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PubMed1996

Distribution of laminin variants and their integrin receptors in human secondary lymphoid tissue. Colocalization suggests that the alpha 6 beta 4-integrin is a receptor for laminin-5 in lymphoid follicles.

Laminins are a family of multifunctional basement membrane glycoproteins. Over the last years, many laminin isoforms have been characterized, which were shown to be composed of distinct combinations of variant alpha, beta and gamma chains. Some of these isoforms show remarkable tissue specificity, which suggests functional involvement in local processes. In this study the previously described mAb 4C7, which recognize epithelial basement membranes as well as endothelial basement membranes in lymphoid follicles, was identified as an anti-laminin-5 antibody. Using a set of mAbs against various variant laminin chains we established that specifically the gamma 2 chain of laminin-5 was confined to the endothelial basement membranes of vessels in lymphoid follicles, whereas other variant laminin chains were also expressed elsewhere in the lymphoid follicles, whereas other variant laminin chains were also expressed elsewhere in the lymphoid tissue. Additionally, the expression of the known integrin receptors of laminin-5 was also examined. The alpha 6 beta 4 integrin-receptor for laminin was found to be colocalized with the laminin-5 gamma 2 chain on the abluminal surface of endothelial cells, whereas the alpha 3 integrin chain could not be detected in lymphoid follicles. This finding suggests that the alpha 6 beta 4 integrin (and not the alpha 3 beta 1 integrin) serves as a laminin-5 receptor on endothelial cells in the follicular compartment of lymphoid tissue. Furthermore, alpha 6 beta 4 was also found in the same punctuated pattern on FDCs as laminin-5. The function of the laminin-alpha 6 beta 4 complex in this particular localisation is still obscure, but a role in the maintainance of the follicular compartment via hemidesmosome-like attachment sites is postulated.

Antibodies, Monoclonal↗
PubMed1996

Transfection of beta 4 integrin subunit into a neoplastic keratinocyte line fails to restore terminal differentiation capacity or influence proliferation.

Loss of expression of specific integrins is a feature of poorly differentiated oral squamous cell carcinomas (SCCs) and cell lines derived from them. In order to test whether there is a direct link between reduced alpha 6 beta 4 integrin expression and abnormal keratinocyte growth and differentiation we 'repaired' an SCC line. H376, by transfection of the beta 4 integrin subunit. We analysed five independent beta 4 transfectant clones and compared them with four empty vector control clones and with the parental cell line. Elevated cell surface expression of alpha 6 beta 4 was not correlated with changes in anchorage dependent or independent growth and was not sufficient to induce expression of the terminal differentiation marker, involucrin. Introduction of the beta 4 integrin subunit did not have a major effect on cell adhesion to laminin 1 or 5 and did not result in formation of stable anchoring contacts. We conclude that loss of alpha 6 beta 4 is not directly responsible for the abnormal behaviour of the H376 cell line.

Antigens, CD↗
PubMed1998

Down-regulation of laminin-binding integrins by 1 alpha,25-dihydroxyvitamin D3 in human melanoma cells in vitro.

In the present investigation the effect of 1 alpha,25(OH)2D3 on the expression of the integrin laminin receptor on the melanoma cell line SK-MEL-28 has been examined. The SK-MEL-28 cells were shown to contain high-affinity receptors for 1 alpha,25(OH)2D3 and cell proliferation was found to be inhibited in a dose-dependent manner in response to the hormone. Using monoclonal antibodies against the alpha 6-sub-unit of the integrin laminin receptor, immunocytochemistry demonstrated that exposure of cells to 1 alpha,25(OH)2D3 for 5 days caused a reduced staining intensity. This observation was further confirmed by dot blot analysis, where a dose-dependent decline of alpha 6 expression was obtained after treatment of the cells with 1 alpha,25(OH)2D3 for 6 days. FACS-analysis was performed in order to quantify this decline, and it was found that the level of alpha 6-subunits on the cell surface was reduced by more than 40%. Additional investigations including Northern blot analyses of poly(A)+RNA extracts also showed a dose-dependent reduction of alpha 6 mRNA. Interestingly, the decrease of alpha 6 expression on the surface of SK-MEL-28 melanoma cells was accompanied by a reduced ability of the cells to adhere to an artificial basement membrane. In conclusion, the present investigation shows that besides having an antiproliferative effect on the SK-MEL-28 melanoma cells, 1 alpha,25(OH)2D3 is also able to inhibit the surface expression of the alpha 6-subunit of the integrin laminin receptor. Moreover, the results strongly indicate that 1 alpha,25(OH)2D3 exerts its regulatory effect on the alpha 6-subunit at the transcriptional level rather than at the protein level.

