Tags

Type your tag names separated by a space and hit enter

Co-operation between the AKT and ERK signaling pathways may support growth of deep endometriosis in a fibrotic microenvironment in vitro.
Hum Reprod. 2015 Jul; 30(7):1606-16.HR

Abstract

STUDY QUESTION

How can deep endometriotic stromal cells proliferate and persist in a fibrotic environment?

SUMMARY ANSWER

The serine/threonine kinase AKT and extracellular regulated kinase (ERK) signaling pathways may co-operate to support growth of deep endometriotic lesions by enhancing endometriotic stromal cell proliferation and survival in a fibrotic microenvironment in vitro.

WHAT IS KNOWN ALREADY

Endometriosis, particularly deep infiltrating endometriosis, is characterized histologically by dense fibrous tissue that is primarily composed of type I collagen. This tissue may cause pelvic pain and infertility, which are major clinical issues associated with endometriosis. Proliferation of normal fibroblasts is tightly regulated, and fibrillar, polymerized type I collagen inhibits normal fibroblast proliferation. However, no studies to date have investigated how deep endometriotic stromal cells can proliferate and persist in a fibrotic environment.

STUDY DESIGN, SIZE, DURATION

Endometrial and/or endometriotic tissues from 104 patients (61 with and 43 without endometriosis) of reproductive age with normal menstrual cycles were analyzed. A total of 25 nude mice received a single injection of endometrial fragments from a total of five samples.

PARTICIPANTS/MATERIALS, SETTING, METHODS

We evaluated cell proliferation, caspase 3/7 activity, and the AKT and ERK signaling pathways in endometrial and endometriotic stromal cells on three-dimensional (3D) polymerized collagen matrices in vitro. In addition, to determine whether aberrant activation of the AKT and ERK pathways is involved during progression of fibrosis in endometriosis in vivo, we evaluated the expression of phosphorylated AKT and ERK1/2 in endometriotic implants in a nude mouse model of endometriosis. Finally, we evaluated the effects of MK2206 (an AKT inhibitor) and U0126 (a MEK inhibitor) on cell proliferation, caspase 3/7 activity, and phosphorylation of AKT and ERK1/2 of endometriotic stromal cells on 3D polymerized collagen matrices.

MAIN RESULTS AND THE ROLE OF CHANCE

Proliferation of endometriotic stromal cells was significantly less inhibited than that of endometrial stromal cells (P < 0.05) on 3D polymerized collagen. Levels of phosphorylated AKT, phosphorylated p70S6K and phosphorylated ERK1/2 were significantly higher in endometriotic stromal cells than in endometrial stromal cells at 24 h (P < 0.05) and at 72 h (P < 0.05) on 3D polymerized collagen. Phosphorylated AKT expression was significantly increased on Days 21 and 28 compared with those on Days 3 and 7 (all P < 0.05) in endometriotic implants during progression of fibrosis in a nude mouse model of endometriosis. Inhibition of AKT or ERK1/2 with MK2206 or U0126, respectively, did not significantly increase caspase 3/7 activity in endometriotic stromal cells on either two-dimensional or 3D collagen matrices. Western blot analysis showed that MK2206 alone decreased levels of phosphorylated AKT; however, it increased levels of phosphorylated ERK in endometriotic cells compared with vehicle-treated cells (both P < 0.05). In addition, U0126 treatment decreased levels of phosphorylated ERK; however, it resulted in increased levels of phosphorylated AKT in endometriotic stromal cells compared with vehicle-treated cells (both P < 0.05).

LIMITATIONS, REASONS FOR CAUTION

Endometriosis involves a number of processes, such as invasion, metastasis, angiogenesis, and apoptosis resistance, and a variety of signaling pathways may be involved in promoting development and progression of the disease. In addition, further animal experiments are required to determine whether the AKT and ERK signaling pathways co-operate to support growth of endometriotic lesions in a fibrotic microenvironment in vivo.

WIDER IMPLICATIONS OF THE FINDINGS

Co-targeting the AKT and ERK pathways may be an effective therapeutic strategy for endometriosis treatment.

STUDY FUNDING/COMPETING INTERESTS

This study was supported in part by Karl Storz Endoscopy & GmbH (Tuttlingen, Germany). No competing interests are declared.

Authors+Show Affiliations

CHU Clermont-Ferrand, CHU Estaing, Chirurgie Gynécologique, Clermont-Ferrand, France Clermont Université, Université d'Auvergne, ISIT UMR6284, Clermont-Ferrand, France CNRS, ISIT UMR6284, Clermont-Ferrand, France sachikoma@aol.com.CHU Clermont-Ferrand, Service d'Anatomie et Cytologie Pathologiques, Clermont-Ferrand, France.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25976656

