Differentiation of human skeletal muscle stem cells into odontoblasts is dependent on induction of α1 integrin expression.

Skeletal muscle stem cells represent an abundant source of autologous cells with potential for regenerative medicine that can be directed to differentiate into multiple lineages including osteoblasts and adipocytes. In the current study, we found that α7 integrin-positive human skeletal muscle stem cells (α7(+)hSMSCs) could differentiate into the odontoblast lineage under specific inductive conditions in response to bone morphogenetic protein-4 (BMP-4). Cell aggregates of FACS-harvested α7(+)hSMSCs were treated in suspension with retinoic acid followed by culture on a gelatin scaffold in the presence of BMP-4.

Transcriptional profiling identifies upregulated genes following induction of epithelial-mesenchymal transition in squamous carcinoma cells.

During the progression of head and neck squamous cell carcinoma (HNSCC), the induction of an epithelial-mesenchymal transition (EMT) program may play a critical role in the dissemination of cells from the primary tumor to distant metastatic foci. The process of EMT involves the activation of several important genes and pathways to help maintain survival and growth and evolve into highly invasive and metastatic variants. In this study, expression microarray analysis identified a set of 145 upregulated genes in EMT-like HNSCC cells.

Bcl-2 overexpression induces a partial epithelial to mesenchymal transition and promotes squamous carcinoma cell invasion and metastasis.

Evidence shows that Bcl-2 family members play a direct role in the development of some human malignancies. However, the mechanism by which Bcl-2 may influence tumor cell invasion and metastasis remains unclear. Ectopic overexpression of Bcl-2 in the human squamous carcinoma cell line HSC-3 enhanced tumorigenicity and experimental pulmonary metastasis.

Sdc1 negatively modulates carcinoma cell motility and invasion.

During cancer progression, tumor cells eventually invade the surrounding collagen-rich extracellular matrix. Here we show that squamous cell carcinoma cells strongly adhere to Type I collagen substrates but display limited motility and invasion on collagen barriers. Further analysis revealed that in addition to the alpha2beta1 integrin, a second collagen receptor was identified as Syndecan-1 (Sdc1), a cell surface heparan sulfate proteoglycan.

Analysis of human muscle stem cells reveals a differentiation-resistant progenitor cell population expressing Pax7 capable of self-renewal.

Studies using mouse models have established a critical role for resident satellite stem cells in skeletal muscle development and regeneration, but little is known about this paradigm in human muscle. Here, using human muscle stem cells, we address their lineage progression, differentiation, migration, and self-renewal. Isolated human satellite cells expressed alpha7-integrin and other definitive muscle markers, were highly motile on laminin substrates and could undergo efficient myotube differentiation and myofibrillogenesis.

STAT3 signaling is induced by intercellular adhesion in squamous cell carcinoma cells.

The signal transducer and activator of transcription-3 (STAT3) frequently activated during tumor progression has been linked to enhanced cell growth. In squamous cell carcinoma of the head and neck (HNSCC), STAT3 signaling has been shown to inhibit apoptosis and induce a more aggressive phenotype through the activation of specific signaling pathways. In the present study, we have examined the potential mechanism by which cell-cell contact initiates STAT3 activation.

Modulation of satellite cell adhesion and motility following BMP2-induced differentiation to osteoblast lineage.

Quiescent satellite cells represent pluripotent stem cells capable of differentiating into other lineages. To define the potential changes in adhesion and motility in these differentiating cells, we utilized an established model system of murine-derived satellite cells induced with BMP2 to undergo osteoblastic differentiation. When mouse myogenic satellite cells were treated with BMP2, myogenesis was inhibited, and interaction with extracellular matrix ligands was altered.

alpha7 integrin expressing human fetal myogenic progenitors have stem cell-like properties and are capable of osteogenic differentiation.

During muscle development, precursor cells fuse to form myofibers. Following injury in adult muscle, quiescent satellite cells become activated to regenerate muscle in a fashion similar to fetal development. Recent studies indicate that murine skeletal myoblasts can differentiate along multiple cell lineages including the osteoblastic pathway.

Alpha7 integrin expression is negatively regulated by deltaEF1 during skeletal myogenesis.

Alpha7 integrin levels increase dramatically as myoblasts differentiate to myotubes. A negative regulatory element with putative sites for deltaEF1 is present in the alpha7 proximal promoter region. To define the role of deltaEF1 in regulating alpha7 integrin expression, we overexpressed deltaEF1 in C2C12 myoblasts.