Antigens, CD↗
PubMed2000

The autoantibodies to alpha 6 beta 4 integrin of patients affected by ocular cicatricial pemphigoid recognize predominantly epitopes within the large cytoplasmic domain of human beta 4.

This study was undertaken to characterize the antigenic determinants recognized by the autoantibodies of patients with ocular cicatricial pemphigoid (OCP). OCP is a subepithelial, blistering, autoimmune disease that mainly affects the conjunctiva and other mucous membranes. We previously demonstrated that a cDNA clone, isolated from a keratinocyte expression library by using immunoaffinity-purified OCP autoantibody, encoded the cytoplasmic domain of beta 4 integrin subunit. Our subsequent studies showed that sera from all the OCP patients that were tested recognize the human beta 4 integrin subunit. To identify the prevalent epitopes of the anti-beta 4 autoantibodies of OCP, we have used cell lines transfected with vectors encoding a wild-type beta 4 subunit, a tailless beta 4 subunit, or a beta 4 subunit lacking the extracellular domain. Nontransfected cell lines were used as controls. Lysates from these cell lines were analyzed with OCP sera, IgG fractions from OCP sera, and immunoaffinity-purified OCP autoantibodies. Abs to extracellular and cytoplasmic domains of human beta 4 integrin were used as positive controls, whereas normal human sera and normal human IgG fractions were used as negative controls. The reactivity of OCP Abs was determined by using immunoblotting, immunoprecipitation, and FACS analysis. The results of this study indicate that OCP sera, OCP IgG fractions, and immunoaffinity-purified OCP autoantibodies react with the intracellular and not the extracellular domain of human beta 4 integrin subunit. In vitro cell culture experiments demonstrated that OCP autoantibody binds to the cytoplasm of the cells. The relevance of these findings to the pathogenesis of OCP is discussed.

Animals↗
PubMed2001

The metastatic odyssey: the integrin connection.

This article explores the mechanistic basis of carcinoma progression by focusing on the contribution of integrins. Integrins are essential for progression because of their ability to mediate physical interactions with extracellular matrices and their ability to regulate signaling pathways that control actin dynamics and cell movement, and for growth and survival. This article centers on a6 integrins (a6B1 and a6B4), which are receptors for the laminin family of basement membrane components. Numerous studies have implicated these integrins in cancer progression and have provided a rationale for studying the mechanistic basis of their contribution to aggressive disease.

Actins↗
PubMed1992

Overexpression of the A9 antigen/alpha 6 beta 4 integrin in head and neck cancer.

