are expressed in a large variety of non-neuronal tissues including the lung. Aberrant neurotrophin signaling underlies the pathogenesis of several lung-related pathologies, including asthma and lung cancer, however, little is known about the role of neurotrophins in the embryonic development of the lung. To fill this gap in knowledge, we analyzed the pattern of TrkB expression in the murine lung and we observed that TrkB is expressed in alveolar macrophages, type II pneumocytes, neuroepithelial bodies and nerves. Analysis of the structure of lung from mice deficient in TrkB revealed that absence of TrkB signaling results in thinner bronchial epithelium and apparent larger air space, and, more importantly, lack of neuroepithelial bodies, an important reduction in the density of nerve fibres in the bronchial smooth muscle, submucous plexus in bronchioles, and pulmonary artery walls. These findings suggest TrkB is essential for the normal development of the lung and the nervous system in the lung.
[Show abstract][Hide abstract] ABSTRACT: Pleiotrophin (PTN) is a growth factor that has been shown to be involved in hippocampal synaptic plasticity and learning. To further understand the involvement of PTN in memory processes, we performed in vitro electrophysiological studies in PTN-stimulated CA1 from rat hippocampal slices combined with the behavioural testing of PTN deficient (PTN - / - ) mice. We found that PTN inhibited hippocampal long-term potentiation (LTP) induced by high-frequency stimulation (HFS) consisted in three trains of 100 Hz separated by 20 s. To test the possibility that PTN might be involved in behavioural memory processes, we tested the learning behaviour of PTN - / - mice using the Y-maze test. We did not observe significant differences in recognition memory between PTN - / - and Wild Type (WT) mice when a 30 min-interval intertrial (ITI) was used in the Y-maze test. However, whereas WT mice showed disruption of recognition memory using a 60 min-ITI, PTN - / - mice maintained the recognition memory. The data demonstrate that PTN inhibits hippocampal LTP in vitro and might play a role in memory processes in vivo.
[Show abstract][Hide abstract] ABSTRACT: The embryonic development of the enteric nervous system (ENS) from neural crest precursor cells requires neurotrophic signaling. Neurotrophins (NTs) are a family of growth factors that bind Trk receptors to signal diverse functions, including development and maintenance of different cell populations in the peripheral nervous system. In this study we investigated the expression and cell localization of TrkB, the high affinity receptor for brain-derived neurotrophic factor and NT-4, in the murine ENS using Western blot and immunohistochemistry. The results demonstrate that enteric glial cells within the ENS express full-length TrkB at all stages tested. The ENS of TrkB deficient mice have reduced expression of glial cell markers, and a disarrangement of glial cells and the plexular neuropil. These results strongly suggest TrkB has essential roles in the normal development and maintenance of glial cells in the ENS.
[Show abstract][Hide abstract] ABSTRACT: Enhanced angiogenesis is a hallmark of cancer. Pleiotrophin (PTN) is an angiogenic factor that is produced by many different human cancers and stimulates tumor blood vessel formation when it is expressed in malignant cancer cells. Recent studies show that monocytes may give rise to vascular endothelium. In these studies, we show that PTN combined with macrophage colony-stimulating factor (M-CSF) induces expression of vascular endothelial cell (VEC) genes and proteins in human monocyte cell lines and monocytes from human peripheral blood (PB). Monocytes induce VEC gene expression and develop tube-like structures when they are exposed to serum or cultured with bone marrow (BM) from patients with multiple myeloma (MM) that express PTN, effects specifically blocked with antiPTN antibodies. When coinjected with human MM cells into severe combined immunodeficient (SCID) mice, green fluorescent protein (GFP)-marked human monocytes were found incorporated into tumor blood vessels and expressed human VEC protein markers and genes that were blocked by anti-PTN antibody. Our results suggest that vasculogenesis in human MM may develop from tumoral production of PTN, which orchestrates the transdifferentiation of monocytes into VECs.
[Show abstract][Hide abstract] ABSTRACT: This study seeks to integrate recent studies that identify new critical mechanisms through which the 136 amino acid secreted heparin-binding cytokine pleiotrophin (PTN, Ptn) stimulates both normal and pathological angiogenesis.
Pleiotrophin is directly angiogenic; it initiates an angiogenic switch in different cancer models in vivo. It acts as an angiogenic factor through multiple mechanisms that include a unique signaling pathway that activates newly identified downstream tyrosine kinases through a unique mechanism, an interaction with endothelial cells to initiate proliferation, migration, and tube formation, the regulation of basic fibroblast growth factor and vascular endothelial growth factor signaling, the remodeling of the stromal microenvironment, and induction of transdifferentiation of monocytes into endothelial cells. Recently also, domains of PTN that stimulate angiogenesis and peptides that function to inhibit PTN signaling have been identified.
Recent studies have identified new mechanisms dependent on activation of the PTN signaling pathway that regulate angiogenesis and new targets to use PTN to both stimulate angiogenesis and block its activity to control pathological angiogenesis.
