FAP^high α‐SMA^low cancer‐associated fibroblast‐derived SLPI protein encapsulated in extracellular vesicles promotes ovarian cancer development via activation of PI3K/AKT and downstream signaling pathways

Abstract

Ovarian cancer is the most lethal gynecological malignancy worldwide with high metastasis and poor prognosis rates. Cancer‐associated fibroblasts (CAFs), a heterogeneous population of cells that constitutes a major component of the tumor microenvironment, secrete extracellular vesicles (EVs) loading with proteins, lipids, and RNAs to promote tumorigenesis. However, the specific roles of CAF‐derived proteins contained in EVs in ovarian cancer remain poorly understood at present. Using the gene expression microarray analysis, we identified a list of dysregulated genes between the α‐SMA+CAF and FAP+CAF subpopulations, from which secretory leukocyte protease inhibitor (SLPI) was chosen for further validation. Quantitative PCR, western blot, immunohistochemistry, and enzyme‐linked immunosorbent assays were used to assess SLPI expression in ovarian cancer cells, tissues, CAFs, and EVs. Additionally, we evaluated the effects of exogenous SLPI on proliferation, migration, invasion, and adhesion of ovarian cancer cells in vitro. Our results showed SLPI protein was upregulated in CAFs, particularly in the FAPhighα‐SMAlowCAF subpopulation, and associated with increased tumor grade and decreased overall survival (OS). Importantly, CAF‐derived SLPI protein could be encapsulated in EVs for delivery to ovarian cancer cells, thus facilitating cell proliferation, migration, invasion, and adhesion via activating the PI3K/AKT and downstream signaling pathways. Moreover, high plasma expression of SLPI encapsulated in EVs was closely correlated with tumor stage in ovarian cancer patients. Our collective results highlight an oncogenic role of plasma EV‐encapsulated SLPI secreted by CAFs in tumor progression for the first time, supporting its potential utility as a prognostic biomarker of ovarian cancer.

What is new in cancer-associated fibroblast biomarkers?

“…FAP correlates with adverse clinicopathological factors, such as invasion depth in esophageal adenocarcinoma (EAC) [ 11 ], large tumor diameter (> 7 cm), advanced stage (pT3/4), high grade (G3/4), sarcomatoid transformation, tumor necrosis, and early lymph node metastasis of clear cell renal cell carcinoma (CCRCC) [ 12 ]. In ovarian cancer, secretory leukocyte protease inhibitor (SLPI) protein derived from FAP high α-SMA low CAFs can be encapsulated in extracellular vesicles (EVs) and delivered to cancer cells, promoting cell proliferation, adhesion, invasion, and migration via the PI3K/AKT signaling pathway [ 13 ]. It is associated with poor prognosis of NSCLC [ 14 ], gastric cancer [ 10 ], CCRCC [ 12 ], ovarian cancer [ 13 ], and bladder high-grade UC [ 8 ], but not cervical cancer [ 15 ].…”

“…In ovarian cancer, secretory leukocyte protease inhibitor (SLPI) protein derived from FAP high α-SMA low CAFs can be encapsulated in extracellular vesicles (EVs) and delivered to cancer cells, promoting cell proliferation, adhesion, invasion, and migration via the PI3K/AKT signaling pathway [ 13 ]. It is associated with poor prognosis of NSCLC [ 14 ], gastric cancer [ 10 ], CCRCC [ 12 ], ovarian cancer [ 13 ], and bladder high-grade UC [ 8 ], but not cervical cancer [ 15 ]. FAP + CAFs are independent predictive factors to worse tumor regression grade (TRG), that means chemoresistance in gastric cancer [ 16 ].…”

Targeting Tumor Microenvironment Akt Signaling Represents a Potential Therapeutic Strategy for Aggressive Thyroid Cancer

“…We next examined the potential signaling pathways that might mediate the effects of tumor stromal cells on CSCs. According to the findings in recent studies, there are several signaling pathways, including JAK/STAT [ 59 , 60 , 61 , 62 , 63 ], PI3K/Akt [ 64 , 65 , 66 , 67 , 68 , 69 , 70 ], NF-kB [ 71 , 72 , 73 , 74 , 75 , 76 ], and TGF-β signaling [ 77 , 78 , 79 , 80 , 81 , 82 , 83 ], that could possibly be mediating the stromal cell functioning in PTC, as these signaling pathways have been found to be involved in the effects of stromal cells on tumor cells [ 59 , 60 , 61 , 62 , 63 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ]. To unveil the potentially engaged signaling pathways, we examined the expression of specific molecules that indicate different signaling pathway activities with Western blotting analyses.…”

FAP, CD10, GPR77-labeled CAFs cause neoadjuvant chemotherapy resistance by inducing EMT and CSC in gastric cancer

“…This may be caused by the malignant biological behavior due to CAF-induced EMT pathway. In colorectal cancer [38], ovarian cancer [44], non-small cell lung cancer [45],…”