A tumor-associated antigen detected by monoclonal antibody UM-A9 raised against a cultured cell line from a patient with an aggressive SCC of the oral cavity has been defined. The A9 antigen is abnormally expressed in squamous cancers, with loss of basal polarization and increased intensity of expression distinguishing malignant from normal cells. A minority of cultured SCC cell lines and about one third of fresh tumors exhibit polarized A9 expression. The increased intensity and loss of polarized expression of A9 antigen in recurrent and metastatic tumor cell lines when compared with primary or early tumor cell lines from the same patients indicated an association of altered expression with tumor progression. When A9 expression was evaluated in frozen tumor sections, three patterns of expression representing increasing intensity and loss of polarization were observed. Patients whose tumors exhibited the most intense A9 antigen expression had a higher rate of early relapse than patients whose tumors exhibited low intensity and polar expression. Loss of blood group antigen expression was also associated with poor prognosis, and together high A9 antigen expression and loss of blood group defined a group of patients at high risk of early relapse. The A9 antigen is immunologically and biochemically identical to the alpha 6 beta 4 integrin. The association of high expression of the A9/alpha 6 beta 4 integrin as a prognostic factor is supported by similar findings with a mouse model system. The mouse tumor-associated antigen, TSP-180, which is also an alpha 6 beta 4 integrin, distinguishes highly metastatic tumor cells from nonmetastatic variants of the same tumor line. In SCC, the alpha 6 beta 4 integrin contributes to attachment to laminin since anti-alpha 6 subunit specific antibody blocks cell attachment and only the beta 4 subunit is found in association with the alpha 6 subunit in these cells. Similar findings were obtained in colon carcinomas. Antibodies and peptides that block laminin attachment may lead to the development of antimetastatic agents for squamous carcinomas. The beta 4 subunit is unique from other integrins in that it has an unusually long cytoplasmic domain, the function of which is not known. The beta 4 subunit is heavily phosphorylated under conditions that favor anchoring and terminal differentiation in normal keratinocytes. Paradoxically the beta 4 subunit is also heavily phosphorylated in tumor cells, which are highly migratory and immortalized.(ABSTRACT TRUNCATED AT 400 WORDS)

Antigens, Neoplasm↗
PubMed1992

Tumor antigen phenotype, biologic staging, and prognosis in head and neck squamous carcinoma.

Prior studies of alterations in tumor expression of normal blood group antigens and A9/alpha 6 beta 4 integrin, an extracellular matrix receptor, have suggested that these immunohistologic markers reflect the biologic aggressiveness of head and neck squamous carcinomas. To confirm these preliminary observations, prospective long-term follow-up of 82 previously untreated head and neck squamous carcinoma patients was performed. All patients were treated with conventional therapy. Median follow-up was 57 months. Tumor immunohistology for ABH blood group and A9/alpha 6 beta 4 integrin expression was performed and correlated with measures of host cellular immunity, disease-free survival, and overall survival. Loss of blood group expression and high A9/alpha 6 beta 4 integrin expression were each directly related to an increased frequency of early tumor recurrence. The combination of both variables was significantly associated with both disease-free (P = .029) and overall survival (P = .05). Increased expression of A9/alpha 6 beta 4 was associated with impaired T-lymphocyte function (P = .005), and loss of blood group expression was associated with decreased peripheral blood levels of CD8+ T-lymphocytes (P = .013). The findings suggest that these phenotypic characteristics of antigen expression in head and neck squamous carcinomas are important markers of biologically aggressive cancers and impaired host immune response. The clinical use of these biologic staging parameters in the initial assessment of patients should allow selection of more aggressive primary treatment strategies for individual patients.

ABO Blood-Group System↗
PubMedDate not supplied

New insights into the autoantibody-mediated mechanisms of autoimmune bullous diseases and urticaria.

The skin is a common target of cellular and/or antibody mediated pathological immune responses. Pemphigoids, pemphigus vulgaris and dermatitis herpetiformis are bullous disease due to autoantibodies targeting specific proteins of the skin. The pemphigoid autoantigens are the BP180 and the BP230 antigens, two components of the epithelial basement membrane zone. Additional antigenic targets reported in a portion of patients are laminin 5, the alpha6 subunit of the hemidesmosomal integrin alpha6beta4 and a glycoprotein termed p200. The epidermal and mucosal epithelial cells detachment (acantholysis) characteristic of pemphigus vulgaris is induced by autoantibodies directed against the desmoglein 3 and 1. The desmogleins are desmosomal cadherins, which play a major role in the cell-to-cell adhesion. Dermatitis herpetiformis is regarded as cutaneous phenotype of coeliac disease. A novel autoimmune hypothesis of coeliac disease links wheat gliadin and tissue transglutaminase (TG2) in the gut, which leads to T cell response and IgA autoantibody formation. In dermatitis herpetiformis skin the target for IgA deposition seems to be epidermal TG3. Urticaria is a complex syndrome caused by both immune and non-immune mechanisms. In a subsets of patients with chronic urticaria mast cell degranulation is induced by autoantibodies directed against the a-subunit of the high-affinity IgE receptor, and/or the IgE.

