Differences in the cellular composition of small versus large uterine fibroids

Holdsworth-Carson, Sarah J.; Zhao, Dong; Cann, Leonie; Bittinger, Sophie; Nowell, Cameron J.; Rogers, Peter A. W.

doi:10.1530/rep-16-0216

Cited by 28 publications

(20 citation statements)

References 56 publications

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“…Heterogeneity has been documented on the genetic/genomic, proteomic, metabolomic and histologic level. [2, 16–26]. During our ongoing research on the development of treatments for uterine fibroids, we have noted additional heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

Evidence of biomechanical and collagen heterogeneity in uterine fibroids

et al. 2019

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Objective Uterine fibroids (leiomyomas) are common benign tumors of the myometrium but their molecular pathobiology remains elusive. These stiff and often large tumors contain abundant extracellular matrix (ECM), including large amounts of collagen, and can lead to significant morbidities. After observing structural multiformities of uterine fibroids, we aimed to explore this heterogeneity by focusing on collagen and tissue stiffness. Methods For 19 fibroids, ranging in size from 3 to 11 centimeters, from eight women we documented gross appearance and evaluated collagen content by Masson trichrome staining. Collagen types were determined in additional samples by serial extraction and gel electrophoresis. Biomechanical stiffness was evaluated by rheometry. Results Fibroid slices displayed different gross morphology and some fibroids had characteristics of two or more patterns: classical whorled (n = 8); nodular (n = 9); interweaving trabecular (n = 9); other (n = 1). All examined fibroids contained at least 37% collagen. Tested samples included type I, III, and V collagen of different proportions. Fibroid stiffness was not correlated with the overall collagen content (correlation coefficient 0.22). Neither stiffness nor collagen content was correlated with fibroid size. Stiffness among fibroids ranged from 3028 to 14180 Pa (CV 36.7%; p<0.001, one-way ANOVA). Stiffness within individual fibroids was also not uniform and variability ranged from CV 1.6 to 42.9%. Conclusions The observed heterogeneity in structure, collagen content, and stiffness highlights that fibroid regions differ in architectural status. These differences might be associated with variations in local pressure, biomechanical signaling, and altered growth. We conclude the design of all fibroid studies should account for such heterogeneity because samples from different regions have different characteristics. Our understanding of fibroid pathophysiology will greatly increase through the investigation of the complexity of the chemical and biochemical signaling in fibroid development, the correlation of collagen content and mechanical properties in uterine fibroids, and the mechanical forces involved in fibroid development as affected by the various components of the ECM.

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Section: Introductionmentioning

confidence: 99%

Evidence of biomechanical and collagen heterogeneity in uterine fibroids

et al. 2019

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“…While the roles of MAPK and PI3K in LMs have been demonstrated in vitro, the accuracy of conclusions from cell culture studies is in question, as primary cultures of LMs primarily consist of TAFs. In addition, most in vitro studies are performed with LMs of unknown subtype, although the distinctive biology of subtypes has been demonstrated by recent studies and should be taken into account (Holdsworth-Carson, et al 2016; Makinen, et al 2017; Mehine et al 2016; Wu et al 2017). Therefore, we assessed how the activities of these pathways are regulated by E2 and P4 during the regression and regrowth of MED12-LM PDXs.…”

Section: Resultsmentioning

confidence: 99%

Cellular kinetics of MED12-mutant uterine leiomyoma growth and regression in vivo

Serna¹,

Wu²,

Qiang

et al. 2018

Endocrine-Related Cancer

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Cellular mechanisms of uterine leiomyoma (LM) formation have been studied primarily utilizing models. However, recent studies established that the cells growing in the primary cultures of-mutant LM (MED12-LM) do not carry causal mutations. To improve the accuracy of LM research, we addressed the cellular mechanisms of LM growth and regression utilizing a patient-derived xenograft (PDX) model, which faithfully replicates the patient tumors The growth and maintenance of MED12-LMs depend on 17β-estradiol (E2) and progesterone (P4). We determined E2 and P4-activated MAPK and PI3K pathways in PDXs with upregulation of IGF1 and IGF2, suggesting that the hormone actions on MED12-LM are mediated by the IGF pathway. When hormones were removed, MED12-LM PDXs lost approximately 60% of volume within 3 days through reduction in cell size. However, in contrast to general belief, the survival of LM cells was independent of E2 and/or P4, and apoptosis was not involved in the tumor regression. Furthermore, it was postulated that abnormal collagen fibers promote the growth of LMs. However, collagen fibers of actively growing PDXs were well aligned. The disruption of collagen fibers, as found in human LM specimens, occurred only when the volume of PDXs had grown to over 20 times the volume of unstimulated PDXs, indicating disruption is the result of growth not the cause. Hence, this study revises generally accepted theories on the growth and regression of LMs.

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“…Thus, hypoxic 3D cultures show morphologic changes predictive of exposure to hypoxia. However, given the short halflife for HIF-1a (59,60) our ability to detect HIF-1a in 3D cultures was limited by the growth conditions established for 2D cultures at 24 hours of hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Three-dimensional human leiomyoma xenografts induce angiogenesis by inducing hypoxia inducible factor-1 alpha

et al. 2021

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Objective: To characterize the method by which angiogenesis occurred in three-dimensional (3D) leiomyoma xenografts, and to assess the impact of hypoxia on two-dimensional (2D) and 3D myometrial and leiomyoma cells and leiomyoma xenografts in vivo. Design: Laboratory study. Setting: Academic research. Patient(s): Cell cultures from patient-matched myometrial and leiomyoma tissues. Intervention(s): In vivo 3D leiomyoma xenografts from ovariectomized mice treated with gonadal hormones; myometrial and leiomyoma cells in 2D and 3D growth formats exposed to 1% oxygen. Main Outcome Measure(s): Protein expression. Result(s): Blood vessels in the xenograft estradiol group are identified with anti-mouse/anti-rat CD31/PECAM-1 antibody. Hormonestimulated 3D leiomyoma xenografts stain positively for adrenomedullin (ADM). Myometrial cells exposed to 1% oxygen demonstrated an increase in hypoxia-inducible factor (HIF)-1a at 6 hours and a marked increase at 24 hours. Under normoxic conditions, leiomyoma cells at 6 hours show increased expression of HIF-1a, which is further increased at 24 hours. Leiomyoma cells under hypoxia demonstrated a 1.14-fold decrease in HIF-1a expression at 6 hours and no change at 24 hours. Hypoxic myometrium decreased the proangiogenic protein ADM expression at 6 hours and showed a >1.5-fold increase at 24 hours. Normoxic leiomyoma decrease ADM at 24 hours and showed a >1.5-fold increase at 24 hours of hypoxia. Conclusion(s): Hypoxia-induced HIF-1a expression facilitates angiogenesis in 3D xenografts in vivo by increasing the expression of the proangiogenic protein ADM. Angiogenesis contributes to the viability and extended survival of these xenografts. Furthermore, 2D myometrial and leiomyoma cells increase HIF-1a and ADM expression in vitro under hypoxic conditions. (Fertil Steril Sci Ò 2021;2: 219-27. Ó2020 by American Society for Reproductive Medicine.

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Differences in the cellular composition of small versus large uterine fibroids

Cited by 28 publications

References 56 publications

Evidence of biomechanical and collagen heterogeneity in uterine fibroids

Evidence of biomechanical and collagen heterogeneity in uterine fibroids

Cellular kinetics of MED12-mutant uterine leiomyoma growth and regression in vivo

Three-dimensional human leiomyoma xenografts induce angiogenesis by inducing hypoxia inducible factor-1 alpha

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