Endocrine, paracrine and autocrine regulation of trophoblastic metalloproteinases

Gelatinase A and B (MMP-2 and MMP-9) are secreted by cytotrophoblast (CTB); these enzymes digest the major constituents of the endometrial extracellular matrices (ECM). Direct evidence links the expression of MMPs to the metastatic phenotype of tumour cells and tissue inhibitor of metalloproteinases (TIMP) to the inhibition of metastatisation. Gelatinase B (MMP-9, and no other MMP) has been shown in vitro to mediate CTB invasion. ECM components are known to influence adhesion, spreading, migration and differentiation of cells through specific cell surface receptors called integrins. While CTB migrate from the villous into the decidua they modulate their integrin repertoire, secrete MMP-9 and acquire the capacity to digest their environment. Although CTB behave like metastatic cells, in vivo they are only transiently invasive (first trimester) and their invasion is essentially limited to the endometrium and to the proximal myometrium. This temporal and spatial regulation seems to be mediated in a paracrine way by uterine factors and in an autocrine way by trophoblastic factors. We investigated the effects of endometrial regulators such as leukaemia inhibitory factor (LIF), tumour necrosis factor (TNF), transforming growth factor beta (TGFb), interleukin-1 and 6 (IL-1, IL-6) and insulin-like growth factor binding protein-1 (IGFBP-1) as well as trophoblastic factors such as hCG and leptin. All these factors markedly influenced the secretion and/or activation of MMP-2 and MMP-9. Most cytokines influence cell behaviour by modulating phosphorylation of transcription factors. Among these we identified two oncogene products (Jun and Fos) which were activated by TNF or phorbol esters and which promoted the synthesis of MMP-9. We conclude that decidual and trophoblastic products are autocrine or paracrine regulators of trophoblastic invasion of the endometrium and that some of these products act by activating the transcription of early response genes such as transcription factors.