Autoantibodies↗
PubMed1991

The A9 antigen associated with aggressive human squamous carcinoma is structurally and functionally similar to the newly defined integrin alpha 6 beta 4.

We previously reported that altered expression of the A9 antigen (defined by monoclonal antibody UM-A9) is a predictive marker of early recurrence and progression of squamous cell carcinoma (SCC). In normal squamous cells A9 expression is limited to the site of contact with the basement membrane in vivo and the culture surface in vitro, whereas aggressive SCCs exhibit loss of polarity and increased intensity of A9 expression. The potential relationship of the A9 antigen to structures known to be involved in cell adhesion was analyzed by immunobiochemical and cell adhesion assays. UM-A9 precipitates a complex of protein chains reminiscent of the alpha and beta heterodimer glycoproteins that characterize the integrin family of extracellular matrix receptors. Proteins were isolated from A9-positive cells using UM-A9 and well-defined antibodies specific for integrin alpha and beta chains. UM-A9, anti-alpha 6, and anti-beta 4 monoclonal antibodies (mAbs) all precipitated proteins with comparable electrophoretic mobilities. Furthermore, UM-A9 mAb precleared the SCC alpha 6 beta 4 integrin complex isolated with anti-alpha 6 or anti-beta 4 mAbs but not that isolated by anti-beta 1 mAb. The isoelectric points of the A9 complex chains were consistent with those reported for alpha 6 and beta 4. Three of the polypeptide chains (140, 175, and 205 kDa) precipitated by UM-A9 showed peptide homology to one another and to the beta 4 chain precipitated by mAb 439-9B. The A9/alpha 6 subunit is composed of 125- and 30-kDa chains and was distinguished from beta 4 and beta 1 chains by its peptide map and isoelectric point. UM-A9 binds to an epitope common to the beta 4 subunits since in pulse-chase analysis the beta 4 species are precipitated at an early time point, whereas detection of alpha-subunit synthesis is detected during assembly of the mature complex. Immunoprecipitation and preclearing experiments demonstrated that in SCC the alpha 6 subunit is associated primarily with the beta 4 species and not with the 130-kDa beta 1 subunit. In cell adhesion assays on extracellular matrix proteins, the alpha 6-specific GoH3 mAb inhibited binding of SCC to laminin, suggesting that alpha 6 beta 4 may function as a laminin receptor in SCC. These data and our prior observations showing an association between altered A9 expression and early recurrence in SCC provide the first evidence that altered expression of alpha 6 beta 4 integrin is associated with the clinical behavior of human squamous cell carcinomas.

Antigens, Neoplasm↗
PubMed1989

Analysis of the tumor-associated antigen TSP-180. Identity with alpha 6-beta 4 in the integrin superfamily.

The tumor-associated antigen complex, TSP-180, was previously defined in carcinoma cell lines and found to be expressed in higher amounts in tumor than in normal tissue. Here, the mouse TSP-180 complex is shown to consist of three related proteins (bands 1, 2, and 3) associated with a distinct protein (band 5) that is probably derived from a precursor protein (band 4). All of these proteins are cell surface glycoproteins, and the largest protein (band 1) can be readily labeled with 32PO4. The mouse TSP-180 complex described here strongly resembles the recently described human integrin alpha 6-beta 4 complex. This homology was confirmed using two distinct rat anti-alpha 6 monoclonal antibodies, each of which recognized both human alpha 6-beta 4 and mouse TSP-180 complexes. Furthermore, the TSP-180 band 5 protein (mouse alpha 6) had an N-terminal sequence identical to that of human alpha 6. Finally, two different monoclonal antibodies are described, 346-11A and 439-9B, which directly recognize the multiple forms of mouse and human beta 4 proteins, respectively.

Animals↗
PubMed1993

Ultrastructural findings in epidermolysis bullosa.

