Trophoblast cells of the placenta in many species have acquired mechanisms to invade the uterus, inclusive of its blood vessels, to establish efficient fetomaternal exchange of molecules. This invasion is strictly controlled both spatially and temporally and, in humans, usually continues until midgestation. Key mechanisms underlying various steps in trophoblast invasion are: (i) the attachment to the basement membrane, most likely by binding to laminin; (ii) the detachment from the basement membrane matrix, a process requiring the presence of complex-type oligosaccharides on the cell surface; and (iii) the breakdown of basement membrane components, mediated by secretion of metalloproteases (such as type IV collagenases) and serine proteases (plasminogen activator). Activation of trophoblast-derived metalloproteases appears to be plasmin dependent. Trophoblast invasiveness in situ is controlled by the microenvironment, owing to local production of anti-invasive factors by the decidual tissue of the uterus. One of these factors is TIMP (tissue inhibitor of metalloproteases), which neutralizes metalloproteases in an equimolar ratio. Another is TGF-beta (transforming growth factor-beta), which has a dual effect: it induces TIMP-1 secretion by the trophoblast and decidual cells and promotes differentiation of invasive trophoblast cells into multinucleated giant cells, which are presumably noninvasive. Thus, TGF-beta provides the key control of trophoblast invasiveness in situ. This control is lost in certain choriocarcinomas. In contrast to the response shown by the normal trophoblast, JAR and JEG-3 choriocarcinoma cell invasiveness does not seem to be inhibited by TGF-beta. In fact, in preliminary studies, JAR cells responded to TGF-beta by increased invasiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of placental invasion of the uterus and their control.

Implantation and subsequent placental development in many species including the human are dependent on trophoblast invasion of the uterine epithelium, the underlying basement membrane, connective tissue and blood vessels. However, trophoblast invasion in situ is strictly controlled by the microenvironment provided by the pregnant uterus.

Mechanisms of trophoblast invasiveness and their control: the role of proteases and protease inhibitors.

Use of lectins as diagnostic and therapeutic tools for cancer.

Growth factors, proteases and protease inhibitors in the maternal—fetaldialogue

Detection and functions of mammalian lectins--with emphasis on membrane lectins.

Malignant transformation and tumor progression are often accompanied by structural changes in the carbohydrate components of glycoproteins and glycolipids. Studies with tumor cell glycosylation mutants and specific inhibitors of glycosylation indicate that expression of sialylated and beta (1-6) branched asparagine (Asn)-linked oligosaccharides are required for tumor cell invasion and metastasis. The initiation of the beta (1-6) antenna appears to be oncodevelopmentally regulated and may be associated with the aberrant expression of blood group and embryonic carbohydrate sequences in Asn-linked oligosaccharides of tumors. Although the function of these oligosaccharides in the metastatic process remains unclear, there is some evidence that expression of these structures on certain cell-surface glycoproteins may reduce tumor cell adhesion to extracellular matrix. These observations suggest that low-toxicity drugs that inhibit the biosynthesis of these structures may be useful in the treatment of metastatic cancers.

Asparagine-linked oligosaccharides associated with metastatic cancer.

Trophoblast cells of normal first trimester human placenta share with malignant tumor cells the ability for significant cellular proliferation and invasion of basement membranes. Because tumor cell metastasisin vivo and invasion of basement membranesin vitro have recently been shown to require the expression of-GIcNAcβ1–6 Manαl-6 Manβl-branched complex type Asn-linked oligosaccharides in tumor cell surface glycoproteins, we decided to determine if such structures were also necessary for invasion by trophoblast cells. We report here that invasive first trimester trophoblasts express leukoagglutinin-reactive βl-6 branched Asn-linked oligosaccharides on their surface. Moreover, basement membrane invasion by trophoblast was significantly inhibited by pretreating the cells with swainsonine, a non-toxic inhibitor of Golgi α-mannosidase II which blocks β1–6 branching of Asn-linked oligosaccharides. The first trimester trophoblast cells pretreated with swainsonine attached more avidly to the amnion basement membrane and to an extracellular matrix (ECM) preparation compared to control non-treated erophoblast cells. Swainsonine treatment did not inhibit secretion of gelatinase or plasminogen activator activities by trophoblast cells. These results suggest that expression of βl-6 branched oligosaccharides in trophoblast cells may be functionally important for the implantation and placentation processes by reducing cell adhesion to ECM and thereby facilitating trophoblast cell invasion.

S. Yagel

Papers

Asparagine-linked oligosaccharides associated with metastatic cancer.

Basement membrane invasion by first trimester human trophoblast: requirement for branched complex-type Asn-linked oligosaccharides.