The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms/processes that control differentiation of vascular smooth muscle cells (SMC) during normal development and maturation of the vasculature, as well as how these mechanisms/processes are altered in vascular injury or disease. A major challenge in understanding differentiation of the vascular SMC is that this cell can exhibit a wide range of different phenotypes at different stages of development, and even in adult organisms the cell is not terminally differentiated. Indeed, the SMC is capable of major changes in its phenotype in response to changes in local environmental cues including growth factors/inhibitors, mechanical influences, cell-cell and cell-matrix interactions, and various inflammatory mediators. There has been much progress in recent years to identify mechanisms that control expression of the repertoire of genes that are specific or selective for the vascular SMC and required for its differentiated function. One of the most exciting recent discoveries was the identification of the serum response factor (SRF) coactivator gene myocardin that appears to be required for expression of many SMC differentiation marker genes, and for initial differentiation of SMC during development. However, it is critical to recognize that overall control of SMC differentiation/maturation, and regulation of its responses to changing environmental cues, is extremely complex and involves the cooperative interaction of many factors and signaling pathways that are just beginning to be understood. There is also relatively recent evidence that circulating stem cell populations can give rise to smooth muscle-like cells in association with vascular injury and atherosclerotic lesion development, although the exact role and properties of these cells remain to be clearly elucidated. The goal of this review is to summarize the current state of our knowledge in this area and to attempt to identify some of the key unresolved challenges and questions that require further study.

Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease

INTRODUCTION 487 MORPHOLOGY AND OBSERVATION OF FOCAL ADHESIONS 488 FORMATION OF FOCAL ADHESIONS 490 DYNAMICS OF FOCAL ADHESION COMPONENTS ...... 491

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Focal adhesions: Transmembrane junctions between the extracellular matrix and the cytoskeleton

The restricted view of tumour progression as a multistep process defined by the accumulation of mutations in cancer cells has largely ignored the substantial contribution of the tumour microenvironment to malignancy. Even though the seed and soil hypothesis of Paget dates to 1889, it has been less than two decades since researchers have included the tumour microenvironment in their analyses of tumour progression. What have we recently learned from studying tumour-stroma interactions, and will this help to define new targets for therapy?

Friends or foes - bipolar effects of the tumour stroma in cancer.

Fibronectins are large glycoproteins that have been implicated in a wide variety of cellular properties, particularly those involving the interactions of cells with extracellular materials. These properties include cell adhesion, morphology, cytoskeletal organization, migration, differentiation, oncogenic transformation, phagocytosis, and hemostasis. During the past several years, investigations in many laboratories have analyzed the expression, functions, and structure of fibronectins. These studies have revealed that fibronectins have a complex molecular structure consisting of multiple specific binding sites, and the complex biological phenomena in which fibronectins participate can now be considered in terms of this structure. In this brief article we will review the current understanding of the structure and properties of fibronectins. Because a number of comprehensive reviews on various aspects of fibronectins have been published (1-13), we shall focus on overall concepts, recent developments and promising future research directions in this rapidly expanding field.

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Fibronectins: multifunctional modular glycoproteins.

Maintenance of epithelial tissues needs the stroma. When the epithelium changes, the stroma inevitably follows. In cancer, changes in the stroma drive invasion and metastasis, the hallmarks of malignancy. Stromal changes at the invasion front include the appearance of myofibroblasts, cells sharing characteristics with fibroblasts and smooth muscle cells. The main precursors of myofibroblasts are fibroblasts. The transdifferentiation of fibroblasts into myofibroblasts is modulated by cancer cell-derived cytokines, such as transforming growth factor-beta (TGF-beta). TGF-beta causes cancer progression through paracrine and autocrine effects. Paracrine effects of TGF-beta implicate stimulation of angiogenesis, escape from immunosurveillance and recruitment of myofibroblasts. Autocrine effects of TGF-beta in cancer cells with a functional TGF-beta receptor complex may be caused by a convergence between TGF-beta signalling and beta-catenin or activating Ras mutations. Experimental and clinical observations indicate that myofibroblasts produce pro-invasive signals. Such signals may also be implicated in cancer pain. N-Cadherin and its soluble form act as invasion-promoters. N-Cadherin is expressed in invasive cancer cells and in host cells such as myofibroblasts, neurons, smooth muscle cells, and endothelial cells. N-Cadherin-dependent heterotypic contacts may promote matrix invasion, perineural invasion, muscular invasion, and transendothelial migration; the extracellular, the juxtamembrane and the beta-catenin binding domain of N-cadherin are implicated in positive invasion signalling pathways. A better understanding of stromal contributions to cancer progression will likely increase our awareness of the importance of the combinatorial signals that support and promote growth, dedifferentiation, invasion, and ectopic survival and eventually result in the identification of new therapeutics targeting the stroma.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/path.1398

Role of tissue stroma in cancer cell invasion.