BACKGROUND AND DESIGN: Electron microscopy of skin provides diagnostic criteria for distinguishing the simplex, junctional, and dystrophic forms of inherited epidermolysis bullosa (EB). The plane of cleavage in blister formation indicates the localization of structural weakness within the epidermis and basement membrane zone, and, together with ultrastructural changes in affected skin, these are clues to the underlying genetic bases for these disorders. Skin biopsy specimens from individuals with EB were evaluated by electron microscopy to identify structural changes and determine the subtype of EB. RESULTS: Discrete, circumscribed clumps of keratin filaments present in the basal keratinocytes are pathognomonic for EB simplex Dowling-Meara. These and other observations of keratin filament disruption have led to the identification of mutations in keratin genes in Dowling-Meara and Koebner forms of EB simplex. Changes in the density and structure of anchoring fibrils and the relative amount of type VII collagen detected by immunostaining of the dermoepidermal junction in dystrophic EB have led to sequencing of mutations in the type VII collagen gene. Although mutations in junctional EB have not been reported, findings of structural alterations in hemidesmosomes and immunohistochemical studies of kalinin (BM600 and epiligrin), and in junctional EB with pyloric atresia alterations in the integrin alpha 6 beta 4, indicate molecules involved in basal keratinocyte adhesion to the basement membrane that are candidate genes for junctional EB. CONCLUSIONS: Electron microscopy of skin when correlated with mutations in EB will help us understand the significance of these structural molecules in normal skin and the pathogenesis of EB.

Antigens, Surface↗
PubMed1994

Loss of co-localization of alpha 6 beta 4 integrin and collagen VII in bladder cancer.

In normal epithelial cells, the alpha 6 beta 4 integrin co-localizes with the hemidesmosomal anchoring complex on the basolateral surface of basal cells. We studied the co-expression of alpha 6 beta 4 integrin with collagen VII, a component of the hemidesmosomal anchoring complex, in normal bladder tissues and in bladder cancers. In normal bladder, the alpha 6 beta 4 integrin co-localized with collagen VII at the junction of the basolateral surface of the basal urothelial cells and the lamina propria. In five of six noninvasive bladder cancers, the localization of collagen VII remained unchanged, found at the junction of the basal cells and the papillary connective tissue. However, in these tumors the alpha 6 beta 4 expression was not polarized and was expressed on suprabasal as well as basal cells. In invasive bladder cancers, the majority (25 of 30) showed either loss of alpha 6 beta 4 and/or collagen VII expression or showed a lack of co-localization of alpha 6 beta 4 and collagen VII. Our results show derangement of the co-localization of these two components of the hemidesmosomal anchoring complex is a consistent event in bladder cancer. Furthermore, the degree of derangement increases in invasive cancers. Loss of co-expression and co-localization of alpha 6 beta 4 and collagen VII may predispose cancer cells to local invasion and may facilitate metastasis as well.

Antigens, Neoplasm↗
PubMed1995

Dermabrasive scar revision. Immunohistochemical and ultrastructural evaluation.

BACKGROUND: Dermabrasion of facial scars 4-8 weeks after injury frequently completely eliminates visible evidence of scar formation. However, efforts to define the cellular and structural mechanisms by which this phenomenon occurs have been limited in their success. OBJECTIVE: We investigated wound healing after dermabrasive scar revision. METHODS: The surgical scars of seven patients were abraded 6-8 weeks after injury. Comparative electron microscopic and immunohistochemical studies were performed on punch biopsy specimens taken before and after the dermabrasion. Ultrastructural changes in the basement membrane components and dermal structures were evaluated. Monoclonal antibody staining techniques were used to observe the presence, location, and temporal expression of tenascin, epiligrin, cadherins, and integrin subunits. RESULTS: We observed: 1) an increase in collagen bundle density and size with a tendency toward unidirectional orientation of fibers parallel to the epidermal surface, 2) an upregulation of tenascin expression throughout the papillary dermis, and 3) expression of alpha-6/beta-4 integrin subunit on the keratinocytes throughout the stratum spinosum. CONCLUSIONS: The mechanisms by which dermabrasive scar revision alters the events of primary cicatrix formation include modification of extracellular ligand expression, thereby influencing epithelial cell-cell interaction, and reorganization of connective tissue.

Antigens, Surface↗
PubMed1995

Reassembly of the alpha 6 beta 4 integrin and laminin in rabbit corneal basement membrane after excimer laser surgery: a 12-month follow-up.

