Abstract
Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein modulating cell-matrix interactions and was found up-regulated in tumor stroma. To explore the effect of high stromal SPARC on colorectal cancer (CRC) cell behavior and clinical outcome, this study determined SPARC expression in patients suffering from stage II and III CRC using a publicly available mRNA data set and immunohistochemistry of tissue microarray sections. Moreover, in vitro co-culture models using CRC cell lines together with colon-associated fibroblasts were established to determine the effect of fibroblast-derived SPARC on cancer cells. In 466 patient samples, high SPARC mRNA was associated with a shorter disease-free survival. In 99 patients of the tissue microarray cohort, high stromal SPARC in the primary tumor was an independent predictor of shorter survival in patients with relapse (27 cases; HR = 4574, p = 0.004). In CRC cell lines, SPARC suppressed phosphorylation of focal adhesion kinase and stimulated cell migration. Colon-associated fibroblasts increased migration velocity by 30% and doubled track-length in SPARC-dependent manner. In a 3D co-culture system, fibroblast-derived SPARC enhanced tumor cell invasion. Taken together, stromal SPARC had a pro-metastatic impact in vitro and was a characteristic of aggressive tumors with poor prognosis in CRC patients.
Highlights
Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that is produced in many organs in processes of rapid proliferation or remodeling [1] and is essential for wound healing [2]
To investigate the impact of SPARC expression on colorectal cancer (CRC), we analyzed the gene expression of 466 human patients who suffered from stage II or stage III CRC, summarized in the public available dataset GSE39582 [18]
Analyzing Kaplan-Meier plots, there was no significant impact on the 5-year overall survival (OS) based on SPARC expression (Supplementary Figure S1A), but a markedly decreased 5-year disease free survival (DFS) of patients with high compared to low SPARC expressing tumors (Figure 1A)
Summary
Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that is produced in many organs in processes of rapid proliferation or remodeling [1] and is essential for wound healing [2]. The protein is presumed to inhibit cell-matrix interactions in a competitive manner [3]. The biological role of SPARC seems to be highly context-dependent, but matrix remodeling and counter-adhesive effects have been reported consistently (reviewed in [4]). With regard to cancer development, SPARC has been described as a tumorsuppressor in some tumor types (e.g., in ovarian or bladder cancer [5,6]), while it was found overexpressed as a possible promoter of tumorigenesis in others (melanoma, breast cancer, and glioblastoma [7,8,9,10]). In the adult colonic mucosa, the protein is restricted to the muscularis mucosa, but is absent from the epithelium [11].
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