Brigitte Boyer

α2β1 Integrin is Required for the Collagen and FGF-1 Induced Cell Dispersion in a Rat Bladder Carcinoma Cell Line

We have investigated the role of integrins in the epithelial to mesenchymal transition (EMT) induced by either collagen or fibroblast growth factor-1 (FGF-1) in the rat bladder carcinoma cell line NBT-II. The major collagen-binding receptor is the α2β1 integrin. An increase in expression of α2β1 integrin coincided with EMT induced by either collagen or FGF-1. When both inducers were present, a further increase in α2 expression was observed which correlated with an enhancement in the speed of locomotion. Overexpression of human α2 in NBT-II cells did not trigger EMT but rendered cells more sensitive to the dispersing effect of collagen and FGF-1. Anti-human α2 blocking antibodies affected cell scattering and motility induced by either collagen or FGF-1. These data demonstrate that α2β1 integrin is the mediator of the cell scattering effect induced by collagen. They also indicate that a functional α2 integrin is essential for the motile behavior of NBT-II cells during the FGF-1 induced EMT.

Modulations of the epithelial phenotype during embryogenesis and cancer progression

In this chapter, we develop the idea that in order to be able to detach from the primary tumor, invade, and metastasize to distant organs, carcinoma cells must modify their adhesive status and change their cytoskeletal organization. Interestingly, such modifications of cell adhesion and communication systems have been shown to occur during embryogenesis and particulary during migratory process of epithelial-mesenchymal transition (EMT). These embryonic events therefore could represent the prototype of epithelial cell dispersion. Eventually, cells may switch back to a stable epithelial phenotype state that involves local growth and maintenance of this differentiated state, in coordination with the local environment. The delicate modulation of this equilibrium on a specific cell population represents a basic mechanism of embryogenesis. A similar mechanism of epithelial cell plasticity may apply to cancer cells. In this chapter, we first discuss this balance during a well-documented case of induced EMT in a bladder carcinoma. Then we expand the review to examples of EMT occurring during embryogenesis. Finally, we review cancer metastasis, with a special emphasis on breast cancer.

Epithelial cell adhesion mechanisms.

ConclusionWithout the establishment and maintenance of specialized junctions, the specific association of which characterizes epithelial cells, the epithelium-specific polarity would not exist. The major goal of this review has been to develop the idea that relationships between CAMs and junctions do occur. Although CAMs were first described as morphoregulatory molecules essential for the normal development of the embryo, it has become evident that they may also have a role in epithelial cohesiveness as specialized junctions do. The arguments that suggest relationships between Ca2+-dependent CAMs (cadherins) and junctions are the following: (i) Some junction-specific molecules and cadherins are identical. (ii) In some cases, the expression of specific cadherins at the cell surface leads to the establishment of specialized junctions. (iii) The inhibition of cadherin-mediated adhesion blocks the establishment of specialized junctions. (iv) Junctions and cadherins are equally sensitive to Ca2+ ions. Moreover, chelation of external Ca2+ ions dissociates epithelial cells.Despite the existing evidence suggesting that the expression of cadherins could regulate the assembly of junctions, the hierarchy of events leading to epithelial cohesiveness is largely unknown. Furthermore, it is not yet clear whether the mechanisms of epithelial adhesion are regulated at the transcriptional, translational or posttranslational level. Moreover, further studies will have to shed new light on the biological factors involved in the creation and maintenance of epithelial cohesiveness. But the intensive effort of several laboratories will probably be fruitful in the near future and will give further insights into the mechanisms that regulate the assembly/disassembly of junctions and the modulation of cadherins in physiological as well as pathological situations.

Model Systems of Carcinoma Cell Dispersion

The progressive loss of expression of a fully differentiated epithelial phenotype is a hallmark of carcinoma progression in both humans and animals. In the mouse skin system, for example, the loss of epithelial differentiation is accompanied by the appearance of malignant properties. In this well-studied system, chemical carcinogenesis generates multiple benign tumors, a proportion of which develop to form squamous cell carcinomas and, in extreme cases, spindle cell carcinomas that are highly invasive and metastatic tumors (Stoler et al. 1993). The transformation from squamous into spindle cells is characterized by the loss of epithelial features and the acquisition of a fibroblastic appearance. Analogous changes from an epithelial morphology to a fibroblast-like phenotype, correlating with the progression to malignancy, have also been observed in epithelial tumors derived from other sites, including colon and breast. Whether or not these phenotypic alterations can be regarded as authentic epithelium-to-mesenchyme transitions (EMTs), similar to those observed during embryogenesis, remains to be clarified. Nevertheless, since the maintenance of epithelial cell differentiation acts as a suppressor of malignancy (Harris 1990), it is essential to study the genetic and epigenetic events controlling the cellular program driving the transformation of epithelial cells into fibroblast-like cells. In that context, numerous in vitro models have been designed to clarify some aspects of tumor progression.Using this approach, several genes have been identified as potential tumor activators or suppressors: for example, E-cadherin, an epithelial cell adhesion molecule, has been demonstrated to act in vitro as a tumor suppressor gene (Frixen et al. 1991), while the mutant H-ras gene is rensponsible for the increased invasiveness of epithelial cell lines (Mareel et al. 1991).

Multifunctional Growth Factors in Tumor Progression

Our goal is to analyze the role of multifunctional growth factors in epithelial plasticity and, specifically, to study the contribution of these factors to the loss of cohesion among tumor cells leading to the acquisition of motile, invasive, and metastatic behavior.

The junction between cytokines and cell adhesion

Several aspects of the interactions between growth factors and cell adhesion are described. Recent advances in the field come from the identification of molecules resembling growth factors or growth factor receptors, which bear cell adhesion motifs as well as molecules participating in both cell growth control and adhesion.