Table I.
Growth factors and related proteins in human myometrium and leiomyoma: presence, action and steroid regulation.
| Growth factors | Receptors binding proteins | Presence in myometrium and or in leiomyoma | Action on myometrial cells | Regulated by sex steroids (estrogen/progesterone) |
|---|---|---|---|---|
| EGF | EGF-R (HER1) | Expression in myometrium and reduced expression in leiomyomas (Yeh et al., 1991; Dixon et al., 2000) | Mitogenic for myometrium and leiomyomas (Fayed et al., 1989; Rossi et al., 1992). Regulates leiomyoma growth (Yeh et al., 1991; Rossi et al., 1992) | P4 up-regulates EGF expression in leiomyoma (Shimomura et al., 1998; Matsuo et al., 1999; Maruo et al., 2003). E2 reduces EGF but up-regulates EGF-R expression in both leiomyoma and myometrium (Shimomura et al., 1998; Matsuo et al., 1999) |
| TGF-α | EGF-R (HER1) | Minimal expression in leiomyomas and myometrium (Dixon et al., 2000). Expressed in leiomyosarcomas (Moore et al., 2000) | ||
| HB-EGF | HER1 (EGFR1), HER4 | Expression in myometrium and reduced expression in leiomyoma (Mangrulkar et al., 1995; Dixon et al., 2000) | Stimulates leiomyoma and myometrial cell proliferation. Inhibits apoptosis (Wang et al., 2005) | P4 and E2 regulate HB-EGF expression in mouse uterus (Wang et al., 1994). P4 stimulates HB-EGF expression in rat uterine stromal cells (Zhang et al., 1994). E2 enhances HB-EGF expression in rat epithelial cells (Zhang et al., 1994) |
| PDGF | PDGF-Rα, PDGF-Rβ | Expression in leiomyomas and myometrium (Boehm et al., 1990; Mangrulkar et al., 1995). Higher expression of PDGF-CC in leiomyoma than in myometrium (Hwu et al., 2008) | Modulates proliferation of leiomyoma and myometrial cells (Arici and Sozen, 2003). Stimulates DNA synthesis (Fayed et al., 1989). Stimulates VEGF production (Taniguchi et al., 2001) | E2 induces PDGF expression in leiomyoma (Barbarisi et al., 2001) |
| IGF- | IGF-IR, IGF-IIR; IGFBP 1–6 | Expression in leiomyoma and myometrium (Boehm et al., 1990; Gloudemans et al., 1990; Giudice et al., 1993; Van der Ven et al., 1997) as well as leiomyosarcoma (Gloudemans et al., 1990; Van der Ven et al., 1997). Higher IGF-I expression in leiomyomas than in myometrium (Dixon et al., 2000; Wolanska and Bankowski, 2004; Yu et al., 2008; Zhao et al., 2008) | IGF-I stimulates proliferation of leiomyoma cells (Strawn et al., 1995). IGF-I up-regulates leiomyoma cell growth (Gao et al., 2001; Maruo et al., 2003). | P4 modulates IGF-I expression in leiomyoma (Yamada et al., 2004) P4 inhibits the IGF-I expression in cultured leiomyoma cells (Maruo et al., 2003). E2 stimulates IGF-I expression in leiomyoma cells (Di et al., 2008) |
| TGF-β | TGF-β R type I, II, and III | Expression in myometrium (Chegini et al., 1994; Tang et al., 1997) and increased expression in leiomyoma (Dou et al., 1996) | Stimulates leiomyoma cell proliferation (Arici and Sozen, 2000; Lee and Nowak, 2001). Low concentrations stimulate autocrine PDGF secretion (Wolanska and Bankowski, 2007) | P4 appears to stimulate TGF-β3 expression in myometrium and leiomyoma (Arici and Sozen, 2000) |
| VEGF | flt (VEGFR-1), KDR (VEGFR-2) | Expression in myometrium and leiomyomas (Harrison-Woolrych et al., 1995; Dixon et al., 2000; Sanci et al., 2011). Increased expression in leiomyomas (Gentry et al., 2001) | Stimulates angiogenic activity (Flake et al., 2003; Arita et al., 2005; Hong et al., 2001) | E2 and P4 induce VEGF expression in rodent uterus (Hyder et al., 2000) |
| aFGF | FGFR1–4 | Expression in myometrium and increased expression in leiomyomas (Wolanska and Bankowski, 2006) | ||
| bFGF | FGFR-1, FGFR-2 | Expression in leiomyomas and myometrium (Pekonen et al., 1993; Mangrulkar et al., 1995; Dixon et al., 2000; Nowak, 2000; Wu et al., 2001; Wolanska and Bankowski, 2006). Increased expression of FGFR-1 in leiomyomas (Wolanska and Bankowski, 2006) | Regulates angiogenesis (Anania et al., 1997; Hong et al., 2001). Mitogenic for both human uterine myometrial and leiomyoma cells (Rauk et al., 1995) | E2 and P4 regulates bFGF mRNA expression in rat uterus (Rider et al., 1997) |
| Activin | Alk4, ActRIIA, ActRIIB; Follistatin, FLRG | Expression in PHM1 (pregnant human myometrium) cells (Ciarmela et al., 2008) and human myometrium and leiomyoma specimens (Ciarmela et al., 2011) | Inhibits myometrial cell growth. Decreases oxytocin receptor and HoxA-10 mRNA expression. Attenuates of oxytocin and thromboxaneA2 induced intracellular Ca2+ accumulation. Modifies cell morphology (Ciarmela et al., 2008) | E2 modulates activin-A mRNA levels in ovariectomized and steroid-replaced rat (Ciarmela et al., 2009). E2 reduces activin-A mRNA levels in human myometrium (Ciarmela et al., 2011) |
| Myostatin | Alk4, Alk5, ActRIIB; Follistatin, FLRG | Expression in PHM1 cells (Ciarmela et al., 2009) and human myometrium and leiomyoma specimens (Ciarmela et al., 2011). | Inhibits myometrial cell growth (Ciarmela et al., 2009). | E2 modulates the myostatin mRNA levels in ovariectomized and steroid-replaced rat (Ciarmela et al., 2009). E2 reduces myostatin mRNA levels in human myometrium (Ciarmela et al., 2011) |