Lls expressing Thy-1 formed tumors that have been smaller sized and propagated a lot more slowly than ovarian Leishmania Inhibitor Source cancer cells not expressing Thy-1 [28]. Additionally, Thy-1 may possibly function as a tumor suppressor by up-regulating fibronectin and the anti-angiogenic molecule thrombospondin-1 [29] (Fig. 1E). Epigenetic suppression of Thy-1 expression due to promoter hypermethylation has been detected in several nasopharyngeal cell carcinoma (NPC) cell lines, also as in NPC tumor samples. Colony formation of NPC HONE1 cells is decreased following re-expression of Thy-1 [8]. Oncogenic transformation of NIH 3T3 cells by ras oncoproteins, resulting in anchorage-independent growth and soft agar colony formation, is related with loss of Thy-1 surface expression [78]. As with proliferation, the part of Thy-1 in tumorigenesis is unclear. Thy-1 facilitates melanoma cell migration by way of a transendothelial cell monolayer [47], yet functions as a tumor suppressor in ovarian cancer and NPC [8,280]. Differences inside the role of Thy-1 in cell proliferation could possibly be cell type-specific, and also the effects of Thy-1 on tumorigenicity can be mediated through non-proliferative mechanisms. It will likely be interesting to examine whether or not Thy-1 knockout mice are more susceptible to tumor invasion and metastasis.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript5. Thy-1 and cytokine/growth aspect signalingNormal lung fibroblasts are heterogeneous, and the most extensively characterized in vitro model of fibroblast heterogeneity is depending on the cell surface expression of Thy-1 [37,62]. Fibroblasts sorted according to Thy-1 expression differ in their response to and/or production of several cytokines and development variables (Table three;Fig. 1D). Thy-1 (+) splenic fibroblasts secrete greater levels of interleukin (IL)-6 at baseline, but only Thy-1 (-) pulmonary fibroblasts secrete IL-1 following tumor necrosis aspect (TNF)- stimulation [36,79]. Following IL-1 stimulation, Thy-1 (-) pulmonary fibroblasts have improved proliferation and IL-6 expression as in comparison with Thy-1 (+) fibroblasts [38]. Interestingly, each subsets express IL-1 receptor components and activate NFB-1 in response to IL-1, suggesting that Thy-1 may have an effect on noncanonical IL-1 signaling pathways. Thy-1 (-) pulmonary fibroblasts express larger levels of platelet-derived growth aspect (PDGF)- and are selectively responsive to PDGF-AA-induced proliferation [39]. Additionally, PDGF stimulation of human smooth muscle cells IL-6 Antagonist Purity & Documentation increases the levels of Thy-1 localized to lipid rafts [80]. Non-lung fibroblasts also can be divided into heterogeneous populations determined by the expression of Thy-1. Fibroblasts isolated from the human female reproductive tract differ inBiochim Biophys Acta. Author manuscript; accessible in PMC 2007 October 1.Rege and HagoodPagecyclooxygenase (COX) expression and prostaglandin (PG) release. Thy-1 (+) myometrial fibroblasts express high levels of COX-1 and create high levels of PGE2, whereas Thy-1 (-) fibroblasts constitutively express COX-2 and produce low levels of PGE2 [81] (Fig. 1D). The differing responses of Thy-1 (+) vs. (-) fibroblast subpopulations to cytokines and growth elements recommend that Thy-1 may affect fibroblast function in the course of wound healing and fibrosis. In response to fibrogenic stimuli, Thy-1 (-) pulmonary fibroblasts create much more latent TGF than Thy-1 (+) fibroblasts and are selectively able to activate latent TGF-, suggesting Thy-1 expression may possibly offer protection from a fibrogenic respon.