A few years ago, we focused our attention on the science regarding uterine fibroids, benign but extremely problematic tumors that contain abundant altered interstitial collagen. Recently there have been new developments in our understanding of their molecular biology that will lead to advances in their medical treatment. These tumors grow in size due to the accumulation of this altered collagen making them fibrotic tumors. Fibroids display differences in the phenotype between Black and White women. They occur at an earlier age in Blacks who often have multiple tumors compared to Whites and often present with more severe symptoms. This noted health disparity is now being studied at the molecular level to better understand why it occurs so disproportionately. Al-Hendy and colleagues have shown that the transition from normal to a pre fibroid myometrium in Black women occurs by altered extracellular matrix-related pathways.(1) They studied myometrial tissue from fibroid-free myometrium and myometrium from uteri that had fibroids in self- identified Black and White (non-Hispanic, non-Latino) women. Al-Hendy’s group used whole genome RNA-seq to determine global gene expression profiles and conduced enriched pathway analysis and demonstrated that there were distinct differences among the racial groups and the normal fibroid- free myometrium and the myometrium in uteri with fibroids. Genes from pathways associated with the extracellular matrix and mechanosensing were more enriched in the normal myometrium of Black women compared to White women. They found differences in both groups of increased gene for extracellular matrix in the at-risk group. However, in the myometrium of Black women there were increased levels of Tenascin C, Type I collagen α- chain, fibronectin, and phosphor-p38-MAPK in the at-risk myometrium compared to normal myometrium from Black women This was not observed in the normal and at- risk myometrium of White women indicating an explanation of why there might be more altered collagen disposition in Black women (1)
Maxwell and his colleagues have reported studies that demonstrate that fibroids obtained following surgery from black women are more likely to display MED-12 mutations and are more fibrotic and biomechanically stiff then those tumors from white women. This study specifically evaluated somatic mutations in exon 2 0f the Mediator Complex subunit 12 (MED-12). A recent systematic review of the literature revealed that the overall prevalence of these mutations in a global population was 55.8 percent. However, the frequency varied greatly among different studies (2), a fact that caused Maxwell’s group to determine the frequency of this gene mutation in their study. Maxwell and colleagues studied fibroid tissue from 42 Black and 44 White women and utilized ancestory-linked expression quantitative trait loci with altered allele frequencies in African and European populations called ancestory information markers (pAIMS) to determine the sample category and then through multiple methodological approaches they determined the MED-12 mutations and extracellular matrix components and mechanical properties. With multiple and very complete analyses they determined that fibroid tissue from Black woman revealed larger proportion with MED-12 mutations than tissue from White women. Furthermore, the tissue from Blacks contains a greater amount of extracellular extracellular matrix proteins including several collagen types as shown by trichrome staining and secondary harmonic generation microscopy indicting that the MED-12 mutant fibroids were more fibrotic than tumors without a mutation. Shear-wave ultrasound showed that the tissue from Blacks were stiffer or firmer than those of White women even when the fibroids were the same size (3)
Fibroids have long been associated with another genetic alteration, namely overexpression of HMGA2. Paul and colleagues have compared fibroid cells with myometrial cells the overexpress HMGA2 and find that they have the similar transcriptome. This is interesting as it indicates that myometrial cells when overexpressing HMGA2 dedifferentiate to a cell that is mesenchymal cell type. The inference is that these cells are able to synthesize extracellular proteins. It also suggests that fibroids arise from the myometrial cell and not necessarily a stem cell. Further work will determine if this is a reproductible finding. It does indicate that cells overexpressing HMGA2 could possibly secret extracellular proteins as well.
These studies are important in that they provide additional knowledge that will help medical science more fully understand the pathobiology of fibroid formation. Basic knowledge will get us closer to the development of more cost effective and efficient medical treatments of uterine fibroids, especially for Black women world-wide who have an increased burden of disease. It also indicates that treatments to decrease or eliminate fibrosis is now becoming vital. The currently available medical treatments are somewhat effective but recurrences are common. In addition, while the tumors decrease in size and symptoms are eliminated or decreased there often is a residual tumor that is not eliminated. Treatment with a bacterial collagenase that degrades all collagen crosslinks and the molecular collagen chains is one such treatment. The resulting degradation products are processed by autophagy. (5) Other fibrotic agents are also possibilities. These can be combined with current drug regimens as well to work in concert to eliminate fibroids.
References:
(1) Bariani MV, Grimm SL, Coarfa C, Velez Edwards DR, Yang Q, Walker CL, Ali M, Al-Hendy A. Altered extracellular matrix-related pathways accelerate the transition from normal to prefibroid myometrium in Black women. Am J Obstet Gynecol. 2024 May 31:S0002-9378(24)00657-4. doi: 10.1016/j.ajog.2024.05.048. Epub ahead of print. PMID: 38825029.
(2) Amendola ILS, Spann M, Segars J, Singh B. The Mediator Complex Subunit 12 (MED-12) Gene and Uterine Fibroids: a Systematic Review. Reprod Sci. 2024 Feb;31(2):291-308. doi: 10.1007/s43032-023-01297-7. Epub 2023 Jul 29. PMID: 37516697.
(3) Bateman NW, Abulez T, Tarney CM, Bariani MV, Driscoll JA, Soltis AR, Zhou M, Hood BL, Litzi T, Conrads KA, Jackson A, Oliver J, Ganakammal SR, Schneider F, Dalgard CL, Wilkerson MD, Smith B, Borda V, O'Connor T, Segars J, Shobeiri SA, Phippen NT, Darcy KM, Al-Hendy A, Conrads TP, Maxwell GL. Multiomic analysis of uterine leiomyomas in self-described Black and White women: molecular insights into health disparities. Am J Obstet Gynecol. 2024 May7:S0002-9378(24)00577-5. doi: 10.1016/j.ajog.2024.04.051. Epub ahead of print. PMID: 38723985
(4) Paul EN, Carpenter TJ, Pavliscak LA, Bennett AZ, Ochoa-Bernal MA, Fazleabas AT, Teixeira JM. HMGA2 overexpression induces plasticity in myometrial cells and a transcriptomic profile more similar to that of uterine fibroids. F S Sci. 2024 Jul 16:S2666-335X(24)00041-7. doi: 10.1016/j.xfss.2024.07.006. Epub ahead of print. PMID: 39025326
(5) Islam MS, Afrin S, Singh B, Jayes FL, Brennan JT, Borahay MA, Leppert PC, Segars JH. Extracellular matrix and Hippo signaling as therapeutic targets of antifibrotic compounds for uterine fibroids. Clin Transl Med. 2021 Jul;11(7):e475. doi: 10.1002/ctm2.475. PMID: 34323413; PMCID: PMC8255059.