Tumor cell invasion and survival in head and neck cancer.

Squamous cell carcinoma (SCC) is the primary tumor type in head and neck cancer. Typically, these tumor cells show persistent invasion that frequently leads to local recurrence and distant lymphatic metastasis. The process of invasion involves concurrent infiltration and destruction of adjacent tissues.

Integrin engagement differentially modulates epithelial cell motility by RhoA/ROCK and PAK1.

Integrin-ligand binding regulates tumor cell motility and invasion. Cell migration also involves the Rho GTPases that control the interplay between adhesion receptors and the cytoskeleton. We evaluated how specific extracellular matrix ligands modulate Rho GTPases and control motility of human squamous cell carcinoma cells.

Adhesion-mediated squamous cell carcinoma survival through ligand-independent activation of epidermal growth factor receptor.

The survival and growth of squamous epithelial cells require signals generated by integrin-matrix interactions. After conversion to squamous cell carcinoma, the cells remain sensitive to detachment-induced anoikis, yet in tumor cell aggregates, which are matrix-deficient, these cells are capable of suprabasal survival and proliferation. Their survival is enhanced through a process we call synoikis, whereby junctional adhesions between neighboring cells generate specific downstream survival signals.

Promoter methylation regulates cadherin switching in squamous cell carcinoma.

Cadherins are cell adhesion molecules that modulate the epithelial phenotype and regulate tumor invasion. To identify the role of promoter methylation in regulating E-cadherin expression and in the "switching" of cadherins in oral squamous cell carcinoma (SCC), we studied 14 cell lines for cadherin expression. Immunoblotting revealed that only two (HOC-313 and HA-376) showed strong up-regulation of N-cadherin, and neither expressed E-cadherin.

Regulation of alpha7 integrin expression during muscle differentiation.

Expression of the laminin-binding alpha7 integrin is tightly regulated during myogenic differentiation, reflecting required functions that range from cell motility to formation of stable myotendinous junctions. However, the exact mechanism controlling alpha7 expression in a tissue- and differentiation-specific manner is poorly understood. This report provides evidence that alpha7 gene expression during muscle differentiation is regulated by the c-Myc transcription factor.

The beta1 cytoplasmic domain regulates the laminin-binding specificity of the alpha7X1 integrin.

During muscle development, the laminin-specific alpha7 integrin is alternatively spliced in the putative ligand-binding domain to yield either the alpha7X1 or the alpha7X2 variant. The relative level of alpha7X1 and alpha7X2 is developmentally regulated. Similarly, the partner beta1 integrin cytoplasmic domain is converted from the beta1A to the beta1D splice variant.

The extracellular matrix protein betaIG-H3 is expressed at myotendinous junctions and supports muscle cell adhesion.

Molecules of the extracellular matrix (ECM) play important roles in the development and maintenance of myotendinous junctions (MTJs), specialized regions of muscle to bone union. In this report we provide evidence that skeletal muscle cells synthesize the collagen- and fibronectin-binding ECM protein betaIG-H3 and that betaIG-H3 is localized to MTJs. In situ hybridization experiments revealed that during E16.

Oral mucosal carcinogenesis in SENCAR mice.

Animal models of oral carcinogenesis have been developed but most use the hamster buccal pouch or rat oral mucosa. With completion of human and murine genome sequencing, the development of a mouse model of oral carcinogenesis may prove useful for future genomic studies of oral carcinogenesis. To achieve this objective, 30 SENCAR mice were initiated by brush application of palatal, buccal and tongue mucosa with 200 nmol 7,12-dimethylbenz[a]anthracene (DMBA) using 3 treatment regimens, and promoted by brush application with 5 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) for a total of 28 weeks.

Dominant-negative E-cadherin alters adhesion and reverses contact inhibition of growth in breast carcinoma cells.

Cadherins play a crucial role in epithelial morphogenesis and mediate intercellular adhesion. These receptors bind catenins and are involved in signal transduction pathways that regulate cell growth and apoptosis, and are frequently down-regulated in invasive and metastatic carcinomas. In order to assess the role of E-cadherin in cell adhesion and growth, we transfected MCF-7 cells, a human breast cancer cell line, with a dominant-negative construct of E-cadherin (H-2kd-E-cad).