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PubMed2006

Mammary stem cells come of age, prospectively.

Two recent reports have contributed direct evidence for the existence of a pluripotent mouse mammary epithelial stem cell. In both reports, the investigators have prospectively isolated an enriched fraction of mammary stem cells using fluorescence-activated cell sorting from freshly dispersed epithelial cells. This fraction of cells, upon transplantation in limiting dilution (in some cases as a single cell), produces complete mammary development within the host mammary fat pad. These studies extend and confirm earlier work that demonstrated that retroviral-tagged mammary fragments produce complete functional mammary glands comprising their clonal progeny upon fat-pad transplantation. This technical advance opens the possibility to use similar methodologies to isolate and characterize human breast epithelial stem cells, and elucidate their role in regeneration and neoplasia.

Animals↗
PubMed2006

Subventricular zone cells remain stable in vitro after brain injury.

Subventricular zone (SVZ) cells emigrate toward brain injury but relatively few survive. Thus, if they are to be used for repair, ex vivo expansion and autologous transplantation of SVZ cells may be necessary. Since it is unclear how brain injury alters SVZ cell culture, we studied neurosphere formation, differentiation, and migration, after cortical lesions. The number of neurosphere forming cells from lesioned mice was comparable to controls. Also, the proportion of astrocytes and neurons generated in vitro remained unchanged after cortical lesions. Cell emigration from neurospheres was characterized by increased cell-cell contact after injury in adults and neonates. However, neither molecules implicated in SVZ migration nor the extent of migration changed after injury. Thus, neurospheres can be successfully cultured after extensive brain damage, and they are remarkably stable in vitro, suggesting suitability for ex vivo expansion and autologous transplantation.

Animals↗
PubMed2005

PTH-related protein enhances LoVo colon cancer cell proliferation, adhesion, and integrin expression.

Parathyroid hormone-related protein (PTHrP) has been localized in human colon cancer tissue and cell lines. Tumor cell adhesion to extracellular matrix (ECM) proteins plays a major role in the invasion and metastasis of tumor cells, and is mediated via integrin subunits. The LoVo human colon cancer cell line was used as a model system to study the effects of PTHrP on cell proliferation and adhesion to ECM proteins found in normal liver. Clones of LoVo cells engineered to overexpress PTHrP by stable transfection with a PTHrP cDNA showed enhanced cell proliferation vs. control (empty vector-transfected) cells. PTHrP-overexpressing cells also showed significantly higher adhesion to collagen type I, fibronectin, and laminin, and enhanced expression of the [symbol: see text] integrin subunits. These results indicate that PTHrP may play a role in colon cancer invasion and metastasis by increasing cell proliferation and adhesion to the ECM via upregulation of proinvasive integrin expression.

Acid Phosphatase↗
PubMed2006

Isolation of mouse mammary epithelial progenitor cells with basal characteristics from the Comma-Dbeta cell line.

A mouse mammary epithelial cell line with morphogenetic properties in vivo, Comma-Dbeta, was used to isolate and to characterize mammary progenitor cells. We found that a homogeneous cell population expressing high surface levels of stem cell antigen 1 (Sca-1) was able to give rise in vivo to ductal and alveolar structures comprising luminal secretory and basal myoepithelial cells. Unlike the Sca-1(high), the Sca-1(neg/low) cell population displayed a reduced morphogenetic potential. The Sca-1(high) cells presented moderate CD24, high CD44 and alpha6 integrin surface levels, expressed basal cell markers p63, keratins 5 and 14, but no luminal and myoepithelial lineage markers. In culture, the Sca-1(high) cells generated identical daughter cells that retained their in vivo developmental potential, indicating that these cells were maintained by self-renewal. Plated at clonogenic density in Matrigel, Sca-1(high) cells formed spheroids that included luminal and myoepithelial cells. Thus, the isolated Sca-1(high) basal cells possess several features of stem/progenitor cells, including specific markers, self-renewal capacity, and the ability to generate the two major mammary lineages, luminal and myoepithelial. These data provide evidence for the existence of basal-type mouse mammary progenitors able to participate in the morphogenetic processes characteristic of mammary gland development.

