Identification of novel candidate biomarkers of epithelial ovarian cancer by profiling the secretomes of three‐dimensional genetic models of ovarian carcinogenesis

Abstract

Epithelial ovarian cancer (EOC) is still considered the most lethal gynecological malignancy and improved early detection of ovarian cancer is crucial to improving patient prognoses. To address this need, we tested whether candidate EOC biomarkers can be identified using three-dimensional (3D) in vitro models. We quantified changes in the abundance of secreted proteins in a 3D genetic model of early-stage EOC, generated by expressing CMYC and KRAS G12V in TERT-immortalized normal ovarian epithelial cells. Cellular proteins were labeled in live cells using stable isotopic amino acid analogues, and secreted proteins identified and quantified using liquid chromatography-tandem mass spectrometry. Thirty-seven and 55 proteins were differentially expressed by CMYC and CMYC1KRAS G12V expressing cells respectively (p < 0.05; >2-fold). We evaluated expression of the top candidate biomarkers in~210 primary EOCs: CHI3L1 and FKBP4 are both expressed by >96% of primary EOCs, and FASN and API5 are expressed by 86 and 75% of cases. High expression of CHI3L1 and FKBP4 was associated with worse patient survival (p 5 0.042 and p 5 0.002, respectively). Expression of LGALS3BP was positively associated with recurrence (p 5 0.0001) and suboptimal debulking (p 5 0.018) suggesting that these proteins may be novel prognostic biomarkers. Furthermore, within early stage tumours (I/II), high expression of API5, CHI3L1 and FASN was associated with high tumour grade (p 5 3 3 10 24 , p 5 0.016, p 5 0.010, respectively). We show in vitro cell biology models of early-stage cancer development can be used to identify novel candidate biomarkers for disease, and report the identification of proteins that represent novel potential candidate diagnostic and prognostic biomarkers for this highly lethal disease.Despite recent advances in surgery and chemotherapy, epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy, mainly due to the absence of specific symptoms and a lack of effective screening tools. The majority of patients present with advanced stage disease where the 5-year survival rate is only 27%. For advanced stage tumours, recurrence rates are over 60%, and 20% of these patients respond poorly to platinum-based chemotherapy. Therefore, detecting patients with early EOC continues to be an urgent clinical need and it remains a clinical priority to detect highgrade serous EOC early during disease development.Given the difficulties accessing the ovary for biopsy and the rapid rate at which the most aggressive EOC subtypes progress, the identification of clinical biomarkers detectable in the blood would represent a significant advance for the identification of patients with EOC. Currently the most widely used ovarian cancer biomarker is serum CA125, and this marker is particularly good at detecting disease recurrence. A second marker, HE4, was approved in 2009 for monitoring ovarian cancer progression, and can be elevated

Designer Self‐Assembling Peptide Hydrogels to Engineer 3D Cell Microenvironments for Cell Constructs Formation and Precise Oncology Remodeling in Ovarian Cancer

“…Accompanied with the underlying genomic events driving ovarian cancer progression, [ 162 ] it is appreciated that ovarian cancer is as molecularly distinct entity as breast, prostate, and renal cancer. [ 212 ] The comparative molecular studies that fail to recognize the histopathological origins are no longer effective. [ 150,213 ] Novel ovarian cancer cell models are ongoing need to reflect the main scientific aspects for precise oncology remodeling in vitro, such as cancer cell behaviors, exosomes, and acquired chemoresistance, cell–cell coculture and cell–ECM interactions, and tumor spheroids formation, which elaborately recapitulate cell–cell and cell–ECM interactions in ovarian cancer development, progression, metastasis, dissemination or therapeutic recurrence and relapse.…”

Increased risk of poor survival in ovarian cancer patients with high expression of SNAI2 and lymphovascular space invasion

“…During the past decade, researchers have been striving to identity potential prognostic predictors for ovarian cancer [2–5]. For example, debulking status has been associated with the clinical outcome [6, 7].…”

Immune-associated proteins with potential in vivo anti-tumor activities are upregulated in lung cancer cells treated with umbelliprenin: A proteomic approach

“…associated with a poorer prognosis in several types of cancer, including ovary, prostate and breast cancer (25), however, its role in lung cancer requires further clarification. Finally, the function of SF3a3 in cancer has not yet been clarified.…”