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- Pietila, EA, et al.
(författare)
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Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 3904-
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Tidskriftsartikel (refereegranskat)abstract
- Due to its dynamic nature, the evolution of cancer cell-extracellular matrix (ECM) crosstalk, critically affecting metastasis and treatment resistance, remains elusive. Our results show that platinum-chemotherapy itself enhances resistance by progressively changing the cancer cell-intrinsic adhesion signaling and cell-surrounding ECM. Examining ovarian high-grade serous carcinoma (HGSC) transcriptome and histology, we describe the fibrotic ECM heterogeneity at primary tumors and distinct metastatic sites, prior and after chemotherapy. Using cell models from systematic ECM screen to collagen-based 2D and 3D cultures, we demonstrate that both specific ECM substrates and stiffness increase resistance to platinum-mediated, apoptosis-inducing DNA damage via FAK and β1 integrin-pMLC-YAP signaling. Among such substrates around metastatic HGSCs, COL6 was upregulated by chemotherapy and enhanced the resistance of relapse, but not treatment-naïve, HGSC organoids. These results identify matrix adhesion as an adaptive response, driving HGSC aggressiveness via co-evolving ECM composition and sensing, suggesting stromal and tumor strategies for ECM pathway targeting.
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- Jukonen, J, et al.
(författare)
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Aggressive and recurrent ovarian cancers upregulate ephrinA5, a non-canonical effector of EphA2 signaling duality
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 8856-
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Tidskriftsartikel (refereegranskat)abstract
- Erythropoietin producing hepatocellular (Eph) receptors and their membrane-bound ligands ephrins are variably expressed in epithelial cancers, with context-dependent implications to both tumor-promoting and -suppressive processes in ways that remain incompletely understood. Using ovarian cancer tissue microarrays and longitudinally collected patient cells, we show here that ephrinA5/EFNA5 is specifically overexpressed in the most aggressive high-grade serous carcinoma (HGSC) subtype, and increased in the HGSC cells upon disease progression. Among all the eight ephrin genes, high EFNA5 expression was most strongly associated with poor overall survival in HGSC patients from multiple independent datasets. In contrast, high EFNA3 predicted improved overall and progression-free survival in The Cancer Genome Atlas HGSC dataset, as expected for a canonical inducer of tumor-suppressive Eph receptor tyrosine kinase signaling. While depletion of either EFNA5 or the more extensively studied, canonically acting EFNA1 in HGSC cells increased the oncogenic EphA2-S897 phosphorylation, EFNA5 depletion left unaltered, or even increased the ligand-dependent EphA2-Y588 phosphorylation. Moreover, treatment with recombinant ephrinA5 led to limited EphA2 tyrosine phosphorylation, internalization and degradation compared to ephrinA1. Altogether, our results suggest a unique function for ephrinA5 in Eph-ephrin signaling and highlight the clinical potential of ephrinA5 as a cell surface biomarker in the most aggressive HGSCs.
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- Pirhonen, J P, et al.
(författare)
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Frequency of anal sphincter rupture at delivery in Sweden and Finland--result of difference in manual help to the baby's head
- 1998
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Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley. - 1600-0412 .- 0001-6349. ; 77:10, s. 974-977
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Anal sphincter rupture is a serious complication of vaginal delivery and almost half the affected women have persistent defecatory symptoms despite adequate primary repair. During the past decade, the incidence of anal sphincter ruptures has been increasing in Sweden and is currently estimated to occur in 2.5% of vaginal deliveries. The aim of the study was to report the frequency of anal sphincter ruptures in two university hospitals in two Scandinavian countries, Malmo in Sweden and Turku in Finland, and analyze the potential determinants. METHODS: Retrospective analysis of a population of 30,933 deliveries (26,541 vaginal) during the years 1990 to 1994. RESULTS: The incidence of anal sphincter ruptures in Malmo, Sweden was 2.69%, and in Turku, Finland 0.36%. There were no significant population differences for the known risk factors (fetal weight, nulliparity or fetal head circumference). However, there is a difference in manual support given to the perineum and to the baby's head when crowning through the vaginal introitus between Malmo and Turku. The proportion of operative vaginal deliveries and abnormal presentations was significantly higher in Turku reflected in the lower Apgar score at 5 minutes and longer duration of second phase of labor. When high risk deliveries (operative vaginal delivery, abnormal presentation and newborns over 4,000 g) were excluded, the risk for anal sphincter ruptures was estimated to be 13 times higher in Malmo than in Turku. CONCLUSIONS: The difference in the incidence of anal sphincter rupture between Malmo, Sweden and Turku, Finland may be due to the difference in manual control of the baby's head when crowning.
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