Animals↗
PubMed2002

Characterization of gene expression induced by RET with MEN2A or MEN2B mutation.

Germ-line point mutations of the RET gene are responsible for multiple endocrine neoplasia (MEN) type 2A and 2B that develop medullary thyroid carcinoma and pheochromocytoma. We performed a differential display analysis of gene expression using NIH 3T3 cells expressing the RET-MEN2A or RET-MEN2B mutant proteins. As a consequence, we identified 10 genes induced by both mutant proteins and eight genes repressed by them. The inducible genes include cyclin D1, cathepsins B and L, and cofilin genes that are known to be involved in cell growth, tumor progression, and invasion. In contrast, the repressed genes include type I collagen, lysyl oxidase, annexin I, and tissue inhibitor of matrix metalloproteinase 3 (TIMP3) genes that have been implicated in tumor suppression. In addition, six RET-MEN2A- and five RET-MEN2B-inducible genes were identified. Among 21 genes induced by RET-MEN2A and/or RET-MEN2B, six genes including cyclin D1, cathepsin B, cofilin, ring finger protein 11 (RNF11), integrin-alpha6, and stanniocalcin 1 (STC1) genes were also induced in TGW human neuroblastoma cells in response to glial cell line-derived neurotrophic factor stimulation. Because the STC1 gene was found to be highly induced by both RET-MEN2B and glial cell line-derived neurotrophic factor stimulation, and the expression of its product was detected in medullary thyroid carcinoma with the MEN2B mutation by immunohistochemistry, this may suggest a possible role for STC1 in the development of MEN 2B phenotype.

3T3 Cells↗
PubMed2001

Energetic determinants of tyrosine phosphorylation of focal adhesion proteins during hypoxia/reoxygenation of kidney proximal tubules.

Anaerobic mitochondrial metabolism of alpha-ketoglutarate and aspartate or alpha-ketoglutarate and malate can prevent and reverse severe mitochondrial dysfunction during reoxygenation after 60 minutes of hypoxia in kidney proximal tubules.(34) The present studies demonstrate that, during hypoxia, paxillin, focal adhesion kinase, and p130(cas) migrated faster by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, their phosphotyrosine (pY) content decreased to approximately 5% of that in oxygenated tubules without changes in total protein, and the normally basal immunostaining of beta1 and alpha6 integrin subunits, pY, and paxillin was lost or markedly decreased. During reoxygenation without supplemental substrates, recovery of pY and basal localization of the focal adhesion proteins was poor. alpha-Ketoglutarate and aspartate, which maintained slightly higher levels of ATP during hypoxia, also maintained 2.5-fold higher levels of pY during this period, and promoted full recovery of pY content and basal localization of focal adhesion proteins during subsequent reoxygenation. Similarly complete recovery was made possible by provision of alpha-ketoglutarate and aspartate or alpha-ketoglutarate and malate only during reoxygenation. These data emphasize the importance of very low energy thresholds for maintaining the integrity of key structural and biochemical components required for cellular survival and reaffirm the value of approaches aimed at conserving or generating energy in cells injured by hypoxia or ischemia.

Adenosine Triphosphate↗
PubMed2000

Expression of alpha and beta integrins during terminal differentiation of cardiomyocytes.

BACKGROUND: In the myocardium, myocyte cell division is irreversibly blocked shortly after birth. The signal that initiates cell cycle withdrawal is unknown. The purpose of this study was to relate changes in expression of beta1 integrin and its associated alpha subunits to cardiomyocyte cell cycle progression during the fetal-to-neonatal developmental transition in rat. METHODS AND RESULTS: The developmental expression pattern and function of beta 1 integrin and several of its associated alpha subunits were examined using reverse transcription (RT) polymerase chain reaction (PCR) and beta 1 blocking antibodies. During the fetal to neonatal transition, a dramatic shift occurred in the levels of beta1 and alpha isoforms. At the 17-day fetal stage only beta 1A was present, which remained relatively constant until immediately after birth then decreased by 30% at the adult stage. By contrast, beta 1D appeared at fetal day 18, increased at neonatal day 2, and afterwards remained constant. This resulted in a ratio of beta 1A to beta 1D of about 1:1 in the adult heart. The integrin beta 1-associated subunits, alpha 3, alpha 6, and alpha 7, were expressed at extremely low levels in 17-day fetal cardiomyocytes. After birth alpha 3 and alpha 6 transiently increased at the 2-day neonatal stage, while alpha 7 isoforms B, C, and X2 progressively increased to the adult stage. Unlike skeletal muscle cells, fluorescence-activated cell sorting analysis (FACS) showed no down regulation of the alpha 5 beta 1 fibronectin receptor during cell cycle withdrawal. Treatment of cultured cardiomyocytes with beta1 blocking antibody inhibited the cell cycle in fetal but not in neonatal cells. CONCLUSION: These results suggest that progression through the cardiomyocyte cell cycle may be dependent upon cell attachment via integrin beta1 and correlate with changes that occur in beta1 spliced variants and their respective alpha isoforms.

