SPARC in Tumor Pathophysiology and as a Potential Therapeutic Target

Abstract

Cell migration and metastasis greatly contribute to the progression of tumors. Secreted Protein and Rich in Cysteine （SPARC）, as a multi-faceted protein, is highly expressed in highly metastatic tumors while low or undetectable in less metastatic types with aberrant promoter methylation. In highly metastatic tumors, such as glioblastomas, melanoma, breast cancer and prostate cancer, SPARC promotes bone metastasis and epithelial-mesenchymal transition (EMT). In contrast, this protein acts as an anti-tumor factor in anti-angiogenesis, pro-apoptosis, cell proliferation inhibition and cell cycle arrest in less metastatic tumors, such as neuroblastoma, ovarian cancer, pancreatic cancer, colorectal cancer and gastric cancer. Here, we summarize and analyze the paradoxical role of SPARC in different tumors. We believe that further studies on truncated, alternative splicing variants and signal peptide of SPARC are required to elucidate the distinct effects. Most notably, SPARC variants probably play a crucial role in regulation of transforming growth factor beta (TGF-β) induced EMT. This review also provides strategies to target or use SPARC (full-length, truncated and splicing variants) for therapeutic purposes.

Potential options for managing LOX+ ER− breast cancer patients

“…Moreover, our analysis indicates that LOX is likely co-expressed with MMP2, COL1A1 and SPARC, all of which contribute to initiating cancer metastasis and EMT [9, 10, 16–18], and that bisphosphonates inhibit MMP2 activity [19, 20], COL1A1-driven osteoporotic fracture [21] and SPARC-stimulated EMT [22, 23]. Bisphosphonates may also inhibit breast cancer progression by decreasing stromal TGF-β excretion and inhibiting TGF-β signaling in cancer cells [24].…”

SPARC overexpression suppresses radiation-induced HSP27 and induces the collapse of mitochondrial Δψ in neuroblastoma cells

“…Cell cycle distribution of SPARC overexpressing and irradiated SK-N-BE(2) cells, and NB1691 neuroblastoma cells was analyzed using flow cytometry (FACS Calibur System; BD Bioscience, San Jose, CA, USA) with excitation at a wavelength of 488 nm and an emission of 639 nm, following propidium iodide staining according to standard protocols (9). A total of 10,000 cells were sorted to determine cell cycle phase using the Cell Quest Pro software version 5.2.1 (BD Bioscience, San Jose, CA, USA).…”

“…The role of SPARC in tumorigenesis is suggested to be cell type specific due to its diverse function in the microenvironment. In certain types of cancer, including breast, pancreatic and glioblastoma, high levels of SPARC expression have been identified to associate with disease progression and poor prognosis (8,9). In other types of cancer, including ovarian (10), colorectal (11) and neuroblastoma (12–14), SPARC functions as a tumor suppressor.…”

“…It has been reported that there is an inverse correlation between SPARC expression and neuroblastoma progression (14), indicating that SPARC overexpression may be an effective option for the treatment of neuroblastoma. A literature review has established that tumorigenic cell lines exhibit low or undetectable levels of SPARC, whereas non-tumorigenic cells express high levels of SPARC (9). A previous study identified heat shock protein 27 (HSP27) as a mediator of SPARC activity (15).…”

SPARC expression in gastric cancer predicts poor prognosis: Results from a clinical cohort, pooled analysis and GSEA assay

“…Biologically, SPARC was found to promote cancer development in some tumors with highly metastatic characteristics, such as breast cancer and melanoma, but act as a tumor suppressor in some other cancer types [5, 6]. Clinically, SPARC has been uncovered as the potential prognostic marker in several cancer types [7–9].…”