Citation

Matsuzaki, Sachiko, and Claude Darcha. "Co-operation Between the AKT and ERK Signaling Pathways May Support Growth of Deep Endometriosis in a Fibrotic Microenvironment in Vitro." Human Reproduction (Oxford, England), vol. 30, no. 7, 2015, pp. 1606-16.
Matsuzaki S, Darcha C. Co-operation between the AKT and ERK signaling pathways may support growth of deep endometriosis in a fibrotic microenvironment in vitro. Hum Reprod. 2015;30(7):1606-16.
Matsuzaki, S., & Darcha, C. (2015). Co-operation between the AKT and ERK signaling pathways may support growth of deep endometriosis in a fibrotic microenvironment in vitro. Human Reproduction (Oxford, England), 30(7), 1606-16. https://doi.org/10.1093/humrep/dev108
Matsuzaki S, Darcha C. Co-operation Between the AKT and ERK Signaling Pathways May Support Growth of Deep Endometriosis in a Fibrotic Microenvironment in Vitro. Hum Reprod. 2015;30(7):1606-16. PubMed PMID: 25976656.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Co-operation between the AKT and ERK signaling pathways may support growth of deep endometriosis in a fibrotic microenvironment in vitro. AU - Matsuzaki,Sachiko, AU - Darcha,Claude, Y1 - 2015/05/14/ PY - 2015/02/03/received PY - 2015/04/22/accepted PY - 2015/5/16/entrez PY - 2015/5/16/pubmed PY - 2016/4/5/medline KW - 3D culture systems KW - endometriosis KW - endometrium KW - fibrotic microenvironment SP - 1606 EP - 16 JF - Human reproduction (Oxford, England) JO - Hum. Reprod. VL - 30 IS - 7 N2 - STUDY QUESTION: How can deep endometriotic stromal cells proliferate and persist in a fibrotic environment? SUMMARY ANSWER: The serine/threonine kinase AKT and extracellular regulated kinase (ERK) signaling pathways may co-operate to support growth of deep endometriotic lesions by enhancing endometriotic stromal cell proliferation and survival in a fibrotic microenvironment in vitro. WHAT IS KNOWN ALREADY: Endometriosis, particularly deep infiltrating endometriosis, is characterized histologically by dense fibrous tissue that is primarily composed of type I collagen. This tissue may cause pelvic pain and infertility, which are major clinical issues associated with endometriosis. Proliferation of normal fibroblasts is tightly regulated, and fibrillar, polymerized type I collagen inhibits normal fibroblast proliferation. However, no studies to date have investigated how deep endometriotic stromal cells can proliferate and persist in a fibrotic environment. STUDY DESIGN, SIZE, DURATION: Endometrial and/or endometriotic tissues from 104 patients (61 with and 43 without endometriosis) of reproductive age with normal menstrual cycles were analyzed. A total of 25 nude mice received a single injection of endometrial fragments from a total of five samples. PARTICIPANTS/MATERIALS, SETTING, METHODS: We evaluated cell proliferation, caspase 3/7 activity, and the AKT and ERK signaling pathways in endometrial and endometriotic stromal cells on three-dimensional (3D) polymerized collagen matrices in vitro. In addition, to determine whether aberrant activation of the AKT and ERK pathways is involved during progression of fibrosis in endometriosis in vivo, we evaluated the expression of phosphorylated AKT and ERK1/2 in endometriotic implants in a nude mouse model of endometriosis. Finally, we evaluated the effects of MK2206 (an AKT inhibitor) and U0126 (a MEK inhibitor) on cell proliferation, caspase 3/7 activity, and phosphorylation of AKT and ERK1/2 of endometriotic stromal cells on 3D polymerized collagen matrices. MAIN RESULTS AND THE ROLE OF CHANCE: Proliferation of endometriotic stromal cells was significantly less inhibited than that of endometrial stromal cells (P < 0.05) on 3D polymerized collagen. Levels of phosphorylated AKT, phosphorylated p70S6K and phosphorylated ERK1/2 were significantly higher in endometriotic stromal cells than in endometrial stromal cells at 24 h (P < 0.05) and at 72 h (P < 0.05) on 3D polymerized collagen. Phosphorylated AKT expression was significantly increased on Days 21 and 28 compared with those on Days 3 and 7 (all P < 0.05) in endometriotic implants during progression of fibrosis in a nude mouse model of endometriosis. Inhibition of AKT or ERK1/2 with MK2206 or U0126, respectively, did not significantly increase caspase 3/7 activity in endometriotic stromal cells on either two-dimensional or 3D collagen matrices. Western blot analysis showed that MK2206 alone decreased levels of phosphorylated AKT; however, it increased levels of phosphorylated ERK in endometriotic cells compared with vehicle-treated cells (both P < 0.05). In addition, U0126 treatment decreased levels of phosphorylated ERK; however, it resulted in increased levels of phosphorylated AKT in endometriotic stromal cells compared with vehicle-treated cells (both P < 0.05). LIMITATIONS, REASONS FOR CAUTION: Endometriosis involves a number of processes, such as invasion, metastasis, angiogenesis, and apoptosis resistance, and a variety of signaling pathways may be involved in promoting development and progression of the disease. In addition, further animal experiments are required to determine whether the AKT and ERK signaling pathways co-operate to support growth of endometriotic lesions in a fibrotic microenvironment in vivo. WIDER IMPLICATIONS OF THE FINDINGS: Co-targeting the AKT and ERK pathways may be an effective therapeutic strategy for endometriosis treatment. STUDY FUNDING/COMPETING INTERESTS: This study was supported in part by Karl Storz Endoscopy & GmbH (Tuttlingen, Germany). No competing interests are declared. SN - 1460-2350 UR - https://www.unboundmedicine.com/medline/citation/25976656/Co_operation_between_the_AKT_and_ERK_signaling_pathways_may_support_growth_of_deep_endometriosis_in_a_fibrotic_microenvironment_in_vitro_ L2 - https://academic.oup.com/humrep/article-lookup/doi/10.1093/humrep/dev108 DB - PRIME DP - Unbound Medicine ER -