Animals↗
PubMed2001

Identification of downstream target genes of latent membrane protein 1 in nasopharyngeal carcinoma cells by suppression subtractive hybridization.

Nasopharyngeal carcinoma (NPC) is a common cancer in Southern China and is closely associated with infection of Epstein-Barr virus (EBV). The EBV encoded latent membrane protein 1 (LMP1) is frequently detected in NPC and may play a role in its pathogenesis. Previous studies have shown that LMP1 transformed rodent fibroblasts and altered growth properties in B cells and epithelial cells. However, the pathological role of LMP1 in NPC cells is still poorly understood. In order to investigate the downstream target genes of LMP1 in NPC cells, suppression subtractive hybridization was used to clone and identify the genes differentially expressed in a LMP1 expressing NPC cell line, CNE-2. Two subtractive cDNA libraries were constructed: one enriched for the genes upregulated by LMP1 and one was for the genes downregulated by LMP1. A total of 192 clones were screened by reverse Northern blotting. Fourteen of them were confirmed to be overexpressed while eight of them were suppressed. The upregulation of integrin alpha6, laminin 5gamma2, TAP1 and downregulation of p54nrb, RACK1 and p66Shc were further confirmed in three sets of LMP1 expressing NPC cell lines. The expression profiles of differentially expressed genes identified in this study suggest a role of LMP1 in promotion of cell survival and facilitation of tumor invasion.

DNA, Complementary↗
PubMed2003

Purification of adult hepatic progenitor cells using green fluorescent protein (GFP)-transgenic mice and fluorescence-activated cell sorting.

BACKGROUND/AIMS: Recent advances in stem cell research have revealed that hepatic stem/progenitor cells may play an important role in liver development and regeneration. However, a lack of detectable definitive markers in viable cells has hindered their primary culture from adult livers. METHODS: Enzymatically dissociated liver cells from green fluorescent protein (GFP)-transgenic mice, which express GFP highly in liver endodermal cells, were sorted by GFP expression using a fluorescence-activated cell sorter. Sorted cells were characterized, and also low-density cultured for extended periods to determine their proliferation and clonal differentiation capacities. RESULTS: When CD45(-)TER119(-) side-scatter(low) GFP(high) cells were sorted, alpha-fetoprotein-positive immature endoderm-characterized cells, having high growth potential, were present in this population. Clonal analysis and electron microscopic evaluation revealed that each single cell of this population could differentiate not only into hepatocytes, but also into biliary epithelial cells, showing their bilineage differentiation activity. When surface markers were analyzed, they were positive for Integrin-alpha6 and -beta1, but negative for c-Kit and Thy1.1. CONCLUSIONS: Combination of GFP-transgenic mice and fluorescence-activated cell sorting enabled purification of hepatic progenitor cells from adult mouse liver. Further analysis of this population may lead to purification of their human correspondence that would be an ideal cell-source candidate for regenerative medicine.

Age Factors↗
PubMed2001

Downregulation of hemidesmosomal proteins in nasopharyngeal carcinoma cells.