We investigated the reassembly of hemidesmosomes and epithelial basement membrane (BM) following experimental excimer laser photorefractive keratectomy (PRK) immunohistochemically using monoclonal antibodies against integrin subunits alpha 6 and beta 4 (hemidesmosome components) or laminin (a BM component). The rabbits were killed 3 days, 1, 3, 6, or 12 months after a -5.0 D PRK. For untreated corneas, integrin subunits alpha 6 and beta 4 and laminin showed normal distribution at the basal aspect of the basal epithelial cells, appearing as a distinct fluorescent line. The alpha 6 subunit was also found at the basolateral membranes of the basal epithelial cells. The average healing time for the PRK wound was 6 days, but secondary epithelial defects occurred in 17 of 22 corneas. The subepithelial labeling for all the antibodies investigated showed focal discontinuities at the level of the BM in the wound area up to 12 months after PRK. After 6 months, secondary epithelial defects were very rare. In addition to the patchy subepithelial labeling, lamellar anterior stromal immunoreaction for alpha 6 and beta 4 integrin subunits was also present 1-12 months after PRK. Laminin was also observed in the anterior stroma 1-6 months after PRK. Our results suggest that focal discontinuities of hemidesmosomes or BM observed immunohistochemically in the unexpectedly slow-healing PRK wound areas might correlate with the epithelial healing problems observed in most rabbits.

Animals↗
PubMed1995

Adhesion mechanisms in liver metastasis formation.

Our results strongly indicate that integrin mediated adhesion between metastasizing tumour cells and hepatocytes has a decisive role in the formation of liver metastases. However, it is also clear that tumour cells may use different adhesion pathways and furthermore that the adhesion may be modulated by several factors. The role of adhesion has been demonstrated most clearly for LFA1 on T cell hybridomas, which interacts with ICAM1 present in the liver. Alternative pathways must exist, however, given the high invasive capacity of ESb cells, which is apparently LFA1 independent. A possible alternative is adhesion to fibronectin, which is present in abundance on the hepatocyte surface, both in vivo and in vitro. As there is no basement membrane under the endothelium of liver microvessels, so that tumour cells cannot adhere to laminin and collagen type IV as in other organs, adhesion to this fibronectin may be particularly important for metastasis to the liver. Many tumour types can use this pathway, and many different fibronectin receptors may be involved, including VLA-4, VLA-5 and several alpha V integrins. For carcinomas there is another possibility: Fibronectin receptor deficient cells may still adhere using the integrin alpha 6 beta 4, which binds to an unknown ligand present on the hepatocyte surface. Modulation of adhesion can occur in several ways. One example is steric hindrance by mucins that may strongly affect and even abrogate adhesion, despite high levels of appropriate integrins. Another is the activation required for integrins on lymphoma cells, the best known example of which is the activation of LFA1 on T cell hybridomas. It will be evident, therefore, that the role of adhesion in the formation of liver metastases can only be fully understood if the complete set of adhesion molecules on the tumour cells is known as well as their functional status and the possible effects of both cellular and extracellular modulating factors.

Antigens, Surface↗
PubMed1995

Increase in suprabasilar integrin adhesion molecule expression in human epidermal neoplasms accompanies increased proliferation occurring with immortalization and tumor progression.

