Mechanical homeostasis is altered in uterine leiomyoma

Rogers, Robert E.; Norian, J.M.; Malik, Minnie; Christman, Gregory M.; Abu‐Asab, Mones; Chen, Faye; Korecki, Casey L.; Iatridis, James C.; Catherino, William H.; Tuan, Rocky S.; Dhillon, Namisha; Leppert, Phyllis C.; Segars, James H.

doi:10.1016/j.ajog.2007.11.057

Cited by 107 publications

(136 citation statements)

References 41 publications

(10 reference statements)

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“…This increased tissue tension and stretch induces mechanical signaling transmitted from collagen and other fibers in the ECM to intracellular components through transmembrane receptors including integrins and cadherins (153,154). This complex mechanical signaling network involves alterations in cell shape and cytoskeleton in addition to altered stiffness and ECM (155).…”

Section: Extracellular Matrixmentioning

confidence: 99%

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Borahay

Al-Hendy

Kılıç

et al. 2015

Mol Med

128

147

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Uterine leiomyomas are the most common tumors of the female genital tract, affecting 50% to 70% of females by the age of 50. Despite their prevalence and enormous medical and economic impact, no effective medical treatment is currently available. This is, in part, due to the poor understanding of their underlying pathobiology. Although they are thought to start as a clonal proliferation of a single myometrial smooth muscle cell, these early cytogenetic alterations are considered insufficient for tumor development and additional complex signaling pathway alterations are crucial. These include steroids, growth factors, transforming growth factor-beta (TGF-β)/Smad; wingless-type (Wnt)/β-catenin, retinoic acid, vitamin D, and peroxisome proliferator-activated receptor γ (PPARγ). An important finding is that several of these pathways converge in a summative way. For example, mitogen-activated protein kinase (MAPK) and Akt pathways seem to act as signal integrators, incorporating input from several signaling pathways, including growth factors, estrogen and vitamin D. This underlines the multifactorial origin and complex nature of these tumors. In this review, we aim to dissect these pathways and discuss their interconnections, aberrations and role in leiomyoma pathobiology. We also aim to identify potential targets for development of novel therapeutics.

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Section: Extracellular Matrixmentioning

confidence: 99%

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Borahay

Al-Hendy

Kılıç

et al. 2015

Mol Med

128

147

View full text Add to dashboard Cite

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“…In addition to the smooth muscle component, they also possess a significant extracellular matrix consisting of fibroblasts [26]. They are therefore highly fibrous with the collagen fibrils randomly oriented, a characteristic different from the adjacent myometrium in which the collagen fibrils are aligned in an orderly fashion [20,30]. Clinically relevant myomas can be several centimetres in diameter and are usually fully vascularised, with angiogenesis continuously taking place; the absence of necrotic regions in most myomas [11] distinguishes them from other large solid tumours, where poorly vascularised necrotic zones are a prominent feature in vivo [17].…”

Section: Introductionmentioning

confidence: 99%

A Mathematical Model of the Growth of Uterine Myomas

Chen

Ward

2014

Bull Math Biol

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Uterine myomas or fibroids are common, benign smooth-muscle tumours that can grow to 10 cm or more in diameter and are routinely removed surgically. They are typically slow growing, well-vascularised, spherical tumours that, on a macro-scale, are a structurally uniform, hard elastic material. We present a multi-phase mathematical model of a fully vascularised myoma growing within a surrounding elastic tissue. Adopting a continuum approach, the model assumes the conservation of mass and momentum of four phases, namely cells/collagen, extracellular fluid, arterial and venous phases. The cell/collagen phase is treated as a poro-elastic material, based on a linear stress-strain relationship, and Darcy's law is applied to describe flow in the extracellular fluid and the two vascular phases. The supply of extracellular fluid is dependent on the capillary flow rate and mean capillary pressure expressed in terms of the arterial and venous pressures. Cell growth and division is limited to the myoma domain and dependent on the local stress in the material. The resulting model consists of a system of non-linear partial differential equations with two moving boundaries.Numerical solutions of the model successfully reproduce qualitatively the clinically observed three-phase "fast-slow-fast" growth profile that is typical for myomas. The results suggest that this growth profile requires stress-induced resistance to growth by the surrounding tissue and a switch like cell growth response to stress. Analysis of large-time solutions reveal that whilst there is a functioning vasculature throughout the myoma exponential growth results, otherwise power-law growth is predicted. An extensive survey of the effect of parameters on model solutions is also presented and, in particular, the enhanced growth caused by factors such as oestrogen is predicted by the model.

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“…parity, age at first pregnancy, history of infertility, age at menarche, and contraceptive use), seem to explain only a small fraction of the race/ color inequalities 5,6,8 . Alternative hypotheses, not yet explored in depth, point to an increase in polymorphisms and impaired regulation of hormonal receptors involved in the development of uterine leiomyomas 12,13 , as well as vitamin D deficiency 14,15 and psychosocial stress 16,17 , as potential high-impact causes of tumors in black women.…”

Section: Introductionmentioning

confidence: 99%