Hemidesmosome (HD) is a transmembrane complex that mediates attachment of epithelial cells to the basement membrane. Abnormal expression of HD components has been reported in several types of human cancers and is believed to play a role in tumor invasion and metastasis. Using differential gene display, we have identified downregulation of BPAG1 expression in nasopharyngeal carcinoma cells. BPAG1 is a major component of hemidesmosome. In the present study, we have extended our work to investigate the expression pattern of other components in the HD complex, namely, BPAG2, ITGalpha6 and ITGbeta4 in three distinct biological groups of nasopharyngeal epithelial cells: (a) non-malignant nasopharyngeal epithelial cells established from primary culture of nasopharyngeal explants, (b) non-malignant nasopharyngeal epithelial cells immortalized by viral oncogenes, SV40 or HPV16E6E7, and (c) nasopharyngeal carcinoma (NPC) cells. Both non-malignant primary cultured nasopharyngeal epithelial cells and immortalized nasopharyngeal epithelial cell lines expressed all the HD components examined, although the immortalized cells expressed a lower level of HD components compared with the non-malignant nasopharyngeal cells established from primary culture. In contrast, downregulation of HD components is commonly observed in nasopharyngeal carcinoma cells. Loss of HD expression in NPC may be associated with the undifferentiated properties of NPC cells and may have prognostic significance.

Antigens, CD↗
PubMed1996

Expression of integrin subunits in normal and malignant human salivary gland cell clones and its regulation by transforming growth factor-beta 1.

In this study, we have examined the expression of integrin subunits in normal and malignant human salivary gland cell clones as well as its regulation by transforming growth factor-beta 1 (TGF-beta 1). By the analysis using immunofluorescence staining, an SV40 immortalized normal human salivary gland duct cell clone (NS-SVDC) with no tumorigenic ability by s.c. implantation into nude mice was identified to express the integrin beta 1, alpha 2, alpha 3 and alpha 6 subunits on the cell surface, while the expression of these subunits, except for beta 1 subunit, was reduced or completely diminished in a neoplastic human salivary gland duct cell clone (HSGc) with tumorigenic but not metastatic potential in nude mice and metastatic cell clones derived after in vitro exposure of HSGc to N-methyl-N-nitrosourea. In addition, immunoblot analysis also exhibited the same results as those obtained with immunofluorescence staining. The alpha 1 subunit was not demonstrable in any of the cell clones by both techniques. TGF-beta 1 augmented the expression of the beta 1 subunit in NS-SV-DC, while HSGc and metastatic cell clones demonstrated no changes in the expression of the beta 1 subunit in response to TGF-beta 1. These findings, therefore, suggest that there is an inverse relationship between the malignancy and the expression mode of integrin subunits, especially alpha 2 subunit, in human salivary gland cell clones with varying degrees of malignant potential, and that TGF-beta 1 is a positive regulatory factor in the expression of the beta 1 subunit in normal but not malignant cell clones.

Animals↗
PubMed1996

Expression of cell adhesion molecules in lung cancer cell lines.

Cell adhesion mechanisms are among the basic aspects in organism development. Adhesion molecules are involved in the building of complex structures and of association of the tissue. They also mediate as substratum adhesion molecules and are involved in the building of the scaffold. The process of tumor growth and metastasis is a complex cascade of events (FIDLER 1989). For many of these steps the tumor cells must be able to change their degree of adherence. Tumor progression and metastatic dissemination are tightly linked with the ability of the tumor cells to interact with other cells and with the extracellular matrix. The first step of metastasis is the active migration of tumor cells into the surrounding tissue.

Antigens, CD↗
PubMed1997

The expression of VLA integrins in the human tonsilla palatina.

The integrin receptors are a family of transmembrane glycoproteins comprising non-covalent heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement and other cell, while their intracellular domains interact with the cytoskeleton. They participate in cell-matrix and cell-cell adhesion in many physiologically important processes including embryological development, hemostasis, thrombosis, wound healing, immune and nonimmune defense mechanisms, and in oncogenic transformation. This investigation was focused on the histological distribution of the beta 1-integrins in the human tonsil using an indirect immunoperoxidase method. Present data suggest that lymphocyte and antigen presenting cells (FDCs, IDCs, and macrophages) interact with each other following adhesion to extracellular matrix proteins (e.g. fibronectin) through their integrin receptors in order to carry out special immunological functions. In addition, stromal elements and epithelial components were shown to express VLA integrins providing interactions for tissue organization and compartmentalization.