In a previous prospective study of 80 patients with squamous cell carcinoma of the upper aerodigestive tract, a progressive increase in expression of the integrin cell adhesion molecule alpha 6 beta 4 in suprabasilar cell layers of the tumor parenchyma was associated with an increase in early recurrence after therapy. In this study, we determined the relationship of the altered expression pattern of the integrin to changes occurring during benign, invasive, or metastatic stages of tumor development. Suprabasilar expression of integrin alpha 6 beta 4 appeared with neoplastic transformation in benign squamous papillomas, but homogeneous expression occurred more frequently in the parenchyma of primary and metastatic squamous cell carcinomas. The variation in the extent of suprabasilar integrin expression among the tumors corresponded to the variation in the population undergoing proliferation as determined by two independent markers of proliferation. Integrin expression was quantified in primary, HPV 16 DNA-immortalized, and v-ki-ras oncogene-transformed keratinocytes, and the pattern of expression was compared with cell cycle progression. Primary keratinocyte lines showed a bimodal distribution of integrin expression, with one population showing decreased integrin expression, cell size, and a block of cell cycle progression consistent with differentiation, whereas another population exhibited high integrin expression and full progression through the cell cycle, consistent with proliferation. HPV-immortalized and v-ki-ras-transformed cell lines undergoing continuous proliferation exhibited uniformly strong integrin expression, which was similar in intensity to that observed in the proliferating population of normal keratinocytes. Similar increases in expression of two additional integrins, alpha 2 beta 1 and alpha 3 beta 1, occurred along with integrin alpha 6 beta 4 in tissue specimens and cell lines derived from neoplasms. Thus, epidermal neoplasms display an increase in a population of cells exhibiting constitutive expression of a repertoire of integrins, which is similar to that found transiently in the acute phase of epidermal wound healing, a physiological response in which hyperproliferation, retention of multiple layers of proliferating cells, and migration occur. The association of a progressive increase in suprabasilar expression of these integrins with early tumor recurrence and advanced neoplasia suggests that constitutive expression and function of the same repertoire of integrins may be advantageous, rather than sufficient, for tumor progression.

Antigens, Surface↗
PubMed1996

Selective changes in laminin adhesion and alpha 6 beta 4 integrin regulation are associated with the initial steps in keratinocyte maturation.

In skin, the distribution of integrins is compartmentalized. Whereas the alpha 6 beta 4 integrin complex is polarized to the basal portion of proliferating cells in the basal layer juxtaposed to the basement membrane, alpha 3 beta 1 integrin receptors are localized on the cell surface surrounding basal and suprabasal cells, suggesting beta 1 integrins mediate both cell-matrix and cell-cell interactions. As initiation of maturation in skin is associated with the detachment of cells from the basement membrane, the early loss of alpha 6 beta 4, but not alpha 3 beta 1, integrin expression could be a determining factor in the transition from the proliferating to a differentiating keratinocyte. We have studied the regulation of adhesion potential and integrin expression during differentiation of mouse basal keratinocytes culture in 0.05 mM Ca2+ medium and induced to differentiate in 0.12 mM Ca2+ medium. Within 12-24 h after elevation of Ca2+, a selective loss of the alpha 6 beta 4 integrin complex is associated with the induction of the spinous cell marker keratin 1. This early differentiation phenotype coincides with loss of cell attachment mediated by alpha 6 beta 4 to laminins 1 and 5 but not a fibronectin or collagen IV. Selective loss of attachment to laminin is also detected in spinous cells isolated from newborn epidermis in vivo. The loss of alpha 6 and beta 4 protein expression is a consequence of transcriptional and posttranscriptional events, including reduction in mRNA transcripts, reduced synthesis of the alpha 6 protein, and enhanced processing of the alpha 6 and beta 4 chains as determined by Western blots and pulse-chase experiments in metabolically labeled keratinocytes. Selective processing of the beta 4 intracellular domain is detected before loss of beta 4 from the cell surface in basal keratinocytes, and this process is accelerated during differentiation. Whereas early keratinocyte maturation is linked to the selective loss of the alpha 6 beta 4 complex, loss of both beta 1 and beta 4 integrin mRNA and protein occurs as cells proceed to later stages in the differentiation program as induced by 0.5 mM Ca2+ or suspension culture. These conditions are characterized by accelerated expression of transglutaminase; reduced keratin 1 protein; loss of adhesion to fibronectin, laminin 1, laminin 5, and collagen IV; and rapid cell death. Contributing to the down-regulation of beta 1 integrins during terminal differentiation is a selective sensitivity of alpha 3 beta 1 but not alpha 6 beta 4 to down-regulation by transforming growth factors beta 1 and beta 2, factors that are also expressed differentially in normal skin. This study indicates that down-regulation of the alpha 6 beta 4 but not beta 1 integrins occurs during the initial steps of keratinocyte differentiation and is associated with detachment from the laminin matrix. Such changes could contribute an important signal to initiate the process of terminal keratinocyte differentiation.

Animals↗