Stemness and hybrid epithelial-mesenchymal profiles guide peritoneal dissemination of malignant mesothelioma and pseudomyxoma peritonei.

Publisher: Wiley-Liss Country of Publication: United States NLM ID: 0042124 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-0215 (Electronic) Linking ISSN: 00207136 NLM ISO Abbreviation: Int J Cancer Subsets: MEDLINE

Publication: 1995- : New York, NY : Wiley-Liss
Original Publication: 1966-1984 : Genève : International Union Against Cancer

Peritoneal Neoplasms*/secondary ; Peritoneal Neoplasms*/pathology ; Epithelial-Mesenchymal Transition* ; Neoplastic Stem Cells*/pathology ; Neoplastic Stem Cells*/metabolism ; Mesothelioma, Malignant*/pathology ; Pseudomyxoma Peritonei*/pathology ; Pseudomyxoma Peritonei*/metabolism; Humans ; Male ; Female ; Middle Aged ; Aged ; Aldehyde Dehydrogenase 1 Family/metabolism ; Aldehyde Dehydrogenase 1 Family/genetics ; Mesothelioma/pathology ; Mesothelioma/genetics ; Prognosis ; Lung Neoplasms/pathology ; Lung Neoplasms/genetics ; Hyperthermic Intraperitoneal Chemotherapy ; Tumor Cells, Cultured ; Retinal Dehydrogenase/metabolism ; Retinal Dehydrogenase/genetics ; Adult

Intrabdominal dissemination of malignant mesothelioma (MM) and pseudomyxoma peritonei (PMP) is poorly characterized with respect to the stemness window which malignant cells activate during their reshaping on the epithelial-mesenchymal (E/M) axis. To gain insights into stemness properties and their prognostic significance in these rarer forms of peritoneal metastases (PM), primary tumor cultures from 55 patients selected for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy were analyzed for cancer stem cells (CSC) by aldehyde dehydrogenase 1 (ALDH1) and spheroid formation assays, and for expression of a set of plasticity-related genes to measure E/M transition (EMT) score. Intratumor heterogeneity was also analyzed. Samples from PM of colorectal cancer were included for comparison. Molecular data were confirmed using principal component and cluster analyses. Associations with survival were evaluated using Kaplan-Meier and Cox regression models. The activity of acetylsalicylic acid (ASA), a stemness modifier, was tested in five cultures. Significantly increased amounts of ALDH1 ^bright -cells identified high-grade PMP, and discriminated solid masses from ascitic/mucin-embedded tumor cells in both forms of PM. Epithelial/early hybrid EMT scores and an early hybrid expression pattern correlated with pluripotency factors were significantly associated with early peritoneal progression (p = .0343 and p = .0339, respectively, log-rank test) in multivariable models. ASA impaired spheroid formation and increased cisplatin sensitivity in all five cultures. These data suggest that CSC subpopulations and hybrid E/M states may guide peritoneal spread of MM and PMP. Stemness could be exploited as targetable vulnerability to increase chemosensitivity and improve patient outcomes. Additional research is needed to confirm these preliminary data.
(© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

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J93C22001090001 Italian Ministry of Health - 5x1000; J98D20000000001 Italian Ministry of Health - Ricerca Corrente

Keywords: CRS‐HIPEC; cancer stem cells; epithelial‐mesenchymal plasticity; malignant mesothelioma; pseudomyxoma peritonei

EC 1.2.1 (Aldehyde Dehydrogenase 1 Family)
EC 1.2.1.36 (ALDH1A1 protein, human)
EC 1.2.1.36 (Retinal Dehydrogenase)

Date Created: 20240815 Date Completed: 20241105 Latest Revision: 20241105

20241106

10.1002/ijc.35137

39146488