Antibodies, Monoclonal↗
PubMed1999

Normalization of keratinocyte-type integrins during the establishment of the oral mucosa phenotype in vitro.

In stratified epithelia, integrins play a fundamental role in mediating basal cell attachment to a variety of extracellular matrix molecules. To assess whether keratinocyte-specific integrins are expressed in a similar way as in the normal situation also under in vivo related conditions, we processed oral mucosa equivalents consisting of keratinocytes and fibroblasts from non-cornified gingiva. In this model histomorphology, the expression of differentiation-specific keratins and keratinocyte-type integrins exhibited similarity to the tissue of origin. The stages of tissue normalization were assessed on frozen sections by indirect immunofluorescence. The initial activated stage (1 week) was characterized by (i) incomplete epithelial organization and a weak presence of the suprabasal mucosa type keratin K4, (ii) diffuse expression of the integrin chains beta 1 and alpha 6 and (iii) abundance of the wound healing-associated integrin alpha v throughout the whole epithelium. After 2 weeks, the increase in epithelial organization was characterized by (i) the presence of a basal and suprabasal cell compartment, (ii) extension of K4 in the suprabasal compartment, (iii) extended expression of the keratinocyte integrins beta 1 and alpha 6 and (iv) concentration of alpha v integrin underneath basal cells. Further normalization of tissue architecture was indicated by (i) a slight increase in K4 extension, (ii) appearance of keratinocyte integrins beta 1 and alpha 6 in basal and parabasal cells and (iii) interruption of the band-like alpha v integrin immunolocalization at the subepithelial site. The findings in the in vitro model system indicate that these oral mucosa equivalents exhibit similarities to the in vivo situation of non-cornified gingiva, thus rendering them a suitable model for the assessment of stages during epithelial reconstruction or in vivo relevant studies on material effects.

Antigens, CD↗
PubMed2000

Genetic analysis of integrin function in man: LAD-1 and other syndromes.

The integrins are cell membrane receptors composed of alpha and beta subunits which orchestrate adhesive events in all tissues of the body (Hynes, R.O., 1992. Integrins: versatility, modulation, and signalling in cell adhesion. Cell 69, 11-25; and Hynes, R.O., 1999. Cell adhesion: old and new questions. Trends Cell Biol. 9, M33-37). At present 18 alpha subunits and 8 beta subunits have been identified which are loosely organised into families. There are three inherited autosomal recessive diseases in man which involve germline mutations in genes coding for integrins. Leukocyte adhesion deficiency-1 (LAD-1) is the result of mutations in the beta2 subunit of the CD11/CD18 integrins, LFA-1, Mac-1, p150,95 and alphadbeta2. The bleeding disorder Glanzmann thrombasthenia is caused by mutations in either the alpha or beta subunit of the platelet integrin, alphaIIbbeta3. Thirdly, it is now recognised than one of the variants of the usually lethal skin blistering disorder, epidermolysis bullosa (JEB-PA), is caused by mutation in either the alpha or beta subunit of the epithelial hemidesmosome integrin, alpha6beta4. Many of the mutations cause defective alphabeta heterodimer formation. The majority of the beta subunit mutations are in the conserved N-terminal region known as the betaI domain. It is suggested that this region participates in alphabeta heterodimer formation.

Animals↗
PubMedDate not supplied

Mesothelium expression of integrins in vivo and in vitro.

OBJECTIVE: To characterize the expression of alpha subunits of integrin adhesion molecules in peritoneal tissue in vivo and in vitro. METHOD: Peritoneum from the anterior abdominal wall (n = 22) and the serosa of the posterior uterus (n = 11) was obtained from women of reproductive age without endometriosis who were undergoing surgery for benign conditions. Immunohistochemical studies were performed on serial sections of peritoneum from the anterior abdominal wall, the uterine serosa, mesothelial monolayer cultures, and peritoneum explants from the abdominal wall using monoclonal antibodies to alpha subunits of integrin adhesion molecules. Electron microscopy was performed to localize these adhesion molecules in the mesothelium. RESULTS: The mesothelial expression of alpha integrin subunits was identical in the anterior peritoneum and uterine serosa. In vivo the mesothelium strongly expressed alpha 2 and alpha 3 and variably expressed alpha 6. In the monolayer cultures there was moderate/strong staining for alpha 2, alpha 3, and alpha 5; there was minimal expression of alpha v. In the explants there was moderate/strong expression of alpha 2, alpha 3, alpha 5, and alpha v; alpha 6 was variably expressed. The ultrastructure of the mesothelium was unique in the anterior peritoneum, uterine serosa, and the monolayer cultures. The integrin subunits were distributed throughout the cytoplasm, were expressed in the plasma membrane, and were present on the surface (i.e., towards the peritoneal cavity) of the mesothelium. CONCLUSION: Integrins are expressed by the mesothelium of the peritoneum. The mesothelium expression of integrins in vivo differs from that of the mesothelium integrin expression in monolayer culture and explant culture.