Current Opinion in Hematology 06/2008; 15(3):210-4. · 4.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The search for molecular biomarkers for diagnosing and classifying dementias is becoming a high priority need. Neurosin (Kallikrein 6, hk6) is one molecule with promising preliminary results since its levels in brain tissue, cerebrospinal fluid and blood have been found to be abnormal in Alzheimer's disease (AD). In this study, we measured plasmatic levels of neurosin in healthy individuals and patients with cognitive symptoms independently of what the final diagnosis was. We collected plasma samples from 228 controls and 447 patients finally diagnosed with either AD, Mild Cognitive Impairment, Dementia with Lewy Bodies or Parkinson-Dementia, Frontotemporal Dementia, Huntington's disease, Primary Progressive Aphasia, Corticobasal degeneration, Creutzfeldt-Jakob's disease or Pseudodementia. We found that plasmatic levels of neurosin increase with age in healthy individuals and decrease in patients with AD. Plasmatic levels of neurosin differ significantly between AD and Vascular Dementia, Pseudodementia and the control group. Analyses comparing any other form of neurodegenerative dementia to the AD group did not show significant differences. In conclusion, measurement of plasmatic levels of neurosin is useful to distinguish AD patients from subjects without neurodegenerative dementia (either Pseudodementia, Vascular Dementia or controls) although it is not useful to distinguish among neurodegenerative dementias.
[Show abstract][Hide abstract] ABSTRACT: The sensory deficit in TrkB deficient mice was evaluated by counting the neuronal loss in lumbar dorsal root ganglia (DRG), the absence of sensory receptors (cutaneous--associated to the hairy and glabrous skin - muscular and articular), and the percentage and size of the neurocalcin-positive DRG neurons (a calcium-binding protein which labels proprioceptive and mechanoceptive neurons). Mice lacking TrkB lost 32% of neurons, corresponding to the intermediate-sized and neurocalcin-positive ones. This neuronal lost was accomplished by the absence of Meissner corpuscles, and reduction of hair follicle-associated sensory nerve endings and Merkel cells. The mutation was without effect on Pacinian corpuscles, Golgi's organs and muscle spindles. Present results further characterize the sensory deficit of the TrkB-/- mice demonstrating that the intermediate-sized neurons in lumbar DRG, as well as the cutaneous rapidly and slowly adapting sensory receptors connected to them, are under the control of TrkB for survival and differentiation. This study might serve as a baseline for future studies in experimentally induced neuropathies affecting TrkB positive DRG neurons and their peripheral targets, and to use TrkB ligands in the treatment of neuropathies in which cutaneous mechanoreceptors are primarily involved.
[Show abstract][Hide abstract] ABSTRACT: Mild Cognitive Impairment (MCI) is a disorder considered to be a transitional stage from health to dementia. Diagnosis of dementias at these early stages is always troublesome because the pathophysiologic events leading to dementia precede clinical symptoms. Thus, the development of biomarkers that can be used to support the diagnosis of dementias at early stages is rapidly becoming a high priority. We have recently reported the value of measuring plasmatic levels of neurosin in the diagnosis of Alzheimer's disease (AD). The aim of this study is to determine whether measuring plasmatic concentration of neurosin is a valuable test to predict progression of MCI.
Plasmatic neurosin concentrations were measured in 68 MCI patients and 70 controls subjects. Blood samples were obtained at the beginning of the study. Sixty six patients diagnosed with MCI were observed for 18 months. In 36 patients a second blood sample was obtained at the endpoint.
The mean value of plasmatic neurosin concentration differs significantly between MCI patients who converted to Dementia with vascular component, those who converted to AD, or those who remained at MCI stage. The relative risk of developing Dementia with vascular component when neurosin levels are higher than 5.25 ng/ml is 13 while the relative risk of developing mild AD when neurosin levels are lower than 5.25 ng/ml is 2. Increases in the levels of neurosin indicate progression to Dementia with vascular component.
The measurement of plasmatic neurosin level in patients diagnosed with MCI may predict conversion from MCI to Dementia with vascular component. A single measurement is also valuable to estimate the risk of developing AD and Dementia with vascular component. Finally, repeated measurement of plasmatic neurosin might be a useful test to predict outcome in patients with MCI.
International Archives of Medicine 02/2008; 1(1):11. · 1.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Increasing evidence suggests mutations in human breast cancer cells that induce inappropriate expression of the 18-kDa cytokine pleiotrophin (PTN, Ptn) initiate progression of breast cancers to a more malignant phenotype. Pleiotrophin signals through inactivating its receptor, the receptor protein tyrosine phosphatase (RPTP)beta/zeta, leading to increased tyrosine phosphorylation of different substrate proteins of RPTPbeta/zeta, including beta-catenin, beta-adducin, Fyn, GIT1/Cat-1, and P190RhoGAP. PTN signaling thus has wide impact on different important cellular systems. Recently, PTN was found to activate anaplastic lymphoma kinase (ALK) through the PTN/RPTPbeta/zeta signaling pathway; this discovery potentially is very important, since constitutive ALK activity of nucleophosmin (NPM)-ALK fusion protein is causative of anaplastic large cell lymphomas, and, activated ALK is found in other malignant cancers. Recently ALK was identified in each of 63 human breast cancers from 22 subjects. We now demonstrate that RPTPbeta/zeta is expressed in each of these same 63 human breast cancers that previously were found to express ALK and in 10 additional samples of human breast cancer. RPTPbeta/zeta furthermore was localized not only in its normal association with the cell membrane but also scattered in cytoplasm and in nuclei in different breast cancer cells and, in the case of infiltrating ductal carcinomas, the distribution of RPTPbeta/zeta changes as the breast cancer become more malignant. The data suggest that the PTN/RPTPbeta/zeta signaling pathway may be constitutively activated and potentially function to constitutively activate ALK in human breast cancer.
Biochemical and Biophysical Research Communications 11/2007; 362(1):5-10. · 2.41 Impact Factor