The expression of several differentiation markers in normal human mammary gland myoepithelium and in certain stromal fibroblasts ("myofibroblasts") associated with breast carcinomas was studied by immunofluorescence microscopy of frozen sections. Several antibodies to smooth muscle-specific proteins (smooth muscle c-actin, smooth mus- cle myosin heavy chains, calponin, a1-integrin, and high molecular weight caldesmon) and to epithelial-specific proteins (cytokeratins, E-cadherin, and desmoplakin) were used to show that myoepithelial cells concomitantly express epithelial and smooth muscle markers whereas adjacent luminal cells express only epithelial markers. The same antibodies were used to establish that stromal myofibroblasts exhibit smooth muscle phenotypic properties characterized by the expression of all the smooth muscle markers examined except for high molecular weight caldesmon. In addition, both myoepithelium and rnyo- fibroblasts show a significant degree of heterogeneity in smooth muscle protein expression. Thus, myoepithelial cells and stro- mal myofibroblasts are epithelial and mesenchymal cells, re- spectively, which coordinately express a set of smooth muscle markers while maintaining their specific original features. The dual nature of myoepithelial cells and the phenotypic transition of fibroblasts to myofibroblasts are examples of the plasticity of the differentiated cell phenotype.

Expression of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue (smooth muscle differentiation/breast carcinoma)

We have analyzed the structure, origin and expression of the high-molecular-mass muscle-specific variant of vinculin, called meta-vinculin. The meta-vinculin-specific inserts from the human and avian molecules have been isolated and sequenced and the sequences confirmed via cloning of the corresponding cDNA. Comparison of the human, avian and determined porcine sequences revealed cross-species identity in the C-terminal half of the insert. Human and porcine meta-vinculin were highly similar in the insert region, showing only five amino acid exchanges; avian meta-vinculin showed 22 exchanges in the same region compared to human meta-vinculin and exhibited, in addition, one extra amino acid, making 69 in all. Each insert was flanked by characteristic KWSSK motifs. Evidence for two vinculin mRNA species in human uterus smooth muscle was provided by reverse transcription combined with the polymerase chain reaction, as well as by ribonuclease-mapping analysis of cDNA/mRNA hybrids. One of the mRNA species contained an additional 204-nucleotide insert that precisely encoded the meta-vinculin-specific peptide. Sequence analysis of the appropriate portion of the human vinculin gene showed that the section coding for the meta-vinculin-specific insert is present as a discrete exon. Thus, meta-vinculin and vinculin mRNA are generated by alternative splicing. Vinculin is a 11 7-kDa cytoskeletal protein associated with membrane actin-filament-attachment sites of cell-cell and cellmatrix adherens-type junctions [I, 21. Several studies have shown a remarkable microheterogeneity of vinculin in the form of antigenically indistinguishable isoelectrophoretic variants, some of which show tissue-specific expression [3- 51. In addition to iso-vinculins, smooth muscle and striated muscle contain an 150-kDa protein, denoted as meta-vinculin, which shares similar peptide-map patterns, antigenic and functional properties with vinculin [6- 1 I]. Meta-vinculin and vinculin are localized in the same cellular adhesive structures, in microfilament-associated membrane-bound plaques of smooth muscle, in intercalated discs and costameres of cardiac muscle, and in focal contacts of cultivated smooth-muscle cells [ll, 121. Recently it was established that meta-vinculin may serve as a specific marker of smooth muscle [lo, 13, 141; it was identified in all human, chicken and porcine smooth muscles but not in non-muscle tissues and cultured cells [lo, 13, 141. The expression of meta-vinculin in human aortic smooth

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1992.tb16692.x

An additional exon in the human vinculin gene specifically encodes meta-vinculin-specific difference peptide. Cross-species comparison reveals variable and conserved motifs in the meta-vinculin insert.

Antibodies to Novel Myoepithelium-Associated Proteins Distinguish Benign Lesions and Carcinoma in Situ From Invasive Carcinoma of the Breast

Human plasma fibronectin promotes the adhesion and spreading of platelets on surfaces coated with fibrillar collagen.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2881%2980992-1

V.E. Koteliansky

Papers

Expression of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue (smooth muscle differentiation/breast carcinoma)

An additional exon in the human vinculin gene specifically encodes meta-vinculin-specific difference peptide. Cross-species comparison reveals variable and conserved motifs in the meta-vinculin insert.

Antibodies to Novel Myoepithelium-Associated Proteins Distinguish Benign Lesions and Carcinoma in Situ From Invasive Carcinoma of the Breast

Human plasma fibronectin promotes the adhesion and spreading of platelets on surfaces coated with fibrillar collagen.

Identification of a filamin-like protein in chicken heart muscle