Specific loss of chondromodulin-I gene expression in chondrosarcoma and the suppression of tumor angiogenesis and growth by its recombinant protein in vivo

AbstractChondromodulin-I (ChM-I) was previously identified as an angiogenesis inhibitor in cartilage. Here, we demonstrated that the level of ChM-I transcripts was substantially reduced to 100 or even less in the lower-grade chondrosarcomas, in articular cartilage or other benign cartilage tumors. We implanted human chondrosarcoma OUMS-27 cells into nude mice that reproducibly produced tumors with cartilaginous matrix. Tumor-induced angiogenesis was evident when the tumors were excised 30 days after implantation. However, the local administration of recombinant human ChM-I almost completely blocked vascular invasion and tumor growth in vivo. Moreover, ChM-I also inhibited the growth of HT-29 colon adenocarcinoma in vivo, implying its therapeutic potential for solid tumors

Changes in serum anti-Müllerian hormone levels may predict damage to residual normal ovarian tissue after laparoscopic surgery for women with ovarian endometrioma.

We measured serum anti-Müllerian hormone levels before and after surgery in women undergoing unilateral and monolocular cystectomy for benign ovarian diseases. Comparing to control benign cysts, we found a significant decline in serum anti-Müllerian hormone levels with consequent depletion of follicles in tissue specimens after surgery for women with ovarian endometrioma

Effect of human seminal fluid on the growth of endometrial cells of women with endometriosis.

OBJECTIVES: We investigated the effect of human seminal fluid on the growth of endometrial cells derived from women with and without endometriosis. STUDY DESIGN: Seminal plasma (SP) was collected from 18 healthy fertile men. Serum, peritoneal fluid (PF) and tissue specimens of eutopic and ectopic endometrium were collected from 45 women with endometriosis and 20 women without endometriosis during laparoscopic surgery. Prostaglandin (PG) E2, hepatocyte growth factor (HGF), and estradiol (E2) levels in each sample of SP, serum and PF were measured by enzyme-linked immunosorbent assay. The growth pattern of cells derived from eutopic and ectopic endometria in response to SP was examined by 5-bromo-2-deoxyuridine (BrdU) incorporation assay. RESULTS: Seminal plasma was able to significantly stimulate the growth of epithelial cells and stromal cells derived from the eutopic and ectopic endometria of women with endometriosis (2-3-fold) when compared with control media. The SP-promoted proliferation of both gland cells and stromal cells derived from eutopic endometria was also remarkably higher in women with endometriosis than that of women without endometriosis. Although levels of PGE2, HGF and E2 in SP were variable when compared with other body fluids, the levels of PGE2 and HGF in SP were significantly higher than those in either peritoneal fluid or serum of women with or without endometriosis. Pretreatment of cells with individual anti-PGE2 antibody, anti-HGF antibody and two selective estrogen receptor modulators, tamoxifen and raloxifene was unable to suppress SP-mediated growth of endometrial cells. However, pretreatment of cells with combined anti-PGE2 antibody plus anti-HGF antibody or combined anti-PGE2 antibody plus anti-HGF antibody plus tamoxifen or raloxifene was able to significantly suppress SP-promoted growth of eutopic and ectopic endometrial cells. CONCLUSION: Human seminal fluid enriched with different macromolecules may promote the growth of endometrial cells derived from women with endometriosis. Our findings may suggest some detrimental effect of unprotected sexual intercourse in women with endometriosis

Changes in tissue inflammation, angiogenesis and apoptosis in endometriosis, adenomyosis and uterine myoma after GnRH agonist therapy

