Toll-like receptors (TLRs) play a crucial role in the innate immune response and the subsequent induction of adaptive immune responses against microbial infection or tissue injury. Recent findings show that functional TLRs are expressed not only on immune cells but also on cancer cells. TLRs play an active role in carcinogenesis and tumor progression during chronic inflammation that involves the tumor microenvironment. Damage-associated molecular patterns (DAMPs) derived from injured normal epithelial cells and necrotic cancer cells appear to be present at significant levels in the tumor microenvironment, and their stimulation of specific TLRs can foster chronic inflammation. This review discusses how carcinogenesis, cancer progression, and site-specific metastasis are related to interactions between cancer cells, immune cells, and DAMPs through TLR activation in the tumor microenvironment.

Abstract. More than 99% of follicles undergo a degenerative process known as "atresia", in mammalian ovaries, and only a few follicles ovulate during ovarian follicular development. We have investigated the molecular mechanism of selective follicular atresia in mammalian ovaries, and have reported that follicular selection dominantly depends on granulosa cell apoptosis. However, we have little knowledge of the molecular mechanisms that control apoptotic cell death in granulosa cells during follicle selection. To date, at least five cell death ligand-receptor systems [tumor necrosis factor (TNF)α and receptors, Fas (also called APO-1/CD95) ligand and receptors, TNF-related apoptosisinducing ligand (TRAIL; also called APO-2) and receptors, APO-3 ligand and receptors, and PFG-5 ligand and receptors] have been reported in granulosa cells of porcine ovaries. Some cell death ligand-receptor systems have "decoy" receptors, which act as inhibitors of cell death ligand-induced apoptosis in granulosa cells. Moreover, we showed that the porcine granulosa cell is a type II apoptotic cell, which has the mitochondrion-dependent apoptosis-signaling pathway. Briefly, the cell death receptor-mediated apoptosis signaling pathway in granulosa cells has been suggested to be as follows. (1) (7) Cytochrome c and ATP-dependent oligimerization of apoptotic protease-activating factor-1 (Apaf-1) allows recruitment of procaspase-9 into the apoptosome complex. Activation of procaspase-9 is mediated by means of a conformational change. (8) The activated caspase-9 cleaves downstream effector caspases (caspase-3). (9) Finally, apoptosis is induced. Recently, we found two intracellular inhibitor proteins [cellular FLICE-like inhibitory protein short form (cFLIPS) and long form (cFLIPL)], which were strongly expressed in granulosa cells, and they may act as anti-apoptotic/survival factors. Further in vivo and in vitro studies will elucidate the largely unknown molecular mechanisms, e. g.

Abstract. In the mammalian ovary, follicular development and atresia are closely regulated by cell death and survival-promoting factors, including hormones (gonadotropins) and intraovarian regulators (gonadal steroids, cytokines, and intracellular proteins). Several hundred thousand primordial follicles are present in the mammalian ovary; however, only a limited number of primordial follicles develop to the preovulatory stage and ovulate. The others, more than 99% of follicles, will be eliminated via a degenerative process known as "atresia". The endocrinological regulatory mechanisms involved in follicular development and atresia have been characterized to a large extent, but the precise temporal and molecular mechanisms involved in the regulation of these events have remained largely unknown. Recent studies suggest that the apoptosis of ovarian granulosa cells plays a major role in follicular atresia. In this review, we provide an overview of development and atresia of follicles, and apoptosis of granulosa cells in mammals. Key words: Anti-apoptotic factor, Apoptosis, Follicular atresia, Granulosa cell, Porcine ovary, Proapoptotic factor (J. Reprod. Dev. 52: [695][696][697][698][699][700][701][702][703][704][705] 2006) poptosis plays a significant role in almost all physiological functions in vertebrate and invertebrate species. It is a form of cell death essential for elimination of cells that are damaged, senescent, potentially harmful, or no longer useful [ 1 ] . T h e m a j o r f e a t u r e s o f a p o p t o s i s a r e internucleosomal DNA fragmentation, cell shrinkage, plasma membrane blebbing, and the formation of apoptotic bodies. Stimulation by death ligands or deprivation of key survivalpromoting growth factors is the main contributor to apoptosis, while stress inducers, including drugs, toxicants, oxidative stress, and radiation, are also known to cause apoptosis.Studies have revealed that apoptosis also plays a crucial role in maintaining the reproductive a p p a r a t u s . D u r i n g f o l l i c u l a r g r o w t h a n d development, more than 99% of follicles disappear, primarily due to apoptosis of granulosa cells [2][3][4][5] (Fig. 1). Both the biochemical and morphological characteristics of apoptosis have been observed in the granulosa cells of atretic follicles [6][7][8]. Apoptotic stimuli and intracellular signal transduction pathways involved in the apoptosis of granulosa cells remain to be determined, and investigators are studying potential triggers of apoptosis and how intracellular apoptotic signals are transmitted in granulosa cells.