Characterization and Clinical Relevance of Endometrial CAFs: Correlation between Post-Surgery Event and Resistance to Drugs

• Published in: International journal of molecular sciences 2023-03, Vol.24 (7), p.6449
• Main Authors: Sulaiman, Raed, De, Pradip, Aske, Jennifer C, Lin, Xiaoqian, Dale, Adam, Gaster, Kris, Espaillat, Luis Rojas, Starks, David, Dey, Nandini
• Format: Article
• Language: English
• Subjects: CAF markers; CAFs primary culture; Cancer therapies; Cancer-Associated Fibroblasts - pathology; CD45 antigen; Clinical Relevance; Development and progression; Drug resistance; Endometrial cancer; endometrial cancers; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - pathology; Endometrial Neoplasms - surgery; Endometrium; Endometrium - pathology; Endometrium - surgery; Fallopian tubes; Female; Flow cytometry; Humans; Medical prognosis; Medical research; Medicine, Experimental; Metastasis; Paclitaxel; patient-specific aggressive CAFs; Patients; PD-L1 protein; post-surgery event; Protein expression; Proteins; S100A4 protein; Solid tumors; Surgery; Thy-1 Antigens; Treatment resistance; Tumor cells; Tumor Microenvironment; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24076449

Cancer-associated fibroblasts (CAFs) within a solid tumor can support the progression of cancer. We studied the identification and characterization of patient-derived endometrial CAFs in the context of their clinical relevance in endometrial cancers. We established patient-derived primary cultures of CAFs from surgically resected tumors (TCAF) and tumor-adjacent normal (NCAF) tissues in 53 consented patients with success rates of 97.7% and 75%, respectively. A passage of CAF was qualified by the (1) absence of CK 8,18,19, EpCAM, CD45, and CD31, and (2) presence of SMAalpha, S100A4, CD90, FAP, TE-7, CD155, PD-L1, TGFB, PDGFRA (qRT-PCR, flow cytometry, Western blot, ICC). Out of the 44 established CAFs, 31 were aggressive (having an early, i.e., 4-7 week, establishment time and/or >3 passages) compared to 13 which were non-aggressive. A post-surgery-event (PSE) was observed in 7 out of 31 patients bearing aggressive CAFs, 2 of whom were also positive for CTCs, while none of the 13 patients bearing non-aggressive CAFs had events. A positive correlation was found between patients with grade 3 ( = 0.025) as well as stage 3/4 diseases ( = 0.0106) bearing aggressive CAFs and the PSE. Finally, aggressive TCAFs from patients with PSE resisted the effects of paclitaxel and lenvatinib on the growth of HUVEC and endometrial tumor cells. Our study is the first to report and provides an undeniable reason to study the in-depth mechanism of CAF function towards the development of treatment resistance in endometrial cancers.