Background: Information is limited regarding multifunctional role of GnRH agonist (GnRHa) therapy in reproductive diseases. We investigated pattern of changes in inflammatory reaction, micro-vessel density and apoptosis in the tissues collected from women with endometriosis, adenomyosis and uterine myoma who were treated with or without GnRHa therapy. Methods: Biopsy specimens were collected from lesions, myometria and corresponding endometria of 45 women with ovarian endometrioma, 35 women with adenomyosis, and 56 women with uterine myoma. A fraction of these women were treated with GnRHa therapy for a variable period of 3-6 months before surgery. We performed immunohistochemical analysis of CD68, a macrophage (Mφ) marker, and von Willebrand factor (VWF), a vessel marker, using respective antibodies. The changes in apoptosis were examined using TdT-mediated dUTP-biotin nick end-labeling (TUNEL) assay and by the immunoexpression of activated caspase-3 in tissues after GnRHa therapy. Results: The infiltration of CD68-positive M φ and VWF-positive micro-vessel density were significantly decreased in the endometria of women with endometriosis, adenomyosis and uterine myoma in the GnRHa-treated group when compared with that in the non-treated group. A marked decrease in inflammatory and angiogenic responses were observed in lesions and myometria of these diseases. When compared with non-treated group, a significantly increase in apoptotic index (apoptotic cells per 10 mm2 area) and quantitative-histogram (Q-H) scores of activated caspase-3 after GnRHa therapy were observed in the eutopic endometria, lesions and myometria of these diseases. Conclusion: GnRH agonist was able to markedly reduce the inflammatory reaction and angiogenesis and significantly induce apoptosis in tissues derived from women with endometriosis, adenomyosis and uterine myoma. These multiple biological effects at the tissue level may be involved in the regression of these reproductive diseases

Toll-Like Receptors in Innate Immunity: Role of Bacterial Endotoxin and Toll-Like Receptor 4 in Endometrium and Endometriosis.

Macrophages, dendritic cells, and Toll-like receptors (TLRs) are integral components of the innate immune system. This rapidly reactive system responds immediately to infectious or other non-self agents, thereby inducing an inflammatory response to protect the host until the activation of the slower adaptive immune system. The fundamentals of the innate immune system, functional characteristics of TLRs, and signaling pathways of TLR4 are discussed for the easy understanding by readers. Studies showed that the growth and progression of endometriosis continue even in ovariectomized animals. This indicates that besides ovarian steroid hormones, the growth of endometriosis can be regulated by the innate immune system in the pelvic environment. As a component of the innate immune system, increased infiltration of macrophages has been described in the intact tissue and peritoneal fluid of women with endometriosis. In this review article, we discuss the role of bacterial endotoxin and TLR4 in endometrium and endometriosis and outline the involvement of endotoxin in causing adverse reproductive outcome

Peritoneal fluid and serum levels of hepatocyte growth factor may predict the activity of endometriosis

Background. The suitable parameter in PF as well as in serum that may predict the activity of endometriosis is not well described. Therefore, we tried to examine the peritoneal fluid (PF) and serum concentrations of hepatocyte growth factor (HGF) in different revised American Society of Reproductive Medicine (r-ASRM) staging and morphologic appearances of endometriosis in an attempt to determine whether HGF can be clinically useful to predict the activity of pelvic endometriosis. Methods. Peritoneal fluid was collected from 137 women with endometriosis and 57 women without endometriosis during laparoscopy and blood sampling was collected from 37 women with endometriosis and 21 women without endometriosis before laparoscopy. The concentration of HGF in PF and serum was measured by enzyme-linked immunosorbent assay. The ability of isolated macrophages and stroma to secrete HGF in response to lipopolysaccharide (LPS) was evaluated. Results. A significantly increased concentration of HGF in PF was found in women with endometriosis (1451.75±90.7 pg/mL) than that in non-endometriosis (1120.5±77.3 pg/mL, p <0.01) without any remarkable difference in HGF levels between women with stage I-/II endometriosis and stage III-/IV endometriosis. When we distributed serum and PF levels of HGF according to different color appearances of endometriosis, we found a significantly higher serum and PF levels of HGF in women containing dominant red peritoneal lesions in pelvic cavity (740±109.3 pg/mL for serum; 1685±183.4 pg/mL for PF) than those having other pigmented lesions (649±79.5 pg/mL, p <0.05 for serum; 1224±67.8 pg/mL, p <0.05 for PF) or chocolate cysts (485±43.1 pg/mL, p <0.05 for serum; 1118±83.1 pg/mL, p <0.01 for PF). Exogenous stimulation with LPS significantly increased the production of HGF in the culture media by macrophages and stroma derived from women with endometriosis than that in women without endometriosis. Conclusions. These results suggest that women with early or advanced endometriosis as measured by r-ASRM scoring system are not associated with an increase in either serum or PF concentrations of HGF. Rather HGF levels in serum and PF were significantly increased in women harboring blood-filled red peritoneal lesions and may be clinically useful to predict the activity of pelvic endometriosis