Autocrine transforming growth factor beta (TGFB) in normal epithelial cells inhibits cell cycle progression. Loss of or diminished response to TGFB's growth inhibitory activity is a hallmark of tumorigenesis and progression in many types of cancer. This is apparently due to the dys-regulation of cell cycle machinery and/or reduced expression of TGFB receptors in most cases. However, an increasing number of studies have shown that many carcinomas over-express TGFB isoforms, which can drive tumor progression. Currently, TGFB is believed to promote tumor progression in a paracrine fashion by stimulating angiogenesis and inhibiting host immune surveillance. Since TGFB signaling pathway is operational in most carcinoma cells although many of them are resistant to its growth inhibitory activity, the endogenous TGFB isoforms should also act in an autocrine fashion. However, little is known about the role of the autocrine TGFB in supporting tumor progression. With the support from the current funding cycle, we found that antagonization of autocrine TGFB activity in the human breast carcinoma cells with over-expression of a soluble TGFB type III receptor (sRIIIl) significantly inhibited cell growth on plastic and clonogenicity in soft agarose even though sRIII expression slightly accelerated cell cycle progression. This apparent paradox was explained by the fact that sRIII-expressing cells were significantly more apoptotic than the control cells. Similar results were obtained after autocrine TGFB signaling was either blocked by dominant-negative TGFB receptors or attenuated with a recombinant sRIII protein. Therefore, we hypothesize that the majority carcinoma cells evade autocrine TGFB's growth inhibitory activity not only to gain the growth advantage from loss of negative cell cycle regulation, but also to utilize autocrine TGFB signaling for their survival and growth. To test this hypothesis, we will determine the role of autocrine TGFB in supporting cell survival and growth in transformed and untransformed epithelial cells, the intracellular mediators for autocrine TGFB's cell survival signal, and the role of cell adhesion in autocrine TGFB-regulated cell survival. Accomplishment of these specific aims will reveal whether and how antagonization of both autocrine and paracrine TGFB activity can be exploited for novel therapeutic strategies.
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