Antigens, CD↗
PubMed1997

Comparison of integrin alpha chain expression in benign and malignant salivary gland tumors.

OBJECTIVE: This study investigates the distribution of the alpha chain of the integrin family of extracellular matrix receptors in a series of adenomas and carcinomas of salivary gland origin to determine if the malignant phenotype is associated with modification of the expression of these receptors. STUDY DESIGN: Cryostat sections of 36 tumor specimens were stained by a standard streptavidin-biotin-peroxidase technique using primary monoclonal antibodies against alpha 1-6 and alpha v integrin chains. The immunohistochemical reaction was scored using a three-point scale and the results were analyzed using Fisher's exact test. RESULTS: In salivary adenomas, alpha 2, alpha 3, alpha 4, alpha 6, and alpha v chains were widely expressed in most of the cases studied. The alpha 1 subunit was prominently expressed by the epithelial cells of Warthin's tumor, whereas a minority of pleomorphic adenomas showed immunoreactivity for this antigen. We observed alpha 5 subunit expression only in the mesenchymal-like component of pleomorphic adenomas. In salivary carcinomas, integrin alpha chain expression was heterogeneous, varying greatly between different histotypes and within the same histotype. The distribution of the antigens was similar to that of adenomas, except for the alpha 6 chain, which localized not only at the interface between cell and matrix, but also at sites of cell-cell contact. When the immunohistochemical levels of integrin alpha chain expression were compared in adenomas and carcinomas, expression significantly decreased for the alpha 6 and alpha v chains (p = 0.0007; p = 0.002, respectively). CONCLUSIONS: Loss of alpha 6 and alpha v integrin subunits occurring in salivary gland carcinomas could modify the adhesive properties of malignant cells, contributing to the invasive potential of these tumors.

Adenocarcinoma↗
PubMed1998

Altered expression of alpha 6 integrin subunit in oral squamous cell carcinoma and oral potentially malignant lesions.

The expression and distribution of integrin chains alpha 2, alpha 3, alpha 5, alpha 6, beta 1, beta 4, collagen type IV, laminin 1 and laminin 5 in oral squamous cell carcinoma (SCC) and oral keratoses with and without dysplasia (OL) have been studied by immunochemistry and western blotting. Focal interruptions of basement membrane protein staining were detected in SCC indicating a loss of continuity, whereas tumour nests were apparently completely surrounded by laminin 1, type IV collagen and laminin 5; the loss of basement membrane components in OL was found in only one specimen showing severe dysplasia. The localisation of integrins showed altered suprabasal and pericellular expression of the alpha 6 chain in all but one SCC, as well as in many OL samples, whereas the beta 4 subunit showed only a faint pericellular redistribution in SCC. In OL, beta 4 was often seen in a normal basally polarised distribution. Western blotting analysis confirmed that alpha 6 protein levels were abnormally high in cancerous lesions, whereas quantitative recovery of the beta 4 subunit in SCC was only minimal, suggesting a dissociation in the synthetic ratios of the two chains of the alpha 6 beta 4 heterodimer in SCC. Because alterations in the polarised expression of integrin alpha 6 beta 4 have been seen during epithelial tumour progression and wound healing, we suggest that the lack of restricted basal polarisation of alpha 6 could be an early but non-specific marker of oral malignancy, indicating that the generation of abnormal signals from the extracellular matrix may be involved.

Antigens, CD↗